BιταμίνεςOι βιταμίνες αντιπροσωπεύουν οργανικέςουσίες απαραίτητες για τον ομαλό ενδογενήμεταβολισμό.

Περικλείονται σε μικρέςποσότητες στις φυσικές τροφές. Tο κανονικόδιαιτολόγιο προσφέρει επαρκή ποσότηταβιταμινών για την κάλυψη των ημερήσιωναναγκών, εφόσον περιλαμβάνονται τρόφιμααπό όλες τις πέντε κατηγορίες τροφίμων.

Υποκλινικές ή και κλινικές μορφές υποβιταμίνωσης μπορεί να προκληθούν :

σε αυξημένες απαιτήσεις (κύηση, γαλουχία),

μακρόχρονη αδυναμία λήψης τροφής (χειρουργικές

επεμβάσεις κυρίως γαστρεντερικού),

σύνδρομα εντερικής δυσαπορρόφησης,

καταστροφή της φυσιολογικής εντερικήςχλωρίδας από χρήση αντιβιοτικών

o σε σημαντική απώλεια βιταμινώνκατά την εφαρμογή μακρόχρονης παρεντερικής διατροφής χωρίς προσθήκη επαρκούς ποσότητας βιταμινών

o και χρόνιας τεχνητής υποκατάστασης της νεφρικής λειτουργίας (αιμοκάθαρση και περιτοναϊκή κάθαρση).

Tέλος, ένδεια μπορεί να προέλθειαπό :

o αλληλεπίδραση μεταξύ βιταμινών καιάλλων φαρμάκων,

o από παρεμπόδιση εντερικής απορρόφησης ή του μετασχηματισμού στην τελική δραστική τους μορφή,

φαινόμενο που παρατηρείται και σε διάχυτη

βλάβη ορισμένων οργάνων, στα οποία κατ’

αποκλειστικότητα λαμβάνει χώρα ο μετασχηματισμός

αυτός.

Oι παραπάνω καταστάσειςαντιπροσωπεύουν τις κύριες ενδείξεις

θεραπευτικής χρήσης των βιταμινών.

Tα τελευταίαόμως χρόνια γίνεται ολοένα και συχνότερακατάχρηση βιταμινών για πρόληψηκαρκίνων και μακροζωία, γεγονός που δενέχει καμία επιστημονική τεκμηρίωση.

Αντίθετα,μπορεί να δημιουργηθούν σοβαρέςπαρενέργειες ή τοξικές επιδράσεις.

o Διάφορεςπολυνευρίτιδες, o ψυχικές παθήσεις, o ο καρκίνος, o η αρτηριοσκλήρυνση, o το γήρας,o το κοινό κρυολόγημα

αποτελούν το νέο θεραπευτικό φάσμα πολλώνβιταμινών.

H χρησιμότητά τους αυτή δεν έχειτεκμηριωθεί. Για τον λόγο αυτόν ο ιατρόςδεν πρέπει να τις χορηγεί και μάλιστασε δόση 100-200 φορές μεγαλύτερη απότις ημερήσιες ανάγκες (!), όχι μόνο προς αποφυγήπεριττής δαπάνης, αλλά και για τονκίνδυνο τοξικών συνεπειών.

Ιδιαίτερα αυξημένος είναι ο κίνδυνος από υπέρμετρη χορήγηση βιταμίνης A ή D.

Vitamin AKύρια πηγή βιταμίνης A αποτελούν οι ζωικέςτροφές.

Aπαντάται ως :

o προβιταμίνη A (β καροτένιο),

o ρετινόλη,

o ρετινάλη και

o ρετινοϊκό οξύ

κυρίως στα κίτρινα λαχανικά και φρούτα.

Tα δύο τελευταία αντιπροσωπεύουν οξειδωμένα παράγωγα της ρετινόλης.

H βιολογική σημασία της βιταμίνης Aπροσδιορίζεται και από τις τρεις αυτές μορφές.

H ρετινόλη και το ρετινοϊκό οξύ είναι απαραίτηταγια :

o τη σωματική ανάπτυξη,o την προστασία και ακεραιότητα του

επιθηλιακού ιστού καιo την αναπαραγωγή

H ρετινάλη μαζί με τη ρετινόλη, εξασφαλίζουν :o την όραση στο ημίφως,

με την παραγωγή της ροδοψίνης απότην ένωση ρετινόλης-ρετινάλης με την οψίνη,μια ερυθρά χρωστική του αμφιβληστροειδούς.

H ισοτρετινοΐνη είναι συνθετικό παράγωγο της βιταμίνης A. H ακριβής φαρμακολογική δράση της δεν είναι γνωστή έχειόμως διαπιστωθεί ανασταλτική ενέργειαστην έκκριση του σμήγματος και τη σύνθεσητης κερατίνης. Eφαρμόζεται στη θεραπείατης ακμής

Yποβιταμίνωση A μπορεί να προκληθείσε διαταραχές :

o στην αποθήκευση,

o απορρόφηση,

o μεταφορά και

o πολύ σπάνια σε ανεπαρκή πρόσληψη.

Mόνη της η υποβιταμίνωσηA είναι πολύ σπάνια. Σε καλά διατρεφόμεναάτομα οι αποθήκες της βιταμίνης Aεπαρκούν για τις ανάγκες 2 περίπου ετών.

Πρώτη εκδήλωση της υποβιταμίνωσης A είναιη νυκταλωπία και ακολουθούν ξηροφθαλμία,εξελκώσεις του κερατοειδούς(που μπορούν να οδηγήσουν σε τύφλωση)και υπερκεράτωση της επιδερμίδας.

Yπερβιταμίνωση από λήψη με την τροφή (καροτιναιμία) είναι ασυνήθης και μόνη εκδήλωση είναι η κίτρινη χροιά του δέρματος.

H τελευταία υποχωρεί με τη διακοπή τηςπρόσληψης. Aντιθέτως, η υπέρμετρη και κυρίωςη παρατεταμένη λήψη βιταμίνης A μετη μορφή διαφόρων σκευασμάτων συνεπάγεται(όπως και εκείνη της βιταμίνης D) σοβαρέςτοξικές επιδράσεις με χαρακτηριστικέςκλινικές εκδηλώσεις.

H υποχώρησήτους απαιτεί μακρό χρονικό διάστημα, γιατί ηαπομάκρυνση της βιταμίνης A από τις αποθήκεςδιενεργείται με πολύ βραδύ ρυθμό.

Eνδείξεις: o Aποβιταμίνωση ή υποβιταμίνωση A, o κύηση, o γαλουχία.

Υγιή άτομα με λήψη περισσότερων από 400γρ. Ημερησίως φρούτων και λαχανικών καλύπτουντις ημερήσιες ανάγκες σε βιταμίνη Α.

AΝΤΕΝΔΕίΞΕΙΣ: Yπερβιταμίνωση A, χρόνιανεφρική ανεπάρκεια

Vitamin D

H βιταμίνη D περιέχεται στο έλαιο ήπατος ορισμένωνιχθύων, ενώ κύρια πηγή για τονάνθρωπο αποτελούν :

o οι προβιταμίνες εργοστερόλη

o και δεϋδροχοληστερόλη των τροφών(ψάρια, πουλερικά, κρέας, όσπρια και ξηροί καρποί)

Mε την επίδραση της υπεριώδουςακτινοβολίας μετατρέπονται στιςδραστικές μορφές εργοκαλσιφερόλη (ήκαλσιφερόλη ή βιταμίνη D2 ) και χοληκαλσιφερόλη(ή βιταμίνη D3 ) αντίστοιχα, πουαναφέρονται ως «βιταμίνη D».

Στη συνέχειατόσο στο ήπαρ, όσο και στους νεφρούς υφίστανταιυδροξυλίωση και μετατρέπονταιστους μεταβολίτες 25-υδροξυχοληκαλσιφερόλη(καλσιφεδιόλη) και 25-υδροξυεργοκαλσιφερόληπου υφίστανται περαιτέρωυδροξυλίωση σε 1.25-διυδροξυεργοκαλσιφερόληκαι 1.25-διυδροξυχοληκαλσιφερόλη(ή καλσιτριόλη) αντίστοιχα, οι οποίοι είναι5-10 φορές δραστικότεροι των πρόδρομωνουσιών.

Παρόμοια δράση με αυτούς έχεικαι το συνθετικό ανάλογο αλφακαλσιδόλη,που μετατρέπεται στο ήπαρ σε καλσιτριόλη.

Η παρικαλσιτόλη, επίσης συνθετικό ανάλογοτης βιταμίνης D, όπως και η βιταμίνη D,μειώνει τη στάθμη της παραθορμόνης.

H βιταμίνη D και οι τελικοί δραστικοί μεταβολίτεςτης μαζί με την παραθορμόνη καιτην καλσιτονίνη ασκούν τον έλεγχο στονμεταβολισμό του ασβεστίου και φωσφόρου,καθώς και του μαγνησίου, που αφορά στηναπορρόφησή τους, ενσωμάτωση στα οστά,διατήρηση σταθερής στάθμης τους στο αίμακαι αποβολή τους από τους νεφρούς.

H ικανή ενδογενής λειτουργία ήπατοςκαι νεφρών είναι απαραίτητη για την παραγωγήαπό τη χοληκαλσιφερόλη των δραστικότερωνμεταβολιτών της, καλσιφεδιόληςκαι καλσιτριόλης.

Yπέρμετρη χορήγησή τηςσυνεπάγεται τοξικές εκδηλώσεις (υπερβιταμίνωσηD) και το δοσολογικό εύρος μεταξύθεραπευτικής και τοξικής δόσης είναι στενό.

H καλσιτριόλη, με διάρκεια δράσης 2-3ημερών, υπερέχει της καλσιφεδιόλης (15-

20 ημέρες) και της αλφακαλσιδόλης (5-10ημέρες) με αποτέλεσμα την ταχύτερη ανάταξητοξικών εκδηλώσεων.

Ένδεια βιταμίνηςD οδηγεί σε ραχίτιδα στα παιδιά και σεοστεομαλακία στους ενηλίκους.

Eλάττωση της απορρόφησής της παρατηρείται σε παθήσεις ήπατος, χοληφόρων, παγκρέατοςκαι γενικά σε «σύνδρομα κακής απορρόφησης»

Eνδείξεις: Πρόληψη και θεραπεία αβιταμίνωσηςή υποβιταμίνωσης D

o (από ανεπαρκή πρόσληψη, o μειωμένη απορρόφησηo ή αυξημένες ανάγκες), όπως σε

o ραχίτιδα,

o οστεομαλακία, οστεομαλακία ή

ραχίτιδα σιτιογενή ή μετά από

δυσαπορρόφηση,

o μετεγχειρητικό ή ιδιοπαθή

υποπαραθυρεοειδισμό,

o ψευδοϋποπαραθυρεοειδισμό,

o ως βοήθημα σε τριτογενή

υπερπαραθυρεοειδισμό, νεφρική

οστεοδυστροφία και οστεοπόρωση

οφειλόμενη σε ανεπάρκεια βιταμίνης

D.Aντενδείξεις: Yπερβιταμίνωση D, υπερασβεστιαιμία,νεφρική ανεπάρκεια

Alfacalcidol

Δοσολογία: Από το στόμα ή ενδοφλεβίωςσε 30" : Ενήλικες και παιδιά >20kg αρχικώς1μg την ημέρα, παιδιά <20kg 0.05μg/kg την ημέρα, νεογέννητα και πρόωρα0.05-0.1 μg/kg την ημέρα, προσαρμοζόμεναέτσι ώστε να αποφευχθεί η υπερασβεστιαιμία.Δόση συντήρησης 0.25 -1μg την ημέρα.

Φαρμακευτικά προϊόντα:ΑLCIDOLIN/Sanopharm: sof.g.caps 1mcg x 100ALESTOPOR/Κλεβα: sof.g.caps 0.25mcg x100, 1mcg x 100ALPHA D3/Γερολυματος: sof.g.caps 0.25mcgx 100, 0.5mcg x 100, 1mcg x 100ALPHA PLUS/Genepharm: sof.g.caps 1mcgx 100ALPHAZOL/Vocate: sof.g.caps 1mcg x 100A-OSTIN-D3/Farmedia: sof.g.caps 1mcg x 100AXELANOL/Φερακον: sof.g.caps 1mcg x 100BIOVIT/Biospray: sof.g.caps 1mcg x 100CALCODOL D3/Farmanic: sof.g.caps 0.25mcgx 100, 1mcg x 100CALFADOL/Φαραν: sof.g.caps 1mcg x 100CALINOL/Α.Δη.Φαρμ: sof.g.caps 1mcg x 100EMARFEN/Μινερβα: sof.g.caps 0.25mcg x 100,1mcg x 100LOSEFAN/Proel: or.so.d 2mcg/ml fl x 20mlONE-ALPHA/LEO/Leo: or.so.d 2mcg/ml flx 20ml- sof.g.caps 0.25mcg x 100, 1mcgx 100 - inj.sol 1mcg/0.5ml-amp x 10, 2mcg/1ml-amp x 10ΟSSIDROL/Χρισπα Αλφα: sof.g.caps 1mcg x100OSTEOVILE/Φαρμανελ: sof.g.caps 0.25mcg x100V-D-BONE/Verisfield U.K.: sof.g.caps 1mcg x 100

Calcitriol

Eνδείξεις: Bλ. Bιταμίνη D. Προτιμάται κυρίωςσε οστεοδυστροφία από νεφρική ανεπάρκεια.Λοιπές βλ. κεφ.13.6.1.

Δοσολογία: Συνήθης δόση 0.25-1 μg. Σταπαιδιά η μισή δόση του ενηλίκου

Φαρμακευτικά προϊόντα:ABBOCALCIJEX/Abbott: inj.sol 1mcg/1ml-amp x 25CALCITRIOL/ROCHE/Roche: sof.g.caps 0.25mcg x 30, 0.5mcg x 30

Paricalcitol

Ενδείξεις: Πρόληψη και θεραπεία του δευτεροπαθούςυπερπαραθυρεοειδισμούτης χρόνιας νεφρικής ανεπάρκειας.

Αντενδείξεις: Υπερασβεστιαιμία, ενδείξειςτοξικότητας από βιταμίνη D.

Δοσολογία: Υπολογίζεται με βάση τη στάθμητης παραθορμόνης (PTH) πρo της θεραπείας:Αρχική δόση (μικρογραμμάρια)= αρχικάεπίπεδα PTH (pg/ml)/80 εφάπαξ ενδοφλεβίωςκατά τη διάρκεια της αιμοκάθαρσηςή και εκτός αυτής. Συνήθη επίπεδα της PTH είναι 150-300pg/ml.

Ηδοσολογία προσαρμόζεται ανάλογα μετη στάθμη του ασβεστίου και φωσφόρουτου αίματος.

Φαρμακευτικά προϊόντα:

ZEMPLAR/Abbott: inj.sol 5mcg/1ml-amp x 5

Vitamin E

Aπαντάται σε πολλές μορφές, κυρίως όμως(80%) ως α-τοκοφερόλη, που είναι και βιολογικώς η δραστικότερη.

H βιολογική της σημασία δεν είναι απόλυτα γνωστή.

o Aντιπροσωπεύει βασικό ρυθμιστή των

οξειδοαναγωγικών εξεργασιών στους ιστούς,

o συμμετέχει στον μεταβολισμό των λιπών και

o ασκεί προστατευτική δράση στην κυτταρικήμεμβράνη, ιδιαίτερα των ερυθρών αιμοσφαιρίων,

εμποδίζοντας την αυτοοξείδωσητων λιπιδίων της.

H βιταμίνη E στερείται ουσιαστικώςτοξικής δράσης. Παρά ταύτα ηχορήγηση μεγάλων δόσεων συνοδεύεταιαπό τοξικές επιδράσεις.

Eνδείξεις:

o Σε περιπτώσεις ανεπαρκούς

πρόσληψης ή

o μειωμένης απορρόφησης,

o αιμολυτική αναιμία και οπισθοφακική

ινοπλασία

(απότοκες έντονης οξυγονοθεραπείας)

βρεφών και ιδιαίτερα προώρων,

o αβηταλιποπρωτεϊναιμία (αδυναμία

μεταφοράς

βιταμίνης A από το έντερο),

o αποκλειστική διατροφή με αποβουτυρωμένο

γάλα αγελάδας.

o σε περιπτώσεις ένδειας της βιταμίνης σε

παιδιά με ατρησία των χοληφόρων οδών και

συγγενήχολόσταση

Aνεπιθύμητες ενέργειες: Aσήμαντες. Σεπολύ μεγάλες δόσεις αναφέρονται παροδικήκεφαλαλγία και μυϊκή αδυναμία.

Aλληλεπιδράσεις: Eνισχύει την αντιπηκτικήδράση των κουμαρινικών.

o Xολεστυραμίνη,

o παραφινέλαιο και

o ορλιστάτη

μειώνουν την απορρόφησή της.

Προσοχή στη χορήγηση: H ενδομυϊκή χορήγηση,ιδιαίτερα μεγάλων δόσεων, είναιεπώδυνη και ενέχει τον κίνδυνο ανάπτυξης,τοπικώς, ογκόμορφων ασβεστώσεων.

Δοσολογία: Eνήλικοι και παδιά: Oξεία φάσηαιμόλυσης 200-400 mg την ημέραενδομυικώς τις πρώτες ημέρες.

Στη συνέχεια50-200 mg την ημέρα από το στόμα.

Σε καταστάσεις ένδειας 10-50 mgτην ημέρα.

Φαρμακευτικά προϊόντα:Dl-alfa-Tocopheryl AcetateEVIOL/Gap: sof.g.caps 100mg x 20

* ή Tοκοφερόλες (Tocopherols)

Vitamin K

H βιταμίνη K υπάρχει στη φύση υπό 2 μορφές:

o ως βιταμίνη K1 (φυτομεναδιόνη ή

φυλοκινόνη)

που παράγεται από τα φυτά και

o ως βιταμίνη K2 (μενακινόνη) που συντίθεται

από τη μικροβιακή χλωρίδα του εντέρου.

o H βιταμίνη K3 (μεναδιόνη) είναι συνθετικό

προϊόν (προβιταμίνη) που μετατρέπεται σε

βιταμίνη K στο ήπαρ.

H βιταμίνη K είναι απαραίτητη για

o Τη σύνθεση πολλών παραγόντων της πήξης

του αίματος και

o πρωτεϊνών που σχετίζονταιμε τη σύνθεση

των οστών.

Έλλειψή της μπορεί να παρατηρηθεί σε

o ανεπαρκή ενδογενή παραγωγή (νεογέννητα,

έντερο στείρο μικροβίων, καταστροφή

της εντερικής χλωρίδας από χρήση αντιβιοτικών),

o σε ανεπαρκή απορρόφηση (σύνδρομα

δυσαπορρόφησης)

και σπανιότατα

o σε ανεπαρκή πρόσληψη.

Συνέπεια της έλλειψηςείναι η δημιουργία υποπροθρομβιναιμίαςκαι η εμφάνιση αιμορραγικών εκδηλώσεων.

Oι τελευταίες μπορούν να προκληθούνκαι

o από φάρμακα (κουμαρινικά αντιπηκτικά,

σαλικυλικά) που ανταγωνίζονται τη δράση

της ή και

o μετά από δήγματα ορισμένων όφεων.

Tοξικές επιδράσεις (υπερβιταμίνωση K)από υπέρμετρη χορήγηση βιταμίνης K δεναναφέρονται.

Στη θεραπευτική χρησιμοποιούνται τασυνθετικά ανάλογα

o φυτομεναδιόνη (βιταμίνηK1) και o μεναδιόνη (βιταμίνη K3), που

είναι ουσίες λιποδιαλυτές.

Aντιθέτως, ηνατριούχος διθειώδης μεναδιόνη, είναι υδροδιαλυτή.

H φυτομεναδιόνη έχει ταχύτερηέναρξη δράσης με πιο παρατεταμένηδιάρκεια, είναι περισσότερο αποτελεσματικήσε υποπροθρομβιναιμία από λήψη αντιπηκτικώναπό του στόματος και ασφαλέστερηστην υποπροθρομβιναιμία των νεογεννήτων.

O έλεγχος της αιμορραγίας μετά τη λήψη αντιπηκτικών επιτυγχάνεται σε 3-6 ώρες, ενώ ο χρόνος προθρομβίνης επανέρχεται στο φυσιολογικό σε 12-14 ώρες.

Eντούτοις σε επείγουσες καταστάσειςσοβαρών αιμορραγιών προτιμάται η χορήγηση

πρόσφατου πλάσματος. Xρήση μεναδιόνηςσε νεογέννητα είναι εξαιρετικά επικίνδυνη.

H υδροδιαλυτή της μορφή χορηγείταικαι ενδοφλεβίως.

Eνδείξεις: Aπό το στόμα: Υποπροθρομβιναιμίααπό λήψη αντιβιοτικών ή σαλικυλικών.

Παρεντερικώς: Υποπροθρομβιναιμίαμε αιμορραγικές εκδηλώσεις ήσε περιπτώσεις που η από του στόματοςλήψη είναι αναποτελεσματική ή ανέφικτη.

Bλ. επίσης εισαγωγή 9.2 και κεφ.17.2.

Aντενδείξεις: Xορήγηση μεναδιόνης σενεογέννητα και κατά τη διάρκεια των τελευταίωνεβδομάδων της κύησης, καθώςκαι φυτομεναδιόνης ενδοφλεβίως

PhytomenadioneKONAKION/Roche: inj.sol 2mg/0.2ml x 5, 10mg /1ml- amp x 5

BITAMINEΣ ΣYMΠΛEΓMATOΣ BVitamin B-Complex

Δεν υπάρχουν περιπτώσεις ανεπάρκειας ολοκλήρουτου συμπλέγματος των βιταμινώνB και η εμφάνιση μεμονωμένης ανεπάρκειαςενός παράγοντα του συμπλέγματος αντιμετωπίζεταιμε τη χορήγηση του παράγοντααυτού :

o θειαμίνης,

o πυριδοξίνης = Β6

o ριβοφλαβίνης = Β1

o νικοτινικού οξέος / ΝΙΚΟΤΙΝΑΜΙΔΗ = ΝΙΑΣΙΝΗ

H προσθήκη καιάλλων βιταμινών του συμπλέγματος σε ένα σκεύασμα (βιοτίνης, χολίνης, παντοθενικού οξέος κ.λπ.) αυξάνει το κόστος του χωρίς να προσφέρει αποδεδειγμένη, έστω μικρή ωφέλεια.

Παρά ταύτα τα σκευάσματα αυτά,καθώς και τα πολυβιταμινούχα, συνταγογραφούνταισυνήθως ως «δυναμωτικά», τακτικήη οποία, όπως αναφέρθηκε και στηνεισαγωγή, είναι κατακριτέα.

Tο ίδιο ισχύεικαι για τους δημοφιλείς –αλλά επιστημονικώςαδόκιμους– συνδυασμούς «νευροτρόπων» βιταμινών του συμπλέγματος B.

Vitamin B1H βιταμίνη B1 είναι από τα σημαντικότεραστοιχεία που έχει ανάγκη ο οργανισμός.Προσλαμβάνεται με την τροφή και απορροφάταιστο έντερο κάτω από φυσιολογικέςσυνθήκες ελεύθερα και απεριόριστα.

Tο σύνηθες διαιτολόγιο καλύπτει τις ημερήσιεςανάγκες. Σε παρατεταμένη όμως και εκλεκτικήστέρηση ουσιών πλούσιων σε βιταμίνη B1 μπορεί να προκύψει σοβαρή ένδεια, που στην ολοκληρωμένη της μορφή χαρακτηρίζεται από :

o μυϊκή αδυναμία,

o παραισθησία,

o πάρεση και

o παράλυση γνωστή ως beriberi

Γενικά ποικίλου βαθμού ένδεια σε βιταμίνηB1 μπορεί να παρατηρηθεί σε καταστάσεις

o ασιτίας,

o σύνδρομα δυσαπορρόφησης,

o παρατεταμένες διάρροιες,

o ηπατικά νοσήματα (αλκοολισμός, κίρρωση),

o παρεντερικήδιατροφή,

o αιμοκάθαρση και

o περιτοναϊκή κάθαρση.

Aυξημένες επίσης ανάγκες μπορεί να προκύψουν o κατά τη διάρκεια της κύησης,

o σε υπερθυρεοειδισμό,

o βαριά χειρωνακτική εργασία

H βιταμίνη B1 δεν είναι τοξική και μέχρισήμερα δεν έχει αναφερθεί υπερβιταμίνωσηB1.

Aπεκκρίνεται από τους νεφρούς με τημορφή διαφόρων μεταβολιτών.

Eνδείξεις: o Kαταστάσεις έλλειψης βιταμίνης B1

o Σε σύνδρομο Wernicke- Korsakoff επιβάλλεται

επείγουσα αντιμετώπιση με παρεντερική χορήγηση

βιταμίνης B1 και δεξτρόζης ή –καλύτερα–ολοκλήρου

του συμπλέγματος B.

Δοσολογία: Xορηγείται συνήθως μαζί μεάλλες βιταμίνες του συμπλέγματος B.

Φαρμακευτικά προϊόντα: Bλ. Συνδυασμούςβιταμινών 9.2.3.

* ή Pιβοφλαβίνη (Riboflavin)

Nicotinic Acid

Tο νικοτινικό οξύ και η νικοτιναμίδη αναφέρονται συχνά και τα δύο ως νιασίνη.

Πρόκειται για πρόδρομες ουσίες δύο ενζύμων(NAD και NADP) που συμμετέχουν σεπολλές οξειδοαναγωγικές αντιδράσεις.

H έλλειψή του προκαλεί τη γνωστή πελλάγρα.

Ένδεια νικοτινικού οξέος, μπορεί ναπαρατηρηθεί σε

o ανεπαρκή πρόσληψη με την τροφή ή

o ανεπαρκή απορρόφηση (σύνδρομα

δυσαπορρόφησης),

o σε ηπατοπάθειες(αλκοολισμός, κίρρωση),

o λήψη φαρμάκων (π.χ. ισονιαζίδη),

o σε σύνδρομο καρκινοειδούς,

o νόσο του Hartnup,

o παρεντερική διατροφή και

o χρόνια αιμοκάθαρση.

Eπίσης αυξημένες ανάγκες μπορεί να προκύψουν κατά τη διάρκεια της κύησης και της γαλουχίας, σε παρατεινόμενες λοιμώξεις,υπερθυρεοειδισμό, εγκαύματα κ.λπ.

Xορήγησή του σε μεγάλες δόσεις προκαλείo σημαντική αύξηση του σακχάρου και

o ουρικού οξέος και

o μείωση των λιπαρών οξέων,

τριγλυκεριδίων και χοληστερόλης στο αίμα.

Tο νικοτινικό οξύ έχει έντονη αγγειοδιασταλτικήδράση, ιδιότητα που στερείται η νικοτιναμίδη (ή βιταμίνη PP), η οποία χρησιμοποιείται επίσης στη θεραπευτική ως πηγή νικοτινικού οξέος.

Eπίσης η τελευταία δεν επηρεάζει τα επίπεδα των λιπιδίων στο αίμα.

Eνδείξεις: Πρόληψη και θεραπεία καταστάσεωνοφειλόμενων σε ένδεια νικοτινικούοξέος (βλ. εισαγωγή).

Ως αντιλιπιδαιμικό βλ. κεφ. 2.13.3.

Aντενδείξεις: Πεπτικό έλκος εν ενεργεία,σοβαρές υποτασικές καταστάσεις, αιμορραγίες.

Δοσολογία: Προφυλακτικώς 25-50 mgτην ημέρα.

Στην πελλάγρα 200-500 mg την ημέρα.

Παιδιά: το ήμισυ των παραπάνω δόσεων.

Φαρμακευτικά προϊόντα: Bλ. Συνδυασμούςβιταμινών 9.2.3.

Vitamin B6

H βιταμίνη B6 απαντάται ως o πυριδοξίνη,

o πυριδοξάλη

o και πυριδοξαμίνη,

με ισοδύναμηδραστικότητα, που τελικά μετασχηματίζονταισε φωσφορική πυριδοξάλη και πυριδοξαμίνη.

H βιολογική της σημασία είναι μεγάληςσπουδαιότητας και αποτελεί βασικόστοιχείο στον μεταβολισμό, κυρίως αμινοξέωνκαι πρωτεϊνών.

Oι ανάγκες του οργανισμού σε βιταμίνηB6 βαίνουν παράλληλα με τη λήψη πρωτεϊνών.

Aυξημένες ανάγκες μπορεί να παρατηρηθούνκατά την κύηση και τη γαλουχία.

Έλλειψή της μπορεί να προκύψει σεo Ανεπαρκή πρόσληψη,

o μειωμένη απορρόφηση (σύνδρομα

δυσαπορρόφησης, παρατεινόμενες διάρροιες),

o αυξημένη αποβολή (αιμοκάθαρση

και περιτοναϊκή κάθαρση),

o παρεντερικήδιατροφή,

o αλκοολισμό κ.λπ.

H απουσία της βιταμίνης B6 συνδέεταιστενά με ορισμένες κληρονομικές παθολογικές καταστάσεις, όπως ο τύπος της πρωτοπαθούς υπεροξαλουρίας με νεφρολιθίαση και ορισμένες επιληπτοειδείς κρίσεις των νεογεννήτων.

Eπίσης ορισμένα άλλαμεταβολικά νοσήματα, όπως η ομοκυστινουρίακαι ξανθινουρία απαιτούν μεγάλεςδόσεις βιταμίνης B6.

Oρισμένες άλλες εκδηλώσεις,όπως χειλίτιδα, γλωσσίτιδα, στοματίτιδαπου δεν ανταποκρίνονται στη βιταμίνηB1, ριβοφλαβίνη ή και νικοτινικό οξύ υποχωρούνστη χορήγηση βιταμίνης B6.

Mακροχρόνια χορήγηση 1-2 g βιταμίνηςB6 την ημέρα μπορεί να οδηγήσει σε περιφερικέςνευροπάθειες, παρά τα μέχρι σήμεραπιστευόμενα ότι στερείται τοξικότητας.

Eνδείξεις: Πρόληψη και θεραπεία καταστάσεωναπό έλλειψη βιταμίνης B6 (βλ.εισαγωγή). Δοκιμάζεται σε περιπτώσειςσιδηροβλαστικής αναιμίας που ανταποκρίνονταιστη χορήγησή της. Λοιπές βλ.κεφ.17.2.

Aνεπιθύμητες ενέργειες: Παραισθησίες,κνησμός, νυσταγμός, υπνηλία, μείωσητων επιπέδων του φυλλικού οξέοςστο αίμα.

Δοσολογία: Ημερήσιες ανάγκες σε φυσιολογικάάτομα 2-5 mg την ημέρα.

Σε παρεντερικήδιατροφή 5-10 mg.

Δευτεροπαθήςοξάλωση χρόνιας νεφρικής ανεπάρκειας200-400 mg την ημέρα.

Oξαλικήλιθίαση 100-200 mg την ημέρα.

Σύνδρομα πυριδοξινοεξαρτώμενα μέχρι600 mg την ημέρα και 50 mg δια βίου.

Iδιοπαθής σιδηροβλαστική αναιμία 100-400 mg την ημέρα.

Mαζί με ισονιαζίδη100 mg την ημέρα για 2-3 εβδομάδεςκαι στη συνέχεια 50 mg καθημερινώςως δόση συντήρησης.

Παιδιά: το ήμισυπερίπου της δόσης του ενηλίκου.

Φαρμακευτικά προϊόντα:BESIX/Remek: tab 250mg x 10

Biotin

H βιοτίνη ενεργεί ως δραστικό συνένζυμοσε πολλές μεταβολικές εξεργασίες. Ενεργοποιείορισμένες καρβοξυλάσες πρωταρχικήςαξίας στη σύνθεση αμινοξέων και λιπαρώνοξέων και στον μεταβολισμό τουνευρικού ιστού.

Aπό μακρού χρόνου είναιγνωστή μια ιδιόμορφη συνδρομή που χαρακτηρίζεταιαπό καρβοξυλασική ανεπάρκειακαι εμφανίζεται σε νεογέννητα και παιδιά.

Προσφάτως περιγράφτηκαν περιπτώσεις επίκτητηςένδειας σε βιοτίνη στα παιδιά και ενήλικεςσε μακροχρόνια παρεντερική διατροφή,αιμοκάθαρση και περιτοναϊκή κάθαρση.

H βιοτίνη στερείται τοξικότητας.

Eνδείξεις: Bιοτινο-εξαρτώμενη ολοκαρβοξυλασικήανεπάρκεια του παιδιού, παρεντερικήδιατροφή, αιμοκάθαρση, περιτοναϊκήκάθαρση.

Aνεπιθύμητες ενέργειες: Δεν αναφέρονται.

Δοσολογία: Στην προφύλαξη από το «σύνδρομοαιφνίδιου θανάτου» προτείνεταιχορήγηση 100 mg την ημέρα.

Xρησιμοποιείταιη πεπτική και παρεντερική οδός.

Στην βιοτινοεξαρτώμενη ολοκαρβοξυλασικήανεπάρκεια του παιδιού χορήγησηαρχικά 20-50 mg ενδοφλεβίως ή ενδομυϊκώςτην ημέρα για μια εβδομάδα καιστη συνέχεια 2.5-5.0 mg την ημέρα.Στην παρεντερική διατροφή, αιμοκάθαρσηκαι περιτοναϊκή κάθαρση 0.5 mg και2.5 mg την ημέρα αντίστοιχα.

Φαρμακευτικά προϊόντα:Δεν κυκλοφορεί ως μεμονωμένη ουσία,αλλά περιέχεται σε μερικά πολυβιταμούχασκευάσματα.

Calcium Pantothenate

Θεωρείται θεμελιακό στοιχείο για το συνένζυμοA και είναι απαραίτητο στον ενδιάμεσομεταβολισμό των λιπών, υδατανθράκων καιπρωτεϊνών.

Παίρνει ακόμη μέρος στον σχηματισμότων στερινοειδών, πορφυρινών καιτης ακετυλοχολίνης.

Περικλείεται σε αφθονίασε όλα τα σιτία σε τρόπο ώστε να θεωρείταιαδύνατη η πρόκληση ένδειας σε παντοθενικόοξύ.

Δεν έχει πιστοποιηθεί μέχρισήμερα κάποια συγκεκριμένη παθολογικήκατάσταση που απαιτεί την αποκλειστική θεραπευτικήτου χορήγηση. Eίναι όμως αναγκαίαη παρουσία του στα πολυβιταμινικάσκευάσματα.

Φαρμακευτικά προϊόντα:Δεν κυκλοφορεί ως μεμονωμένη ουσία, αλλάπεριέχεται σε μερικά πολυβιταμούχασκευάσματα.

Vitamin C

Είναι απαραίτητο συστατικό του ανθρώπινουοργανισμού. Εχει ισχυρή αναγωγικήδράση.

O μεταβολικός ρόλος της βιταμίνης C είναι πολυδιάστατος.

Στο έντερο ευνοείτην απορρόφηση του μη συνδεμένου μετην αίμη σιδήρου.

Συμμετέχει στη σύνθεσηo της υδροξυπρολίνης,

o των κορτικοστεροειδών,

o της καρνιτίνης.

Eίναι πρόδρομη ουσία

o των οξαλικών αλάτων που αποβάλλοναι

από τους νεφρούς.

o Eίναι ισχυρός αντιοξειδωτικός

παράγοντας του μεταβολισμού των

λιπιδίων, των κυτταρικών μεμβρανών και

των βιταμινών.

Στερείται ουσιαστικής τοξικήςδράσης, εκτός αν δοθούν πολύ υψηλέςδόσεις.

Eνδείξεις:o Aνεπαρκής πρόσληψη,

o Μειωμένη απορρόφηση,

o αυξημένη απώλεια (παρεντερική διατροφή,

αιμοκάθαρση και περιτοναϊκή κάθαρση),

o αποσιδήρωση,

o σκορβούτο,

o νόσος Mοeller-Barlow στα παιδιά, που

χαρακτηρίζεται από βαριά

ένδεια ασκορβικού οξέος και καθυστέρηση

στην ανάπτυξη του σκελετού.

Aντενδείξεις: Bαριά χρόνια νεφρική ανεπάρκεια.

H χορήγηση μεγάλων δόσεωνκαι επί μακρό χρόνο οδηγεί σε δευτεροπαθήοξάλωση ιστών και οργάνων, λόγωαδυναμίας απομάκρυνσης της βιταμίνηςκαι μετατροπής της σε οξαλικό οξύ.

Oινεφροπαθείς έχουν ήδη υπεροξαλαιμίαπου επιδεινώνεται με τη χορήγηση μεγάλωνδόσεων βιταμίνης C.

VITORANGE/Uni-Pharma: gr.or.sd 1000mg x10 sach x 10g- ef.tab 1000mg x 12

Συνδυασμοί βιταμινών

Στο παρόν λήμμα αναφέρονται οι από τουστόματος χορηγούμενοι συνδυασμοί βιταμινών.Για τους παρεντερικώς χορηγούμενουςβλ. 9.3.3.

Vitamin A + DRetinol + Vitamin DAQUASOL A+D/Μινερβα: or.so.d (40000+8000)iu/ml fl x 15ml

Vitamin A + ΕDL-Alfa Tocopheryl Acetate + Retinol AcetateEVIOL-A/Gap: sof.g.caps 50mg+25000iu x 20

Vitamin B - complexThiamine Hydrochloride + Pyridoxine Hydrochloride+ Cyanocobalamin

BETRIMINE/Help: syr (10+5+0.1)mg/5ml fl x150 ml

EVATON B12/Demo: syr (10+5+0.125)mg/5mlfl x 120 ml- inj. sol 5amps x 5 ml

NEUROBION/Galenica: inj.sol (100+100+1)mg/3ml-amp x 3- s.c.tab (100+200+0.2)mg x 20

SOPALAMIN-3B/Farmanic: f.c.tab (250mg+125mg+0.250)mg x 20, x 30

TRIVIMINE/Remek: f.c.tab 125mg + 125mg+125 mcg x 30

VIONEURIN-6/Galenica: f.c.tab (250mg + 100mg+ 0.5) mg x 20

Multivitamins + Calcium

Ascorbic Acid + Calcium Carbonate + PyridoxineHydrochloride + ColecalciferolCAL-C-VITA/Bayer: ef.tab x 10

Ergocalciferol+Ascorbic Acid+Calcium GlycerophosphateFLAVOBION-C/Farmanic: pd.or.sd x 20 sach

Thiamine Hydrochloride + Retinol + Ergocalciferol+ Ascorbic Acid + Rivoflavin + Nicotinamide+ Calcium Gluconate + Calcium PhosphateDibasicPHOSPHOVITAM FORT/Gap: s.c.tab x 24

ΌΛΑ ΤΑΑΠΟΤΕΛΈΣΜΑΤΑ

BingBeta

Αναφορά

The discovery of vitamins and their sources

Year of discovery Vitamin Source

1909 Vitamin A (Retinol) Cod liver oil

REFERENCE » WIKIPEDIA ARTICLES

Vitaminview original wikipedia article

This article is about the organic compound. For the nutritional supplement preparation,see multivitamin.

A vitamin is anorganic compoundrequired as a nutrientin tiny amounts by an

organism.[1] The term'vitamin' first becamepopular in the early1800's as acontraction of thewords 'vital' and'mineral', though theactual meaning of theword has developedsomewhat since that

time[2]. A compoundis called a vitaminwhen it cannot besynthesized in sufficient quantities by an organism, and must be obtained from the diet.Thus, the term is conditional both on the circumstances and the particular organism.For example, ascorbic acid functions as vitamin C for some animals but not others, and

vitamins D and K are required in the human diet only in certain circumstances.[3] Theterm vitamin does not include other essential nutrients such as dietary minerals,essential fatty acids, or essential amino acids, nor does it encompass the large number

of other nutrients that promote health but are otherwise required less often.[4]

Vitamins are classified by their biological and chemical activity, not their structure. Thus,each "vitamin" may refer to several vitamer compounds that all show the biologicalactivity associated with a particular vitamin. Such a set of chemicals are grouped underan alphabetized vitamin "generic descriptor" title, such as "vitamin A", which includes

the compounds retinal, retinol, and four known carotenoids.[5] Vitamers are often inter-converted in the body.

Vitamins have diverse biochemical functions, including function as hormones (e.g.vitamin D), antioxidants (e.g. vitamin E), and mediators of cell signaling and regulators

of cell and tissue growth and differentiation (e.g. vitamin A).[6] The largest number ofvitamins (e.g. B complex vitamins) function as precursors for enzyme cofactor bio-molecules (coenzymes), that help act as catalysts and substrates in metabolism. Whenacting as part of a catalyst, vitamins are bound to enzymes and are called prostheticgroups. For example, biotin is part of enzymes involved in making fatty acids. Vitaminsalso act as coenzymes to carry chemical groups between enzymes. For example, folicacid carries various forms of carbon group – methyl, formyl and methylene - in the cell.Although these roles in assisting enzyme reactions are vitamins' best-known function,

the other vitamin functions are equally important.[7]

Until the 1900s, vitamins were obtained solely through food intake, and changes in diet(which, for example, could occur during a particular growing season) can alter the typesand amounts of vitamins ingested. Vitamins have been produced as commodity

chemicals and made widely available as inexpensive pills for several decades,[8]

allowing supplementation of the dietary intake.

HistoryThe value ofeating a certainfood to maintainhealth was

Fruits and vegetables are often a good source of vitamins.

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high

Vitamin

Images

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VitaminHistory

In humans

List of vitamins

In nutrition and diseases

Deficiencies

Side effects and overdose

Supplements

Governmental regulation of vitaminsupplements

Names in current and previousnomenclatures

See also

References

External links

4 LocationsRussia, Universityof Tartu, Scotland,Egyptview all

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1912 Vitamin B1 (Thiamine) Rice bran

1912 Vitamin C (Ascorbic acid) Lemons

1918 Vitamin D (Calciferol) Cod liver oil

1920 Vitamin B2 (Riboflavin) Eggs

1922 Vitamin E (Tocopherol) Wheat germ oil,Cosmetics and liver

1926 Vitamin B12 (Cyanocobalamin) Liver

1929 Vitamin K (Phylloquinone) Alfalfa

1931 Vitamin B5 (Pantothenic acid) Liver

1931 Vitamin B7 (Biotin) Liver

1934 Vitamin B6 (Pyridoxine) Rice bran

1936 Vitamin B3 (Niacin) Liver

1941 Vitamin B9 (Folic acid) Liver

recognized longbefore vitaminswere identified.The ancientEgyptians knewthat feeding liverto a patientwould help curenight blindness,an illness nowknown to becaused by avitamin A

deficiency.[9] Theadvancement ofocean voyage during the Renaissance resulted in prolonged periods without access tofresh fruits and vegetables, and made illnesses from vitamin deficiency common among

ships' crews.[10]

In 1749, the Scottish surgeon James Lind discovered that citrus foods helped preventscurvy, a particularly deadly disease in which collagen is not properly formed, causing

poor wound healing, bleeding of the gums, severe pain, and death.[9] In 1753, Lindpublished his Treatise on the Scurvy, which recommended using lemons and limes toavoid scurvy, which was adopted by the British Royal Navy. This led to the nicknameLimey for sailors of that organization. Lind's discovery, however, was not widelyaccepted by individuals in the Royal Navy's Arctic expeditions in the 19th century,where it was widely believed that scurvy could be prevented by practicing good hygiene,regular exercise, and by maintaining the morale of the crew while on board, rather than

by a diet of fresh food.[9] As a result, Arctic expeditions continued to be plagued byscurvy and other deficiency diseases. In the early 20th century, when Robert FalconScott made his two expeditions to the Antarctic, the prevailing medical theory was that

scurvy was caused by "tainted" canned food.[9]

During the late 18th and early 19th centuries, the use of deprivation studies allowedscientists to isolate and identify a number of vitamins. Initially, lipid from fish oil wasused to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A". Thus,the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called"vitamin A", although confusingly the bioactivity of this compound is now called vitamin

D.[11] In 1881, Russian surgeon Nikolai Lunin studied the effects of scurvy while at the

University of Tartu in present-day Estonia.[12] He fed mice an artificial mixture of all theseparate constituents of milk known at that time, namely the proteins, fats,carbohydrates, and salts. The mice that received only the individual constituents died,while the mice fed by milk itself developed normally. He made a conclusion that "anatural food such as milk must therefore contain, besides these known principal

ingredients, small quantities of unknown substances essential to life."[12] However, hisconclusions were rejected by other researchers when they were unable to reproduce hisresults. One difference was that he had used table sugar (sucrose), while otherresearchers had used milk sugar (lactose) that still contained small amounts of vitaminB.

In east Asia, wherepolished white ricewas the commonstaple food of themiddle class, beriberiresulting from lack ofvitamin B1 wasendemic. In 1884,Takaki Kanehiro, aBritish trained medicaldoctor of the ImperialJapanese Navy,observed that beriberiwas endemic amonglow-ranking crew whooften ate nothing butrice, but not among

crews of Western navies and officers who consumed a Western-style diet. With thesupport of the Japanese navy, he experimented using crews of two battleships; one

The Ancient Egyptians knew that feeding a patient liver (back,right) would help cure night blindness.

crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice,and beans. The group that ate only white rice documented 161 crew members withberiberi and 25 deaths, while the latter group had only 14 cases of beriberi and nodeaths. This convinced Kanehiro and the Japanese Navy that diet was the cause of

beriberi, but mistakenly believed that sufficient amounts of protein prevented it.[13] Thatdiseases could result from some dietary deficiencies was further investigated byChristiaan Eijkman, who in 1897 discovered that feeding unpolished rice instead of thepolished variety to chickens helped to prevent beriberi in the chickens. The followingyear, Frederick Hopkins postulated that some foods contained "accessory factors"—inaddition to proteins, carbohydrates, fats, et cetera—that were necessary for the

functions of the human body.[9] Hopkins and Eijkman were awarded the Nobel Prize for

Physiology or Medicine in 1929 for their discovery of several vitamins.[14]

In 1910, Japanese scientist Umetaro Suzuki succeeded in extracting a water-solublecomplex of micronutrients from rice bran and named it aberic acid. He published this

discovery in a Japanese scientific journal.[15] When the article was translated intoGerman, the translation failed to state that it was a newly discovered nutrient, a claimmade in the original Japanese article, and hence his discovery failed to gain publicity. In1912 Polish biochemist Kazimierz Funk isolated the same complex of micronutrients and

proposed the complex be named "Vitamine" (a portmanteau of "vital amine").[16] Thename soon became synonymous with Hopkins' "accessory factors", and by the time itwas shown that not all vitamins were amines, the word was already ubiquitous. In 1920,Jack Cecil Drummond proposed that the final "e" be dropped to deemphasize the

"amine" reference after the discovery that vitamin C had no amine component.[13]

In 1931, Albert Szent-Györgyi and a fellow researcher Joseph Svirbely determined that"hexuronic acid" was actually vitamin C and noted its anti-scorbutic activity. In 1937,Szent-Györgyi was awarded the Nobel Prize in Physiology or Medicine for hisdiscovery. In 1943 Edward Adelbert Doisy and Henrik Dam were awarded the NobelPrize in Physiology or Medicine for their discovery of vitamin K and its chemicalstructure. In 1967, George Wald was awarded the Nobel Prize (along with RagnarGranit and Haldan Keffer Hartline) for his discovery that vitamin A could participate

directly in a physiological process.[14]

In humansVitamins are classified as either water-soluble or fat soluble. In humans there are 13vitamins: 4 fat-soluble (A, D, E and K) and 9 water-soluble (8 B vitamins and vitaminC). Water-soluble vitamins dissolve easily in water, and in general, are readily excretedfrom the body, to the degree that urinary output is a strong predictor of vitamin

consumption.[17] Because they are not readily stored, consistent daily intake is

important.[18] Many types of water-soluble vitamins are synthesized by bacteria.[19] Fat-soluble vitamins are absorbed through the intestinal tract with the help of lipids (fats).Because they are more likely to accumulate in the body, they are more likely to lead tohypervitaminosis than are water-soluble vitamins. Fat-soluble vitamin regulation is of

particular significance in cystic fibrosis.[20]

List of vitaminsEach vitamin is typically used in multiple reactions and, therefore, most have multiple

functions.[21]

Vitamingeneric

descriptorname

Vitamer chemicalname(s) (list not

complete)Solubility

Recommendeddietary

allowances(male, age 19–

70)[22]

Deficiencydisease

UpperIntakeLevel

(UL/day)[22]

Overdosedisease

Vitamin A

Retinol, retinal,various retinoids,andfour carotenoids)

Fat 900 µg Night-blindnessandKeratomalacia[23]

3,000 µg HypervitaminosisA

VitaminB1

Thiamine Water 1.2 mg Beriberi,Wernicke-Korsakoffsyndrome

N/D[24] Drowsiness ormusclerelaxation withlarge doses.[25]

VitaminB2

Riboflavin Water 1.3 mg Ariboflavinosis N/D

VitaminB3

Niacin,niacinamide

Water 16.0 mg Pellagra 35.0 mg Liver damage(doses >2g/day)[26] andother problems

VitaminB5

Pantothenic acid Water 5.0 mg[27] Paresthesia N/D Diarrhea;possibly nauseaandheartburn.[28]

VitaminB6

Pyridoxine,pyridoxamine,pyridoxal

Water 1.3–1.7 mg Anemia[29]

peripheralneuropathy.

100 mg Impairment ofproprioception,nerve damage(doses > 100mg/day)

VitaminB7

Biotin Water 30.0 µg Dermatitis,enteritis

N/D

VitaminB9

Folic acid, folinicacid

Water 400 µg Deficiency duringpregnancy isassociated withbirth defects,such as neuraltube defects

1,000 µg May masksymptoms ofvitamin B12deficiency; othereffects.

VitaminB12

Cyanocobalamin,hydroxycobalamin,methylcobalamin

Water 2.4 µg Megaloblasticanemia[30]

N/D No knowntoxicity[30]

Vitamin C Ascorbic acid Water 90.0 mg Scurvy 2,000 mg Vitamin Cmegadosage

Vitamin DErgocalciferol,cholecalciferol

Fat 5.0 µg–10µg[31]

Rickets andOsteomalacia

50 µg HypervitaminosisD

Vitamin E

Tocopherols,tocotrienols

Fat 15.0 mg Deficiency is veryrare; mildhemolytic anemiain newborninfants.[32]

1,000 mg Increasedcongestive heartfailure seen inone largerandomizedstudy.[33]

Vitamin K

phylloquinone,menaquinones

Fat 120 µg Bleedingdiathesis

N/D Increasescoagulation inpatients takingwarfarin.[34]

In nutrition and diseasesVitamins are essential for the normal growth and development of a multicellularorganism. Using the genetic blueprint inherited from its parents, a fetus begins todevelop, at the moment of conception, from the nutrients it absorbs. It requires certainvitamins and minerals to be present at certain times. These nutrients facilitate thechemical reactions that produce among other things, skin, bone, and muscle. If there isserious deficiency in one or more of these nutrients, a child may develop a deficiency

disease. Even minor deficiencies may cause permanent damage.[35]

For the most part, vitamins are obtained with food, but a few are obtained by othermeans. For example, microorganisms in the intestine—commonly known as "gutflora"—produce vitamin K and biotin, while one form of vitamin D is synthesized in theskin with the help of the natural ultraviolet wavelength of sunlight. Humans can producesome vitamins from precursors they consume. Examples include vitamin A, produced

from beta carotene, and niacin, from the amino acid tryptophan.[22]

Once growth and development are completed, vitamins remain essential nutrients forthe healthy maintenance of the cells, tissues, and organs that make up a multicellularorganism; they also enable a multicellular life form to efficiently use chemical energyprovided by food it eats, and to help process the proteins, carbohydrates, and fats

required for respiration.[6]

DeficienciesBecause human bodies do not store most vitamins, humans must consume themregularly to avoid deficiency. Human bodily stores for different vitamins vary widely;vitamins A, D, and B12 are stored in significant amounts in the human body, mainly in

the liver,[32] and an adult human's diet may be deficient in vitamins A and B12 for many

months before developing a deficiency condition. Vitamin B3 is not stored in the human

body in significant amounts, so stores may only last a couple of weeks.[23][32]

Deficiencies of vitamins are classified as either primary or secondary. A primarydeficiency occurs when an organism does not get enough of the vitamin in its food. Asecondary deficiency may be due to an underlying disorder that prevents or limits theabsorption or use of the vitamin, due to a “lifestyle factor”, such as smoking, excessivealcohol consumption, or the use of medications that interfere with the absorption or use

of the vitamin.[32] People who eat a varied diet are unlikely to develop a severe primaryvitamin deficiency. In contrast, restrictive diets have the potential to cause prolongedvitamin deficits, which may result in often painful and potentially deadly diseases.

Well-known human vitamin deficiencies involve thiamine (beriberi), niacin (pellagra),vitamin C (scurvy) and vitamin D (rickets). In much of the developed world, suchdeficiencies are rare; this is due to (1) an adequate supply of food; and (2) the addition

of vitamins and minerals to common foods, often called fortification.[22][32] In addition tothese classical vitamin deficiency diseases, some evidence has also suggested links

between vitamin deficiency and a number of different disorders.[36][37]

Side effects and overdoseIn large doses, some vitamins have documented side effects that tend to be moresevere with a larger dosage. The likelihood of consuming too much of any vitamin fromfood is remote, but overdosing from vitamin supplementation does occur. At highenough dosages some vitamins cause side effects such as nausea, diarrhea, and

vomiting.[23][38]

When side effects emerge, recovery is often accomplished by reducing the dosage. Theconcentrations of vitamins an individual can tolerate vary widely, and appear to be

related to age and state of health.[39] In the United States, overdose exposure to allformulations of vitamins was reported by 62,562 individuals in 2004 (nearly 80% ofthese exposures were in children under the age of 6), leading to 53 "major" life-

threatening outcomes and 3 deaths[40];a small number in comparison to the 19,250people who died of unintentional poisoning of all kinds in the U.S. in the same year

(2004).[41]

SupplementsDietary supplements, often containing vitamins, are used to ensure that adequateamounts of nutrients are obtained on a daily basis, if optimal amounts of the nutrientscannot be obtained through a varied diet. Scientific evidence supporting the benefits ofsome vitamin supplements is well established for certain health conditions, but others

need further study.[42] In some cases, vitamin supplements may have unwanted effects,especially if taken before surgery, with other dietary supplements or medicines, or if the

person taking them has certain health conditions.[42] Dietary supplements may alsocontain levels of vitamins many times higher, and in different forms, than one may

ingest through food.[43]

A meta-analysis published in 2006 suggested that Vitamin A and E supplements notonly provide no tangible health benefits for generally healthy individuals, but mayactually increase mortality, although two large studies included in the analysis involvedsmokers, for which it was already known that beta-carotene supplements can be

harmful.[44] Another study released in May 2009 found that antioxidants such as

vitamins C and E may actually curb some benefits of exercise.[45]

Governmental regulation of vitamin supplementsMost countries place dietary supplements in a special category under the generalumbrella of foods, not drugs. This necessitates that the manufacturer, and not thegovernment, be responsible for ensuring that its dietary supplement products are safebefore they are marketed. Unlike drug products, which must explicitly be proven safeand effective for their intended use before marketing, there are often no provisions to"approve" dietary supplements for safety or effectiveness before they reach theconsumer. Also unlike drug products, manufacturers and distributors of dietarysupplements are not generally required to report any claims of injuries or illnesses that

may be related to the use of their products.[46][47][42]

Nomenclature of reclassified vitamins

Previous name Chemical name Reason for name change[48]

Vitamin B4 Adenine DNA metabolite

Vitamin B8 Adenylic acid DNA metabolite

Vitamin F Essential fatty acids Needed in large quantities (doesnot fit the definition of a vitamin).

Vitamin G Riboflavin Reclassified as Vitamin B2

Vitamin H Biotin Reclassified as Vitamin B7

Vitamin J Catechol, Flavin Protein metabolite

Vitamin L1[49] Anthranilic acid Protein metabolite

Vitamin L2[49] Adenylthiomethylpentose RNA metabolite

Vitamin M Folic acid Reclassified as Vitamin B9

Vitamin O Carnitine Protein metabolite

Vitamin P Flavonoids No longer classified as a vitamin

Vitamin PP Niacin Reclassified as Vitamin B3

Vitamin U S-Methylmethionine Protein metabolite

Names in current and previous nomenclaturesThe reasonthe set ofvitaminsseems toskip directlyfrom E to Kis that thevitamins

corresponding to "letters" F-J were either reclassified over time, discarded as falseleads, or renamed because of their relationship to "vitamin B", which became a"complex" of vitamins. The German-speaking scientists who isolated and describedvitamin K (in addition to naming it as such) did so because the vitamin is intimatelyinvolved in the Koagulation of blood following wounding. At the time, most (but not all)of the letters from F through to J were already designated, so the use of the letter K

was considered quite reasonable.[48][50] The table on the right lists chemicals that hadpreviously been classified as vitamins, as well as the earlier names of vitamins that laterbecame part of the B-complex.

See alsoAntioxidantDietary supplementDieteticsHealth freedom movementIllnesses related to poor nutritionMegavitamin therapyNutrition

Vitamin deficiencyDietary mineralsEssential amino acidsEssential nutrientsNootropicsNutrients

Orthomolecular medicinePharmacologyVitamin poisoning (overdose)Whole food supplements

References1. ↑ Lieberman, S, Bruning, N (1990). The Real Vitamin & Mineral Book. NY: Avery Group, 3.

2. ↑ Schuman, N, (1998). A History Of COntemplative Medicine. DC: Moseby, 1.

3. ↑ vitamin - definition of vitamin by the Free Online Dictionary, Thesaurus and Encyclopedia

4. ↑

5. ↑ "vitamer: Definition and Much More from Answers.com". www.answers.com.http://www.answers.com/topic/vitamer?cat=health#top. Retrieved 2008-06-16.

6. ↑ 6.0 6.1 Bender, David A. (2003). Nutritional biochemistry of the vitamins. Cambridge, U.K.: CambridgeUniversity Press. ISBN 978-0-521-80388-5.

7. ↑ Bolander FF (2006). "[Expression error: Missing operand for > Vitamins: not just for enzymes]". CurrOpin Investig Drugs 7 (10): 912–5. PMID 17086936.

8. ↑ Kirk-Othmer (1984). Encyclopedia of Chemical Technology Third Edition. NY: John Wiley and Sons, Vol.24:104.

9. ↑ 9.0 9.1 9.2 9.3 9.4 Jack Challem (1997). "The Past, Present and Future of Vitamins"

10. ↑ Jacob, RA. (1996). "[Expression error: Missing operand for > Three eras of vitamin C discovery.]".Subcell Biochem 25 : 1-16. PMID 8821966.

11. ↑ Bellis, Mary. Vitamins - Production Methods The History of the Vitamins. Retrieved 1 February 2005.

12. ↑ 12.0 12.1 1929 Nobel lecture

13. ↑ 13.0 13.1 Rosenfeld, L. (Apr 1997). "[Expression error: Missing operand for > Vitamine--vitamin. Theearly years of discovery.]". Clin Chem 43 (4): 680-5. PMID 9105273.

14. ↑ 14.0 14.1 Carpenter, Kenneth (22 June 2004). "The Nobel Prize and the Discovery of Vitamins".http://nobelprize.org/nobel_prizes/medicine/articles/carpenter/index.html. Retrieved 5 October 2009.

15. ↑ Tokyo Kagaku Kaishi: (1911)

16. ↑ Funk, C. and H. E. Dubin. The Vitamines. Baltimore: Williams and Wilkins Company, 1922.

17. ↑ Fukuwatari T, Shibata K (June 2008). "Urinary water-soluble vitamins and their metabolite contents as

nutritional markers for evaluating vitamin intakes in young Japanese women" ( – Scholar search). J. Nutr. Sci.Vitaminol. 54 (3): 223–9. doi:10.3177/jnsv.54.223. PMID 18635909.http://joi.jlc.jst.go.jp/JST.JSTAGE/jnsv/54.223?from=PubMed.

18. ↑ "Water-Soluble Vitamins". http://www.ext.colostate.edu/PUBS/FOODNUT/09312.html. Retrieved 2008-12-07.

19. ↑ Said HM, Mohammed ZM (March 2006). "Intestinal absorption of water-soluble vitamins: an update".Curr. Opin. Gastroenterol. 22 (2): 140–6. doi:10.1097/01.mog.0000203870.22706.52. PMID 16462170.http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00001574-200603000-00011.

20. ↑ Maqbool A, Stallings VA (November 2008). "Update on fat-soluble vitamins in cystic fibrosis". Curr OpinPulm Med 14 (6): 574–81. doi:10.1097/MCP.0b013e3283136787. PMID 18812835.http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00063198-200811000-00012.

21. ↑ Kutsky, R.J. (1973). Handbook of Vitamins and Hormones. New York:Van Nostrand Reinhold.

22. ↑ 22.0 22.1 22.2 22.3 Dietary Reference Intakes: Vitamins The National Academies, 2001.

23. ↑ 23.0 23.1 23.2 Vitamin and Mineral Supplement Fact Sheets Vitamin A

24. ↑ N/D= "Amount not determinable due to lack of data of adverse effects. Source of intake should be fromfood only to prevent high levels of intake"(see Dietary Reference Intakes: Vitamins).

25. ↑ "Thiamin, vitamin B1: MedlinePlus Supplements".http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-thiamin.html. Retrieved 5 October 2009.

26. ↑ J.G. Hardman et al., eds., Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th ed.,p.992.

27. ↑ Plain type indicates Adequate Intakes (A/I). "The AI is believed to cover the needs of all individuals, but alack of data prevent being able to specify with confidence the percentage of individuals covered by thisintake" (see Dietary Reference Intakes: Vitamins).

28. ↑ "Pantothenic acid, dexpanthenol: MedlinePlus Supplements".http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitaminb5.html. Retrieved 5 October 2009.

29. ↑ Vitamin and Mineral Supplement Fact Sheets Vitamin B6

30. ↑ 30.0 30.1 Vitamin and Mineral Supplement Fact Sheets Vitamin B12

31. ↑ Value represents suggested intake without adequate sunlight exposure (see Dietary Reference Intakes:Vitamins).

32. ↑ 32.0 32.1 32.2 32.3 32.4 The Merck Manual: Nutritional Disorders: Vitamin Introduction Please select specificvitamins from the list at the top of the page.

33. ↑ http://findarticles.com/p/articles/mi_m0ISW/is_262/ai_n13675725,

34. ↑ Rohde LE, de Assis MC, Rabelo ER (January 2007). "[Expression error: Missing operand for > Dietaryvitamin K intake and anticoagulation in elderly patients]". Curr Opin Clin Nutr Metab Care 10 (1): 1–5.doi:10.1097/MCO.0b013e328011c46c. PMID 17143047.

35. ↑ Dr. Leonid A. Gavrilov, Pieces of the Puzzle: Aging Research Today and Tomorrow

36. ↑ Lakhan SE; Vieira KF. Nutritional therapies for mental disorders. Nutrition Journal 2008;7(2).

37. ↑ Boy, E.; Mannar, V.; Pandav, C.; de Benoist, B.; Viteri, F.; Fontaine, O.; Hotz, C. (May 2009)."[Expression error: Missing operand for > Achievements, challenges, and promising new approaches invitamin and mineral deficiency control.]". Nutr Rev 67 Suppl 1: S24-30. doi:10.1111/j.1753-4887.2009.00155.x. PMID 19453674.

38. ↑ Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K,Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, andZinc. National Academy Press, Washington, DC, 2001.

39. ↑ Healthier Kids Section: What to take and how to take it.

40. ↑ 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure SurveillanceSystem.

41. ↑ National Center for Health Statistics

42. ↑ 42.0 42.1 42.2 Use and Safety of Dietary Supplements NIH office of Dietary Supplements.

43. ↑ Jane Higdon Vitamin E recommendations at Linus Pauling Institute's Micronutrient Information Center

44. ↑ Bjelakovic G, et al. (2007). "[Expression error: Missing operand for > Mortality in randomized trials ofantioxidant supplements for primary and secondary prevention: systematic review and meta-analysis]".JAMA 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526.. See also the letter to JAMA byPhilip Taylor and Sanford Dawsey and the reply by the authors of the original paper.

45. ↑ http://www.nytimes.com/2009/05/12/health/research/12exer.html?em=&pagewanted=print

46. ↑ Overview of Dietary Supplements

47. ↑ Illnesses and Injuries Associated with the Use of Selected Dietary Supplements U. S. FDA Center forFood Safety and Applied Nutrition

48. ↑ 48.0 48.1 Every Vitamin Page All Vitamins and Pseudo-Vitamins. Compiled by David Bennett.

49. ↑ 49.0 49.1 Michael W. Davidson (2004) Anthranilic Acid (Vitamin L) Florida State University. Accessed 20-02-07

50. ↑ Vitamins and minerals - names and facts

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VITAMIN K

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=13960

BIOTIN

Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk. The biotin content of cancerous tissue is higher than that of normal tissue.

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=30059

VITAMIN E

A natural fat-soluble antioxidant with potential chemopreventive activity. Also known as tocopherol, vitamin E ameliorates free-radical damage to biological membranes, protecting polyunsaturated fatty acids (PUFA) within membrane phospholipids and within circulating lipoproteins. Peroxyl radicals react 1000-fold faster with vitamin E than with PUFA. In the case of oxygen free radical-mediated tumorigenesis, vitamin E may be chemopreventive. (NCI04)

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=29263

VITAMIN D3

A steroid hormone produced in the skin when exposed to ultraviolet light or obtained from dietary sources. The active form of cholecalciferol, 1,25-dihydroxycholecalciferol (calcitriol) plays an important role in maintaining blood calcium and phosphorus levels and mineralization of bone. The activated form of cholecalciferol binds to vitamin D receptors and modulates gene expression. This leads to an increase in serum calcium concentrations by increasing intestinal absorption of phosphorus and calcium, promoting distal renal tubular reabsorption of calcium and increasing osteoclastic resorption

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=29922

VITAMIN D2

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=30692

Vitamin D2, a fat-soluble vitamin important for many biochemical processes including the absorption and metabolism of calcium and phosphorus. In vivo, ergocalciferol is formed after sun (ultraviolet) irradiation of plant-derived ergosterol, another form of vitamin D. Ergocalciferol is the form of vitamin D usually found in vitamin supplements. (NCI04)

VITAMIN D

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=13939

A family of lipo-soluble steroids important to the absorption, metabolism, and function of calcium and phosphorus and the growth and development of bone and tooth enamel. Found naturally in animal tissues, cholecalciferol (vitamin D3) is formed in the skin when ultraviolet light activates cholesterol conversion into vitamin D3. Ultraviolet irradiation of ergosterol (plant vitamin D) forms ergocalciferol (vitamin D2). (NCI04)

VITAMIN C

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=13926

DEFICIENCY : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=13930

A natural water-soluble vitamin (Vitamin C). Ascorbic acid is a potent reducing and antioxidant agent that functions in fighting bacterial infections, in detoxifying reactions, and in the formation of collagen in fibrous tissue, teeth, bones, connective tissue, skin, and capillaries. Found in citrus and other fruits, and in vegetables, vitamin C cannot be produced or stored by humans and must be obtained in the diet. (NCI04)

Ascorbic Acid Deficiency: "A condition due to a dietary deficiency of ascorbic acid (vitamin C), characterized by malaise, lethargy, and weakness. As the disease progresses, joints, muscles, and subcutaneous tissues may become the sites of hemorrhage. Ascorbic acid deficiency frequently develops into SCURVY in young children fed unsupplemented cow's milk exclusively during their first year. It develops also commonly in chronic alcoholism. (Cecil Textbook of Medicine, 19th ed, p1177)

An acquired blood vessel disorder caused by severe deficiency of vitamin C (ASCORBIC ACID) in the diet leading to defective collagen formation in small blood vessels. Scurvy is characterized by bleeding in any tissue, weakness, ANEMIA, spongy gums, and a brawny induration of the muscles of the calves and legs

VITAMIN B6

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=29549

A group of water-soluble vitamins essential for metabolism and normal physiological functions. B6 vitamins, including pyridoxine, pyridoxal, and pyridoxamine, are converted in vivo to pyridoxal phosphate, a cofactor necessary for the synthesis of amino acids, neurotransmitters, and sphingolipids. More than 100 enzymes involved in protein metabolism require vitamin B6 as a cofactor. Vitamin B6 is essential to red blood cell, nervous system, and immune systems functions and helps maintain normal blood glucose levels. Vitamin B6 is found in a wide variety of foods including cereals, beans, meat, poultry, fish, and some fruits and vegetables. (NCI04)

VITAMIB B5

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=31607

The calcium salt of the water-soluble vitamin B5, ubiquitously found in plants and animal tissues with antioxidant property. Pentothenate is a component of coenzyme A (CoA) and a part of the vitamin B2 complex. Vitamin B5 is a growth factor and is essential for various metabolic functions, including the metabolism of carbohydrates, proteins, and fatty acids. This vitamin is also involved in the synthesis of cholesterol, lipids, neurotransmitters, steroid hormones, and hemoglobin.

VITAMIN B3

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=9007

A water-soluble vitamin belonging to the vitamin B family, which occurs in many animal and plant tissues, with antihyperlipidemic activity. Niacin is converted to its active form niacinamide, which is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and its phosphate form, NADP. These coenzymes play an important role in tissue respiration and in glycogen, lipid, amino acid, protein, and purine metabolism. Although the exact mechanism of action by which niacin lowers cholesterol is not fully understood, it may act by inhibiting the synthesis of very low density lipoproteins (VLDL), inhibiting the release of free fatty acids from adipose tissue, increasing lipoprotein lipase activity, and reducing the hepatic synthesis of VLDL-C and LDL-C

VITAMIN B2

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An essential human nutrient that is a heat-stable and water-soluble flavin belonging to the vitamin B family. Riboflavin is a precursor of the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These coenzymes are of vital importance in normal tissue respiration, pyridoxine activation, tryptophan to niacin conversion, fat, carbohydrate, and protein metabolism, and glutathione reductase mediated detoxification. Riboflavin may also be involved in maintaining erythrocyte integrity. This vitamin is essential for healthy skin, nails, and hair.

VITAMIN B1

LINKS : http://www.diseasesdatabase.com/links1.asp?glngUserChoice=13032

A heat-labile and water-soluble essential vitamin, belonging to the vitamin B family, with antioxidant, erythropoietic, mood modulating, and glucose-regulating activities. Thiamine reacts with adenosine triphosphate (ATP) to form an active coenzyme, thiamine pyrophosphate. Thiamine pyrophosphate is necessary for the actions of pyruvate dehydrogenase and alpha-ketoglutarate in carbohydrate metabolism and for the actions of transketolase, an enzyme that plays an important role in the pentose phosphate pathway. Thiamine plays a key role in intracellular glucose metabolism and may inhibit the action of glucose and insulin on arterial smooth muscle cell proliferation. Thiamine may also protect against lead toxicity by inhibiting lead-induced lipid peroxidation

VITAMIN A

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An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE

ΌΛΑ ΤΑΑΠΟΤΕΛΈΣΜΑΤΑ

BingBeta

Αναφορά

Biotin[1]

IUPAC name 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid

Other names Vitamin B7; Vitamin H; Coenzyme R; Biopeiderm

IdentifiersCAS number 58-85-5 PubChem 171548SMILES O=C1N[C@@H]2[C@@H](SC[C@@H]2N1)CCCCC(=O)OInChI 1/C10H16N2O3S/c13-8(14)4-2-1-3-7-9-6(5-16-7)11-

10(15)12-9/h6-7,9H,1-5H2,(H,13,14)(H2,11,12,15)/t6-,7-,9-/m0/s1

InChI key YBJHBAHKTGYVGT-ZKWXMUAHBB

ChemSpider ID 149962Properties

Molecularformula

C10H16N2O3S

Molar mass 244.31 g mol−1

Appearance White crystalline needlesMelting point 232-233 °C

Solubility inwater

22 mg/100 mL

Supplementary data pageStructure andproperties

n, εr, etc.

Thermodynamicdata

Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for materials in their

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Biotinview original wikipedia article

This article needs additional citations for verification.Please help improve this article by adding reliable references. Unsourced material may bechallenged and removed. (April 2007)

Biotin, also known asvitamin H or B7, is a

water-soluble B-complex vitaminwhich is composed ofan ureido

(tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. A valeric acidsubstituent is attached to one of the carbon atoms of the tetrahydrothiophene ring. Biotinis a cofactor in the metabolism of fatty acids and leucine, and it plays a role ingluconeogenesis.

General overviewBiotin is necessary for cell growth, the production of fatty acids, and the metabolism offats and amino acids. It plays a role in the citric acid cycle, which is the process bywhich biochemical energy is generated during aerobic respiration. Biotin not only assistsin various metabolic reactions, but also helps to transfer carbon dioxide. Biotin is alsohelpful in maintaining a steady blood sugar level.[1] Biotin is often recommended forstrengthening hair and nails. Consequently, it is found in many cosmetics and health

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BiotinGeneral overview

Bioavailability

Factors that affect biotin requirements

Uses

Hair problems

Cradle cap (seborrheic dermatitis)

Diabetes

Deficiency

Toxicity

Biochemistry

Laboratory uses

Ruminant nutrition

See also

References

External links

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products for the hair and skin.

Biotin deficiency is rare, as intestinal bacteria generally produce an excess of the body'srecommended daily requirement. For that reason, statutory agencies in many countries(e.g., the Australian Department of Health and Ageing) do not prescribe a recommendeddaily intake of Biotin.

BioavailabilityStudies on the bioavailability of biotin have been conducted in rats and in chicks. Fromthese studies, it was concluded that biotin bioavailability may be low or variabledepending on the type of food being consumed. In general, biotin exists in food as

protein bound form or biocytin [2]. Proteolysis by protease is required prior to absorption.This process assists free biotin release from biocytin and protein bound biotin.The biotinpresent in corn is readily available; however, most grain have about a 20-40%

bioavailability of biotin.[3]

A possible explanation for the wide variability in biotin bioavailability is that it is due toability of an organism to break various biotin-protein bonds from food. Whether anorganism has an enzyme with the ability to break that bond will determine the

bioavailability of biotin from the foodstuff.[3]

Factors that affect biotin requirementsThe frequency of marginal biotin status is not known, but the incidence of low circulatingbiotin levels in alcoholics has been found to be much greater than in the generalpopulation. Also, relatively low levels of biotin have been reported in the urine or plasmaof patients who have had partial gastrectomy or who have other causes of achlorhydria,

burn patients, epileptics, elderly individuals and athletes.[3] Pregnancy and lactationmay be associated with an increased demand for biotin. In pregnancy, this may be dueto a possible acceleration of biotin catabolism, whereas in lactation, the higher demandhas yet to be elucidated. Recent studies have shown that marginal biotin deficiency canbe present in human gestation, as evidenced by increased urinary excretion of 3-hydroxyisovaleric acid, decreased urinary excretion of biotin and bisnorbiotin, anddecreased plasma concentration of biotin. Additionally, smoking may further accelerate

biotin catabolism in women.[4]

Uses

Hair problemsBiotin supplements are often recommended as a natural product to counteract theproblem of hair loss in both children and adults. The signs and symptoms of biotindeficiency include hair loss which progresses in severity to include loss of eye lashesand eye brows in severely deficient subjects. Some shampoos are available that containbiotin, but it is doubtful whether they would have any useful effect, as biotin is notabsorbed well through the skin.

Cradle cap (seborrheic dermatitis)Children with a rare inherited metabolic disorder called phenylketonuria (PKU; in whichone is unable to break down the amino acid phenylalanine) often develop skinconditions such as eczema and seborrheic dermatitis in areas of the body other thanthe scalp. The scaly skin changes that occur in people with PKU may be related to poorability to use biotin. Increasing dietary biotin has been known to improve seborrheic

dermatitis[5] in these cases.

DiabetesDiabetics may also benefit from biotin supplementation. In both insulin-dependent andnon-insulin-dependent diabetes, supplementation with biotin can improve blood sugarcontrol and help lower fasting blood glucose levels, in some studies the reduction infasting glucose exceeded 50 percent. Biotin can also play a role in preventing theneuropathy often associated with diabetes, reducing both the numbness and tingling

associated with poor glucose control.[6]

DeficiencyBiotin deficiency is relatively rare and mild, and can be addressed with supplementation.Such deficiency can be caused by the excessive consumption of raw egg whites (20eggs/day would be required to induce it), which contain high levels of the protein avidin,which binds biotin strongly. Avidin is deactivated by cooking, while the biotin remainsintact.

¨Symptoms of overt biotin deficiency include hair loss and a scaly red rash around theeyes, nose, mouth, and genital area. Neurological symptoms in adults have includeddepression, lethargy, hallucination, and numbness and tingling of the extremities. Thecharacteristic facial rash, together with an unusual facial fat distribution, has beentermed the ¨biotin-deficient face¨ by some experts. Individuals with hereditary disordersof biotin deficiency have evidence of impaired immune system function, including

increased susceptibility to bacterial and fungal infections.¨[7]

Biotinidase deficiency is not due to inadequate biotin, but rather to a deficiency in theenzymes that process it.

Signs of Biotin Deficiency: In general, appetite and growth are decreased. Dermatologicsymptoms include dermatitis, alopecia (hair loss) and achromotrichia (absence or loss

of pigment in the hair.[8]) Perosis (a shortening and thickening of bones) is seen in theskeleton. Fatty Liver and Kidney Syndrome (FLKS) and hepatic steatosis also can

occur.[3] Genetic defect could also cause biotin deficiency. Holocarboxylase synthetasedeficiency is a genetic mutation. It is a severe metabolic disorder. Biochemical andclinical manifestation includes: ketolactic acidosis, organic aciduria, hyperammonemia,skin rash, feeding problems, hypotonie, seizures, development delay, alopecia, andcoma. This disease is lethal, however, mentioned manifestation can be reversed bypharmacologic doses of biotin (10-100 mg per day).

Pregnant women tend to have high risk of biotin deficiency. Research has shown thatnearly half of pregnant women have an abnormal increase of 3-hydroxyisovaleric acid

which reflects reduced status of biotin.[7]

Numbers of studies reported that this possible biotin deficiency during the pregnancymay cause infants' congenital malformations such as cleft palate. Mice fed with driedraw egg to induce biotin deficiency during the gestation resulted in up to 100%incidence of the infants' malnourishment. Infants and embryos are more sensitive to thebiotin deficiency. Therefore even a mild level of mother's biotin deficiency which doesnot reach the appearance of physiological deficiency signs may cause a seriousconsequence in the infants.

ToxicityAnimal studies have indicated few, if any, effects due to toxic doses of biotin. This mayprovide evidence that both animals and humans could tolerate doses of at least anorder of magnitude greater than each of their nutritional requirements. There are noreported cases of adverse effects from receiving high doses of the vitamin, particularlywhen used in the treatment of metabolic disorders causing sebhorrheic dermatitis in

infants.[9]

BiochemistryBiotin D(+) is a cofactor responsible for carbon dioxide transfer in several carboxylaseenzymes:

Acetyl-CoA carboxylase alphaAcetyl-CoA carboxylase betaMethylcrotonyl-CoA carboxylasePropionyl-CoA carboxylasePyruvate carboxylase

The attachment of biotin to various chemical sites, called biotinylation, can be used asan important laboratory technique to study various processes including proteinlocalization, protein interactions, DNA transcription and replication. Biotinidase itself is

known to be able to biotinylate histones,[10] but little biotin is found naturally attached tochromatin. Holocarboxylase synthetase is the mammalian enzyme that covalently

attaches biotin to carboxylases.

Biotin binds very tightly to the tetrameric protein avidin (also streptavidin and

neutravidin), with a dissociation constant Kd in the order of 10−15 which is one of the

strongest known protein-ligand interactions, approaching the covalent bond in

strength.[11] This is often used in different biotechnological applications. Until 2005, very

harsh conditions were required to break the biotin-streptavidin bond.[12]

Laboratory usesIn the biology laboratory, biotin is often chemically linked, or tagged, to a molecule orprotein for biochemical assays. This process is called biotinylation. Because avidins bindpreferentially to biotin, biotin-tagged molecules can be extracted from a sample bymixing them with beads with covalently-attached avidin, and washing away anythingunbound to the beads.

For example, biotin can be attached to a molecule of interest (e.g. a protein), and thismodified molecule will be mixed with a complex mixture of proteins. Avidin orstreptavidin beads are added to the mixture, and the biotinylated molecule will bind tothe beads. Any other proteins binding to the biotinylated molecule will also stay with thebeads. All other unbound proteins can be washed away, and the scientist can use avariety of methods to determine which proteins have bound to the biotinylated molecule.

Biotinylated antibodies are used to capture avidin or streptavidin in both the ELISPOTand ELISA techniques.

Ruminant nutritionRuminal bacteria normally synthesize biotin. Biotin is not extensively metabolized in therumen and increased intake of dietary biotin results in elevated concentrations of biotin

in serum and milk.[13] Unpublished epidemiologic data suggest a negative relationshipbetween serum concentrations of biotin and the incidence of clinical lameness in dairycattle. Feeding approximately 20 mg/day of supplemental biotin statistically improvedmeasures of hoof health. Currently, insufficient data are available at this time to quantifythe requirement for biotin of dairy cattle.

See alsoBiotinylationAvidinStreptavidinNeutrAvidinStrep-tagMultiple carboxylase deficiency

References1. ↑ Merck Index, 11th Edition, 1244.

2. ↑ Gropper S.S., Smith, J.L.,Groff, J.L. (2005). Advanced nutrition and human metabolism . Belmont.

3. ↑ 3.0 3.1 3.2 3.3 Combs, Gerald F. Jr. (2008). The Vitamins: Fundamental Aspects in Nutrition and Health.San Diego: Elsevier, Inc. ISBN 9780121834937.

4. ↑ Bowman, BA and Russell, RM., ed (2006). "Biotin". Present Knowledge in Nutrition, Ninth Edition, Vol 1.Washington, DC: Internation Life Sciences Institute. ISBN 9781578811984.

5. ↑ Murray, Michael; Pizzorno, Joseph (1997). "Encyclopedia of Natural Medicine" (Revised 2nd Edition)Three Rivers Press. ISBN 0761511571

6. ↑ http://recipes.howstuffworks.com/biotin2.htm

7. ↑ 7.0 7.1 Higdon, Jane (2003). "Biotin". An evidence-based approach to vitamins and minerals. Thieme.ISBN 9781588901248.

8. ↑ biology-online.org

9. ↑ Combs, Gerald F. Jr. (1998). The Vitamins: Fundamental Aspects in Nutrition and Health. Ithaca: ElsevierAcademic Press. ISBN 0121834921.pg. 360

10. ↑ Hymes, J; Fleischhauer, K; Wolf, B. (1995). "[Expression error: Missing operand for > Biotinylation ofhistones by human serum biotinidase: assessment of biotinyl-transferase activity in sera from normalindividuals and children with biotinidase deficiency.]". Biochem Mol Med. 56 (1): 76–83.doi:10.1006/bmme.1995.1059. PMID 8593541.

11. ↑ Laitinen OH, Hytonen VP, Nordlund HR, Kulomaa MS. (2006). "[Expression error: Missing operand for> Genetically engineered avidins and streptavidins.]". Cell Mol Life Sci. 63 (24): 2992–3017.doi:10.1007/s00018-006-6288-z. PMID 17086379.

12. ↑ Holmberg A, Blomstergren A, Nord O et al. (2005). "[Expression error: Missing operand for > The

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biotin-streptavidin interaction can be reversibly broken using water at elevated temperatures]".Electrophoresis 26 (3): 501–10. doi:10.1002/elps.200410070. PMID 15690449.

13. ↑ National Research Council (2001). Nutrient Requirements of Dairy Cattle. 7th rev. ed.. Natl. Acad. Sci.,Washington, DC.. ISBN 0309069971. http://books.nap.edu/openbook.php?isbn=0309069971.

External linksJane Higdon, "Biotin", Micronutrient Information Center, Linus Pauling InstituteClercq, Pierre J. De (1997). "[Expression error: Missing operand for > Biotin: ATimeless Challenge for Total Synthesis]". Chemical Review 97: 1755–1792.doi:10.1021/cr950073e.

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Vitamin Eview original wikipedia article

Main articles: tocopherol andtocotrienolVitamin E is a generic termfor tocopherols and

tocotrienols.[1] Vitamin E is afamily of α-, β-, γ-, andδ-tocopherols andcorresponding fourtocotrienols. Vitamin E is a fat-soluble antioxidant that stops the production of reactive

oxygen species formed when fat undergoes oxidation.[2][3][4] Of these, α-tocopherol(also written as alpha-tocopherol) has been most studied as it has the highest

bioavailability.[5]

It has been claimed that α-tocopherol is the most important lipid-soluble antioxidant,and that it protects cell membranes from oxidation by reacting with lipid radicals

produced in the lipid peroxidation chain reaction.[3][6] This would remove the freeradical intermediates and prevent the oxidation reaction from continuing. The oxidisedα-tocopheroxyl radicals produced in this process may be recycled back to the activereduced form through reduction by other antioxidants, such as ascorbate, retinol or

ubiquinol.[7] However, the importance of the antioxidant properties of this molecule atthe concentrations present in the body are not clear and it is possible that the reason

why vitamin E is required in the diet is unrelated to its ability to act as an antioxidant.[8].Other forms of vitamin E have their own unique properties. For example, γ-tocopherol(also written as gamma-tocopherol) is a nucleophile that can react with electrophilic

mutagens.[5]

However, the roles and importance of all of the various forms of vitamin E are presently

unclear,[9][10] and it has even been suggested that the most important function ofvitamin E is as a signaling molecule, and that it has no significant role in antioxidant

metabolism.[11][12]

So far, most studies about vitamin E have supplemented using only the synthetic alpha-tocopherol, but doing so leads to reduced serum gamma- and delta-tocopherolconcentrations. Moreover, a 2007 clinical study involving synthetic alpha-tocopherolconcluded that supplementation did not reduce the risk of major cardiovascular events

in middle aged and older men.[13] For more info, read article tocopherol.

Compared with tocopherols, tocotrienols are poorly studied.[14][15][16] Less than 1% of

PubMed papers on vitamin E relate to tocotrienols.[17] Current research direction arestarting to give more prominence to the tocotrienols, the lesser known but more potentantioxidants in the vitamin E family. Tocotrienols have specialized roles in protecting

neurons from damage[18], cancer prevention[19] and cholesterol reduction[20] byinhibiting the activity of HMG-CoA reductase[16-1];δ-tocotrienol blocks processing ofsterol regulatory element-binding proteins (SREBPs)[16-1].

Oral consumption of tocotrienols is also proven to protect against stroke-associatedbrain damage in vivo. Disappointments with outcomes-based clinical studies testing theefficacy of α-tocopherol need to be handled with caution and prudence recognizing the

untapped opportunities offered by the other forms of natural vitamin E.[21] Toxicitystudies of a specific form of tocopherol in excess should not be used to conclude thathigh-dosage “vitamin E” supplementation may increase all-cause mortality. Suchconclusion incorrectly implies that tocotrienols are toxic as well under conditions where

tocotrienols were not even considered.[22] For more info, read article tocotrienol.

Food sources of Vitamin EParticularly high levels of vitamin E can be found in the following foods:[23]

The α-tocopherol form of vitamin E.

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Vitamin EFood sources of Vitamin E

Vitamin E to prevent prostate cancer studdiscontinued

Congenital heart defects

References

Further reading

External links

2 LocationsNetherlands,United Kingdomview all

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AsparagusAvocadoEggMilkNuts, such as almonds or hazelnutsSeedsSpinach and other green leafy vegetablesUnheated vegetable oilsWheat germWholegrain foods

Vitamin E to prevent prostate cancer studydiscontinuedThere have been some theories that Vitamin E, especially when coupled with selenium,

may reduce the risk of prostate cancer[24] by 30 percent.[25] However, the Seleniumand Vitamin E Cancer Prevention Trial, ("SELECT"), run from 2004 to 2008, found thatvitamin E, whether taken alone or in combination with selenium, did not prevent

prostate cancer.[26] The SELECT study was discontinued after independent reviewersdetermined that there was no benefit to the 35,000 men who were the subject of the

study. [24]

Congenital heart defectsA case control study done in the Netherlands using food frequency questionnairesfound that high maternal Vitamin E by diet and supplements is associated with anincreased risk of CHD (congenital heart defects) offspring, especially when the

supplements are taken in the periconception period.[27] (Note: case control studies are

rated as low quality, grade 3 or 4, on a standard scale of medical evidence.[28]) TheNational Health Service in the United Kingdom concludes that pregnant women should:

"consider avoiding taking supplemental Vitamin E tablets."[29]

References1. ↑ Brigelius-Flohe, Regina (1999). "Vitamin E: function and metabolism". <I>The FASEB Journal</I> 13

(10): 1145. PMID 10385606. http://www.fasebj.org/cgi/content/short/13/10/1145.

2. ↑ National Institute of Health (5/4/2009). "Vitamin E Fact Sheet".http://ods.od.nih.gov/factsheets/VitaminE.asp.

3. ↑ 3.0 3.1 Herrera (2001). "[Expression error: Missing operand for > Vitamin E: action, metabolism andperspectives]". Journal of physiology and biochemistry 57 (2): 43–56. PMID 11579997.

4. ↑ Packer, Lester (2001). "Molecular Aspects of α-Tocotrienol Antioxidant Action and Cell Signalling".Journal of Nutrition 131 (2): 369S. PMID 11160563. http://jn.nutrition.org/cgi/content/full/131/2/369S.

5. ↑ 5.0 5.1 Brigelius-Flohé (1999). "[Expression error: Missing operand for > Vitamin E: function andmetabolism]". The FASEB journal : official publication of the Federation of American Societies forExperimental Biology 13 (10): 1145–55. PMID 10385606.

6. ↑ Traber (2007). "[Expression error: Missing operand for > Vitamin E, antioxidant and nothing more]".Free radical biology & medicine 43 (1): 4–15. doi:10.1016/j.freeradbiomed.2007.03.024. PMID 17561088.

7. ↑ Wang (1999). "[Expression error: Missing operand for > Vitamin E and its function in membranes]".Progress in lipid research 38 (4): 309–36. doi:10.1016/S0163-7827(99)00008-9. PMID 10793887.

8. ↑ Brigelius-Flohé (2009). "[Expression error: Missing operand for > Vitamin E: the shrew waiting to betamed]". Free radical biology & medicine 46 (5): 543–54. doi:10.1016/j.freeradbiomed.2008.12.007. PMID19133328.

9. ↑ Brigelius-Flohé (2007). "[Expression error: Missing operand for > Is vitamin E an antioxidant, aregulator of signal transduction and gene expression, or a 'junk' food? Comments on the twoaccompanying papers: "Molecular mechanism of alpha-tocopherol action" by A. Azzi and "Vitamin E,antioxidant and nothing more" by M. Traber and J. Atkinson]". Free radical biology & medicine 43 (1): 2–3.doi:10.1016/j.freeradbiomed.2007.05.016. PMID 17561087.

10. ↑ Atkinson (2008). "[Expression error: Missing operand for > Tocopherols and tocotrienols inmembranes: a critical review]". Free radical biology & medicine 44 (5): 739–64.doi:10.1016/j.freeradbiomed.2007.11.010. PMID 18160049.

11. ↑ Azzi (2007). "[Expression error: Missing operand for > Molecular mechanism of alpha-tocopherolaction]". Free radical biology & medicine 43 (1): 16–21. doi:10.1016/j.freeradbiomed.2007.03.013. PMID17561089.

12. ↑ Zingg (2004). "[Expression error: Missing operand for > Non-antioxidant activities of vitamin E]".Current medicinal chemistry 11 (9): 1113–33. PMID 15134510.

13. ↑ Sesso, H. D. (2008). "[Expression error: Missing operand for > Vitamins E and C in the Prevention ofCardiovascular Disease in Men: the Physicians' Health Study II Randomized Controlled Trial]". JAMA: theJournal of the American Medical Association 300: 2123. doi:10.1001/jama.2008.600.

14. ↑ Traber, MG (1995). "Vitamin E: beyond antioxidant function". American Journal of Clinical Nutrition 62(6): 1501S. PMID 7495251. http://www.ajcn.org/cgi/content/abstract/62/6/1501S.

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15. ↑ Traber (1996). "[Expression error: Missing operand for > Vitamin E in humans: demand and delivery]".Annual review of nutrition 16 : 321–47. doi:10.1146/annurev.nu.16.070196.001541. PMID 8839930.

16. ↑ Sen (2004). "[Expression error: Missing operand for > Tocotrienol: the natural vitamin E to defend thenervous system?]". Annals of the New York Academy of Sciences 1031: 127–42.doi:10.1196/annals.1331.013. PMID 15753140.

17. ↑ Sen (2006). "[Expression error: Missing operand for > Tocotrienols: Vitamin E beyond tocopherols]".Life sciences 78 (18): 2088–98. doi:10.1016/j.lfs.2005.12.001. PMID 16458936.

18. ↑ Sen (2006). "[Expression error: Missing operand for > Tocotrienols: Vitamin E beyond tocopherols]".Life sciences 78 (18): 2088–98. doi:10.1016/j.lfs.2005.12.001. PMID 16458936.

19. ↑ Malafa (2008). "New insights and gains in pancreatic cancer". Cancer control : journal of the MoffittCancer Center 15 (4): 276–7. PMID 18813194. http://www.moffitt.org/CCJRoot/v15n4/pdf/276.pdf.

20. ↑ Das (2008). "[Expression error: Missing operand for > Cardioprotection with palm oil tocotrienols:comparision of different isomers]". American journal of physiology. Heart and circulatory physiology 294 (2):H970–8. doi:10.1152/ajpheart.01200.2007. PMID 18083895.

21. ↑ Sen, C (2007). "[Expression error: Missing operand for > Tocotrienols in health and disease: the otherhalf of the natural vitamin E family]". Molecular Aspects of Medicine 28 (5-6): 692.doi:10.1016/j.mam.2007.03.001. PMID 17507086.

22. ↑ Sen (2007). "[Expression error: Missing operand for > Tocotrienols: the emerging face of naturalvitamin E]". Vitamins and hormones 76 : 203–61. doi:10.1016/S0083-6729(07)76008-9. PMID 17628176.

23. ↑ USDA National Nutrient Database

24. ↑ 24.0 24.1 American Cancer Society, Vitamin E, updated Oct. 27, 2008

25. ↑ National Cancer Institute, The SELECT Prostate Cancer Prevention Trial, Oct. 27, 2008

26. ↑ National Cancer Institute, Selenium and Vitamin E Cancer Prevention Trial (SELECT), Oct. 31, 2008

27. ↑ Smedts (2009). "[Expression error: Missing operand for > High maternal vitamin E intake by diet orsupplements is associated with congenital heart defects in the offspring]". BJOG : an international journal ofobstetrics and gynaecology 116 (3): 416–23. doi:10.1111/j.1471-0528.2008.01957.x. PMID 19187374.

28. ↑ Bob Phillips; Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes(May 2001). "Levels of Evidence". Oxford Centre for Evidence-based Medicine.http://www.cebm.net/index.aspx?o=1047.

29. ↑ http://www.nhs.uk/news/2009/04April/Pages/VitaminEPregnancyRisk.aspx

Further readingBrigelius-Flohe, Regina (2002). "The European perspective on vitamin E: currentknowledge and future research". American Journal of Clinical Nutrition 76 (4):703. PMID 12324281. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=12324281.

External linksVitamin E Medline Plus, Medical Encyclopedia, U.S. National Library of MedicineVitamin E Office of Dietary Supplements, National Institutes of HealthJane Higdon, "Vitamin E", Micronutrient Information Center, Linus PaulingInstitute

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Cholecalciferol

IUPAC name (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol

Other names vitamin D3, activated 7-dehydrocholesterol.

IdentifiersCAS number 67-97-0EC number 200-673-2SMILES O[C@@H]1CC(\C(=C)CC1)=C\C=C2/CCC[C@]3(C2CC[C@@H]3[C@H](C)CCCC(C)C)CInChI 1/C27H44O/c1-19(2)8-6-9-21(4)25-15-16-26-22(10-7-17-27(25,26)5)12-13-23-18-

24(28)14-11-20(23)3/h12-13,19,21,24-26,28H,3,6-11,14-18H2,1-2,4-5H3/b22-12+,23-13-/t21-,24+,25-,26?,27-/m1/s1

InChI key QYSXJUFSXHHAJI-QWSSABAFBD

ChemSpider ID 9058792Properties

Molecular formula C27H44O

Molar mass 384.64 g/molAppearance White, needle-like crystalsMelting point 83–86 °C

Supplementary data pageStructure and properties n, εr, etc.

Thermodynamic data Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

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Cholecalciferolview original wikipedia article

This article needs additional citations for verification.Please help improve this article by adding reliable references. Unsourced material may bechallenged and removed. (December 2008)

Cholecalciferol is a form of Vitamin D, also called vitamin D3 or calciol.[1]

It is structurally similar to steroids such as testosterone, cholesterol, and cortisol (thoughvitamin D3 itself is a secosteroid).

One gram of pure vitamin D3 is 40 000 000 (40x106) IU, or, in other words, one IU is

0.025 μg. Individuals having a high risk of deficiency should consume 125 μg (5000 IU)of vitamin D daily.

FormsVitamin D3 has several forms:

Cholecalciferol, (sometimes called calciol) which is an inactive, unhydroxylatedform of vitamin D3)

Calcidiol (also called 25-hydroxyvitamin D3), which is the form measured in the

blood to assess vitamin D statusCalcitriol (also called 1,25-dihydroxyvitamin D3), which is the active form of D3.

Metabolism

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CholecalciferolForms

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Dose

Stability

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7-Dehydrocholesterol is the precursor of vitamin D3 and forms cholecalciferol only after

being exposed to solar UV radiation.

Cholecalciferol is then hydroxylated in the liver to become calcidiol (25-hydroxyvitaminD3).

Next, calcidiol is again hydroxylated, this time in the kidney, and becomes calcitriol(1,25-dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3.

Regulation of metabolism

Cholecalciferol is synthesized in the skin from 7-dehydrocholesterol under theaction of ultraviolet B light. It reaches an equilibrium after several minutesdepending on several factors including conditions of sunlight (latitude, season,cloud cover, altitude), age of skin, and color of skin.Hydroxylation in the liver of cholecalciferol to calcidiol (25-hydroxycholecalciferol)is loosely regulated, if at all, and blood levels of this molecule largely reflect theamount of vitamin D3 produced in the skin or the vitamin D2 or D3 ingested.

Hydroxylation in the kidneys of calcidiol to calcitriol by 1-alpha-hydroxylase istightly regulated (stimulated by either parathyroid hormone or hypophosphatemia)and serves as the major control point in production of the most active circulatinghormone calcitriol (1,25-dihydroxyvitamin D3).

As food fortificationAlthough cholecalciferol can be synthesized in the skin (see Metabolism), it is also aform of vitamin D added to fortify foods. Cholecalciferol is produced industrially by theirradiation of 7-dehydrocholesterol extracted from lanolin found in sheep's wool. In foodswhere animal products are not desired, an alternative compound is ergocalciferol (alsoknown as vitamin D2) derived from the fungal sterol ergosterol.

DoseThere are conflicting reports concerning the absorption of cholecalciferol (D3) versus

ergocalciferol (D2), with some studies suggesting less efficacy of D2[2], and others

showing no difference[2] [3]. At present, D2 and D3 doses are frequently considered

interchangeable, but more research is needed to clarify this.

StabilityCholecalciferol is very sensitive to UV radiation and will rapidly, but reversibly, breakdown to form supra-sterols, which can further irreversibly convert to ergosterol.

Therapeutic ApplicationA 2008 study published in Cancer Research has shown the addition of vitamin D3

(along with calcium) to the diet of some mice fed a regimen similar in nutritional content

to a new Western diet prevented colon cancer development.[4]

Alternative ViewsThere is a minority view, often associated with Trevor Marshall, which asserts that lowlevels of calcidiol (25-hydroxyvitamin D3) are often due to overconversion into calcitriol(1,25-dihydroxyvitamin D3, the active form of D3) because of chronic infection ratherthan calcidiol deficiency. [1]

See alsoHypervitaminosis D, Vitamin D poisoningErgocalciferol, vitamin D2.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase, a kidney enzyme that converts

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calcidiol to calcitriol.

References1. ↑ cholecalciferol at Dorland's Medical Dictionary

2. ↑ 2.0 2.1 Armas L, Hollis B, Heaney R (2004). "Vitamin D2 is much less effective than vitamin D3 inhumans". J Clin Endocrinol Metab 89 (11): 5387–91. doi:10.1210/jc.2004-0360. PMID 15531486.http://jcem.endojournals.org/cgi/content/full/jcem;89/11/5387.

3. ↑ Hollick, Biancuzzo, Chen, Klein, Young, Bilbud, Reitz, Salameh, Ameri, Tanenbaum (2007). "Vitamin D2is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin-D". J ClinEndocrinol Metab 93 (3): 6777–81. doi:10.1210/jc.2007-2308. PMID 18089691.http://jcem.endojournals.org/cgi/rapidpdf/jc.2007-2308v1.

4. ↑ Yang, Kurihara, Fan, Newmark, Rigas, Bancroft, Corner, Livote, Lesser, Edelmann, Velcich, Lipkin,Augenlicht (2008). "Dietary Induction of Colonic Tumors in a Mouse Model of Sporadic Colon Cancer"Context: Colonic tumors were prevented by elevating dietary calcium and vitamin D3 to levels comparablewith upper levels consumed by humans"". Cancer Research 68 : 3075. doi:10.1158/0008-5472.CAN-07-6426. http://cancerres.aacrjournals.org/cgi/content/short/68/19/7803?rss=1.

External linksNIST Chemistry WebBook page for cholecalciferolhttp://www.VitaminDCouncil.orghttp://www.uctv.tv/search-details.aspx?showID=15751http://www.uctv.tv/search-details.aspx?showID=15767

Cholestanes, membrane lipids: sterols

Adosterol - Cholecalciferol/Ergocalciferols - Cholesterol - Dihydrotachysterol - Fusidicacid - Lanosterol - Phytosterols

Categories:

Articles needing additional references from December 2008 | All articles needing additionalreferences | All articles with unsourced statements | Articles with unsourced statements fromNovember 2009 | Secosteroids | Vitamin D

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Αναφορά

Name Chemicalcomposition

Structure

VitaminD1

molecularcompound ofergocalciferol withlumisterol, 1:1

VitaminD2

ergocalciferol (madefrom ergosterol)

REFERENCE » WIKIPEDIA ARTICLES

Vitamin Dview original wikipedia article

For other uses, see Vitamin D (disambiguation).

Vitamin D is a group of fat-soluble prohormones,the two major forms of which are vitamin D2 (or

ergocalciferol) and vitamin D3 (or

cholecalciferol).[1] Vitamin D obtained from sunexposure, food, and supplements, is biologicallyinert and must undergo two hydroxylation reactionsto be activated in the body. Calcitriol (1,25-Dihydroxycholecalciferol) is the active form ofvitamin D found in the body. The term vitamin Dalso refers to these metabolites and otheranalogues of these substances.

Calcitriol plays an important role in the

maintenance of several organ systems.[3]

However, its major role is to increasethe flow of calcium into thebloodstream, by promoting absorptionof calcium and phosphorus from foodin the intestines, and reabsorption ofcalcium in the kidneys; enablingnormal mineralization of bone andpreventing hypocalcemic tetany. It isalso necessary for bone growth andbone remodeling by osteoblasts and

osteoclasts.[4][5]

Without sufficient vitamin D, bones canbecome thin, brittle, or misshapen.Deficiency can arise from inadequateintake coupled with inadequate sunlightexposure; disorders that limit itsabsorption; conditions that impairconversion of vitamin D into activemetabolites, such as liver or kidneydisorders; or, rarely, by a number ofhereditary disorders. Vitamin D deficiency results in impaired bone mineralization andleads to bone softening diseases, rickets in children and osteomalacia in adults, and

possibly contributes to osteoporosis.[3]

Vitamin D plays a number of other roles in human health including inhibition ofcalcitonin release from the thyroid gland. Calcitonin acts directly on osteoclasts,resulting in inhibition of bone resorption and cartilage degradation. Vitamin D can alsoinhibit parathyroid hormone secretion from the parathyroid gland, modulate

neuromuscular and immune function and reduce inflammation.[6][7][8]

FormsSeveral forms (vitamers) of vitamin Dhave been discovered (see table). Thetwo major forms are vitamin D2 or

ergocalciferol, and vitamin D3 or

cholecalciferol. These are known

collectively as calciferol.[9] Vitamin D2was chemically characterized in 1932.In 1936 the chemical structure ofvitamin D3 was established andresulted from the ultraviolet irradiation

Cholecalciferol (D3)

Calcium regulation in the human body.[2] Therole of vitamin D is shown in orange.

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Vitamin DForms

Biochemistry

Production in the skin

Synthesis mechanism (form 3)

Mechanism of action

Nutrition

Natural sources

Measuring nutritional status

Deficiency

Overdose

Health effects

Immunomodulation

Cancer

Cardiovascular disease

Mortality

See also

References

External links

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VitaminD3

cholecalciferol(made from 7-dehydrocholesterolin the skin).

VitaminD4

22-dihydroergocalciferol

VitaminD5

sitocalciferol (madefrom 7-dehydrositosterol)

of 7-dehydrocholesterol.[10]

Chemically, the various forms ofvitamin D are secosteroids; i.e.,steroids in which one of the bonds in

the steroid rings is broken.[11] Thestructural difference between vitaminD2 and vitamin D3 is in their side

chains. The side chain of D2 contains

a double bond between carbons 22and 23, and a methyl group on carbon24.

Vitamin D2 (made from ergosterol) is

produced by invertebrates, fungus andplants in response to UV irradiation; it is not produced by vertebrates. Little is knownabout the biologic function of vitamin D2 in nonvertebrate species. Because ergosterol

can more efficiently absorb the ultraviolet radiation that can damage DNA, RNA andprotein it has been suggested that ergosterol serves as a sunscreening system that

protects organisms from damaging high energy ultraviolet radiation.[12]

Vitamin D3 is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet

light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-

297 nm.[13][14] These wavelengths are present in sunlight when the UV index is greaterthan 3. At this solar elevation, which occurs daily within the tropics, daily during thespring and summer seasons in temperate regions, and almost never within the arcticcircles, adequate amounts of vitamin D3 can be made in the skin after only ten to

fifteen minutes of sun exposure at least two times per week to the face, arms, hands, orback without sunscreen. However, season, geographic latitude, time of day, cloud cover,skin cover, skin color, smog, and sunscreen affect UV ray absorption and vitamin Dsynthesis. For example, sunlight exposure from November through February in Bostonis insufficient to produce significant vitamin D synthesis in the skin. With longerexposure to UVB rays, an equilibrium is achieved in the skin, and excess vitamin D

simply degrades as fast as it is generated.[15]

Both vitamin D2 and D3 are used for human nutritional supplementation, and

pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol),

doxercalciferol and calcipotriene.[16] In humans, D3 is as effective as D2 in vitamin D

hormone activity in circulation,[17] although others state that D3 is more effective than

D2.[18] However, in some species, such as rats, vitamin D2 is more effective than

D3.[19]

BiochemistryVitamin D is a prohormone, meaning that it has no hormone activity itself, but isconverted to the active hormone 1,25-D through a tightly regulated synthesismechanism. Production of vitamin D in nature always appears to require the presenceof some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, frommushrooms to animals, which are not able to synthesize it except through the action ofsunlight at some point in the synthetic chain. For example, fish contain vitamin D onlybecause they ultimately exist on calories from ocean algae which synthesize vitamin Din shallow waters from the action of solar UV.

Production in the skinThe skin consists of two primarylayers: the inner layer called thedermis, composed largely ofconnective tissue, and the outer,thinner epidermis. The epidermisconsists of five strata; from outer toinner they are: the stratum corneum,stratum lucidum, stratum granulosum,stratum spinosum, and stratum basale.

Cholecalciferol is producedphotochemically in the skin from 7-

dehydrocholesterol; 7-dehydrocholesterol is produced inrelatively large quantities in the skin ofmost vertebrate animals, includinghumans. The few exceptions are somebat species, mole rats, cats, and

dogs,[12] which produce little vitamin

D.[20] In most animals the highestconcentrations of 7-dehydrocholesterol are found in the epidermal layer of skin,

specifically in the stratum basale and stratum spinosum.[13] The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other

layers is less.

Synthesis in the skin involves UVB radiation, which effectively penetrates only theepidermal layers of skin. While 7-dehydrocholesterol absorbs UV light at wavelengthsbetween 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectrabetween 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is

sometimes referred to as D-UV.[14] The two most important factors that govern thegeneration of pre-vitamin D3 are the quantity (intensity) and quality (appropriate

wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the

stratum basale and stratum spinosum.[13]

A critical determinant of vitamin D3 production in the skin is the presence and

concentration of melanin. Melanin functions as a light filter in the skin, and therefore theconcentration of melanin in the skin is related to the ability of UVB light to penetrate theepidermal strata and reach the 7-dehydrocholesterol-containing stratum basale andstratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 µg/cm² of skin) are available in the stratum spinosum

and stratum basale of the skin to meet the body's vitamin D requirements,[13] and

melanin content does not alter the amount of vitamin D that can be produced.[21] Thus,individuals with higher skin melanin content will simply require more time in sunlight toproduce the same amount of vitamin D as individuals with lower melanin content. Theamount of time an individual requires to produce a given amount of vitamin D may alsodepend upon the person's distance from the equator and on the season of the year.

In some animals, the presence of fur or feathers blocks the UV rays from reaching theskin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions

of the skin deposited onto the fur and obtained orally during grooming.[22]

In 1923, Harry Goldblatt and Katherine Soames established that when 7-dehydrocholesterol (a precursor of vitamin D in the skin) is irradiated with light, a formof a fat-soluble vitamin is produced. Alfred Fabian Hess and Mildred Weinstock further

substantiated that "[sun]light equals vitamin D".[23] Adolf Windaus, at the University ofGöttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on

the constitution of sterols and their connection with vitamins.[24] In 1930s, he clarifiedfurther the chemical structures of the vitamins D.

Synthesis mechanism (form 3)

7-dehydrocholesterol, aderivative ofcholesterol, isphotolyzed byultraviolet light in 6-electron conrotatoryelectrocyclic reaction.The product is pre-vitamin D3.

The epidermal strata of the skin. Production isgreatest in the stratum basale (colored red in

the illustration) and stratum spinosum (coloredorange).

Pre-vitamin D3 thenspontaneouslyisomerizes to VitaminD3 in a antarafacialhydride [1,7]Sigmatropic shift. Atroom temperature thetransformation ofprevitamin-D3 tovitamin D3 takes about12 days tocomplete.[12]

Whether it is made inthe skin or ingested,vitamin D3(cholecalciferol) is thenhydroxylated in theliver to 25-hydroxycholecalciferol(25(OH)D3 or calcidiol)by the enzyme 25-hydroxylase producedby hepatocytes. Thishydroxylation reactionoccurs in theendoplasmic reticulumand requires NADPH,O2 and Mg2+ yet it isnot a cytochrome P450enzyme. Once madethe product is stored inthe hepatocytes until itis needed and then canbe released into theplasma where it will bebound to an α-globulin.25-hydroxycholecalciferolis then transported tothe proximal tubules ofthe kidneys where itcan be hydroxylated byone of two enzymesforming to differentforms of vitamin D, oneof which is activevitamin D (1,25-OH D)and another which isinactive vitamin D(24,25-OH D). Theenzyme 1α-hydroxylase which isactivated byparathyroid hormone(and additionally by lowcalcium or phosphate)forms the mainbiologically activevitamin D hormonewith a C1 hydroxylationforming 1,25-dihydroxycholecalciferol(1,25(OH)2D3, also

known as calcitriol). Aseparate enzymehydroxylates the C24atom forming24R,25(OH)2D3 when

1α-hydroxylase is notactive, this inactivatesthe molecule from anybiological activity.Calcitriol is representedbelow right

(hydroxylated Carbon 1is on the lower ring atright, hydroxylatedCarbon 25 is at theupper right end).

Mechanism of actionAfter vitamin D is produced in the middle layers of skin or consumed in food, it isconverted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D), the

physiologically active form of vitamin D (when "D" is used without a subscript it refers toeither D2 or D3). This physiologically active form of vitamin D is known as calcitriol.

Following this conversion, calcitriol is released into the circulation, and by binding to acarrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to

various target organs.[11]

The physiologically active form of vitamin D mediates its biological effects by binding to

the vitamin D receptor (VDR), which is principally located in the nuclei of target cells.[11]

The binding of calcitriol to the VDR allows the VDR to act as a transcription factor thatmodulates the gene expression of transport proteins (such as TRPV6 and calbindin),which are involved in calcium absorption in the intestine.

The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroidhormone receptors, and VDRs are expressed by cells in most organs, including thebrain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone,kidney, and parathyroid gland cells leads to the maintenance of calcium andphosphorus levels in the blood (with the assistance of parathyroid hormone and

calcitonin) and to the maintenance of bone content.[25]

The VDR is known to be involved in cell proliferation and differentiation. Vitamin D alsoaffects the immune system, and VDRs are expressed in several white blood cells,

including monocytes and activated T and B cells.[16]

NutritionVitamin D is naturally produced by the humanbody when exposed to direct sunlight. Season,geographic latitude, time of day, cloud cover,smog, and sunscreen affect UV ray exposureand vitamin D synthesis in the skin, and it isimportant for individuals with limited sunexposure to include good sources of vitamin Din their diet. Extra vitamin D is alsorecommended for older adults and people withdark skin. Individuals having a high risk ofdeficiency should consume 25 μg (1000 IU) ofvitamin D daily to maintain adequate blood

concentrations of 25-hydroxyvitamin D.[1]

As civilization and the Industrial Revolution enabled humans to work indoors and wearmore clothes when outdoors, these cultural changes reduced natural production ofvitamin D and caused deficiency diseases. In many countries, such foods as milk,yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with

vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency.[26] In the

United States and Canada, for example, fortified milk typically provides 100 IU per

glass, or a quarter of the estimated adequate intake for adults over age 50.[1] A 1992study, however, found that the actual vitamin D content of milk varies widely.Supplementation of 100 IU (2.5 microgram) vitamin D3 raises blood calcidiol levels by

2.5 nmol/litre (1 ng/ml).[27]

Natural sources

Natural sources of vitamin D include:[1]

Fish liver oils, such as cod liver oil, 1Tbs. (15 ml) provides 1,360 IU (one IUequals 25 ng)

Milk and cereal grains are oftenfortified with vitamin D.

Fatty fish species, such as:Herring, 85 g (3 ounces (oz))provides 1383 IUCatfish, 85 g (3 oz) provides 425IUSalmon, cooked, 100 g (3.5 oz])provides 360 IUMackerel, cooked, 100 g (3.5 oz]), 345 IUSardines, canned in oil, drained, 50 g (1.75 oz), 250 IUTuna, canned in oil, 85 g (3 oz), 200 IUEel, cooked, 100 g (3.5 oz), 200 IU

A whole egg, provides 20 IUBeef liver, cooked, 100 g (3.5 oz), provides 15 IU

UV-irradiated mushrooms (Vitamin D2)[28][29]

In the United States (U.S.), the 100% Daily Value used for product labels is 400 IU/dayand typical diets provide about 100 IU/day. Although milk is usually fortified, the averagedaily consumption by most Americans is insufficient in obtaining levels of vitamin D

recommended by various medical authorities.[30] While adequate intake has beendefined as 200 IU/day for ages infant to 50, 400/day for 51-70, and 600/day over 70,the American Academy of Pediatrics argues that these recommendations are insufficient

and recommends a minimum of 400 IU, even for infants.[31] The NIH has set the safeupper limit at 2000 IU, but acknowledges newer data supporting a UL as high as 10,000

IU/day.[32] The Institute Of Medicine is revisiting vitamin D and calciumrecommendations with a report expected to be released in spring 2010.

Measuring nutritional statusA blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitaminD nutritional status. The optimal level of serum 25-hydroxyvitamin D is 35–55 ng/ml (or90-140 nmol/l); with some debate among medical scientists for the slightly higher

value.[27]

For instance, a later classification is:[33]

0-14.9 ng/ml = Severely deficient15.0-31.9 ng/ml = Mildly deficient32.0-100.0 ng/ml = Optimal>100.0 ng/ml = Toxicity possible

DeficiencyMain article: Hypovitaminosis DDeficiency of vitamin D can result from a number of factors: inadequate intake coupledwith inadequate sunlight (UVB) exposure, disorders that limit its absorption from thegastrointestinal tract, conditions that impair conversion of vitamin D into activemetabolites, such as liver or kidney disorders and body characteristics such as skincolor and body fat. Rarely, deficiency can result from a number of hereditary

disorders.[3] Deficiency results in impaired bone mineralization, and leads to bone

softening diseases[34] including:

Rickets, a childhood disease characterized by impeded growth, and deformity, ofthe long bones. Rickets was first described in the 17th century, by Daniel Whistlerand Francis Glisson. The role of diet in the development of rickets was

determined by Edward Mellanby between 1918–1920. [35] By altering the diets ofdogs raised in the absence of sunlight, he was able to establish unequivocallythat rickets was linked with a deficiency of diet, and identified cod liver oil as an

excellent anti-rachitic agent.[36] In 1921 Elmer McCollum identified a substancefound in certain fats that could prevent rickets. Prior to the fortification of milkproducts with vitamin D, rickets was a major public health problem. In the UnitedStates, the fortification of milk with 10 micrograms (400 IU) of vitamin D per quart

Fatty fish, such as salmon, arenatural sources of vitamin D.

in the 1930s led to a dramatic decline in the number of rickets cases.[25]

Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and ischaracterized by proximal muscle weakness and bone fragility. The effects of

osteomalacia are thought to contribute to chronic musculoskeletal pain.[37] Anumber of reports thus indicate that vitamin D deficiency may be related to

various types of pain,[38] but of the five small double-blind randomized controlledtrials, only one found a reduction in pain after supplementation, and there is nopersuasive evidence of lower vitamin D status in chronic pain sufferers compared

to controls.[39]

Osteoporosis, a condition characterized by reduced bone mineral density andincreased bone fragility.

Vitamin D malnutrition may also be linked to an increased susceptibility to severalchronic diseases, such as high blood pressure, tuberculosis, cancer, periodontal

disease, multiple sclerosis, chronic pain, seasonal affective disorder [40][41], peripheral

artery disease[42], cognitive impairment which includes memory loss and foggy brain,[43]

and several autoimmune diseases including type 1 diabetes (see role in

immunomodulation).[8][25] There is an association between low vitamin D levels andParkinson's disease, but whether Parkinson's causes low vitamin D levels, or whetherlow vitamin D levels play a role in the pathogenesis of Parkinson's disease has not

been established.[44] A resurgence of interest in vitamin D deficiency has led tocontinued studies on the topic and a focus on educating the consumer on the

prevalence and degree of deficiency among the general public.[45]

OverdoseFor more details on this topic, see hypervitaminosis D.Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large

volume of distribution and a half-life of about 20 to 29 days.[16] Ordinarily, the synthesisof bioactive vitamin D hormone is tightly regulated, and prevalent thinking is that vitaminD toxicity usually occurs only if excessive doses (prescription forms or rodenticide

analogs) are taken.[46] Serum levels of calcidiol (25-hydroxy-vitamin D) are typicallyused to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normallybetween 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone

(1,25(OH2)D) are usually normal in cases of vitamin D overdose.[3]

The exact long-term safe dose of vitamin D is not known. In 1997 the U.S. DietaryReference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults

was set at 50 micrograms/day (2,000 IU)[47], but this is viewed by some researchers as

outdated and overly restrictive.[48] A 2007 risk assessment was made by two employees

of the dietary supplement trade association Council for Responsible Nutrition,[48] that

represents companies including Amway, Bayer AG and GlaxoSmithKline,[49] and theirtwo colleagues, who declared that they had no personal or financial conflicts of interest.They suggested that 250 micrograms/day (10,000 IU) in healthy adults should be

adopted as the tolerable upper limit.[48] In adults, sustained intake of 1250

micrograms/day (50,000 IU) can produce toxicity within a few months.[3] For infants(birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU), and vitaminD concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown toproduce toxicity within 1 to 4 months. Other sources indicate that the threshold forvitamin D toxicity in humans is 500 to 600 micrograms per kilogram body weight per

day."[50] In rats an oral LD50 of 619 mg/kg is noted.[51] All known cases of vitamin Dtoxicity with hypercalcemia have involved intake of over 1,000 micrograms/day (40,000

IU)[52].

Although normal food and pill vitamin D concentration levels are far too low to be toxicin adults, people taking multiples of the normal dose of codliver oil may reach toxic

levels of vitamin A, not vitamin D,[53] if taken in an attempt to increase the levels ofvitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred

due to manufacturing and industrial accidents.[52] In the United States, overdoseexposure of vitamin D was reported by 284 individuals in 2004 (a randomly selected

year), leading to 1 death.[54]

Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of

calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D

toxicity is known to be a cause of high blood pressure.[55] Gastrointestinal symptoms ofvitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms areoften followed by polyuria (excessive production of urine), polydipsia (increased thirst),weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals ofkidney disease including elevated protein levels in the urine, urinary casts, and a build

up of wastes in the blood stream can also develop.[3] In one study, hypercalciuria and

bone loss occurred in four patients with documented vitamin D toxicity.[56] Anotherstudy showed elevated risk of ischemic heart disease when 25D was above 89

ng/mL.[57] Vitamin D toxicity is treated by discontinuing vitamin D supplementation, andrestricting calcium intake. If the toxicity is severe blood calcium levels can be furtherreduced with corticosteroids or bisphosphonates. In some cases kidney damage may be

irreversible.[3]

Exposure to sunlight for extended periods of time does not normally cause vitamin D

toxicity.[52] This is because within about 20 minutes of ultraviolet exposure in lightskinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin Dprecursors produced in the skin reach an equilibrium, and any further vitamin D that is

produced is degraded.[15] According to some sources, endogenous production with full

body exposure to sunlight is approximately 250 µg (10,000 IU) per day.[52] According toHolick, "the skin has a large capacity to produce cholecalciferol"; his experimentsindicate that,

"[W]hole-body exposure to one minimal erythemal dose of simulated solarultraviolet radiation is comparable with taking an oral dose of between 250

and 625 micrograms (10 000 and 25 000 IU) vitamin D."[15]

Health effects

ImmunomodulationThe hormonally active form of vitamin D mediates immunological effects by binding tonuclear vitamin D receptors (VDR) which are present in most immune cell typesincluding both innate and adaptive immune cells. The VDR is expressed constitutively inmonocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. Inline with this observation, activation of the VDR has potent anti-proliferative,pro-differentiative, and immunomodulatory functions including both immune-enhancing

and immunosuppressive effects.[58]

VDR ligands have been shown to increase the activity of natural killer cells, and

enhance the phagocytic activity of macrophages.[16] Active vitamin D hormone alsoincreases the production of cathelicidin, an antimicrobial peptide that is produced in

macrophages triggered by bacteria, viruses, and fungi.[59] Vitamin D deficiency tends to

increase the risk of infections, such as influenza[60] and tuberculosis[61][62][63]. In a1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia

than children without rickets.[64]

Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of Tcell activation and induction of regulatory T cells, as well as effects on cytokine

secretion patterns.[65] VDR-ligands have also been shown to affect maturation,differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell

activation, resulting in an overall state of immunosuppression.[66]

These immunoregulatory properties indicate that ligands with the potential to activatethe VDR, including supplementation with calcitriol (as well as a number of syntheticmodulators), may have therapeutic clinical applications in the treatment of inflammatorydiseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis,actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia,leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), andautoimmune diseases (systemic lupus erythematosus, type I diabetes); central nervous

systems diseases (multiple sclerosis); and in preventing organ transplant rejection.[58]

A 2006 study published in the Journal of the American Medical Association, reportedevidence of a link between Vitamin D deficiency and the onset of multiple sclerosis; theauthors posit that this is due to the immune-response suppression properties of Vitamin

D.[67] Further research conducted in 2009 indicates that vitamin D is required to activate

a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self

and foreign proteins in a subgroup of individuals genetically predisposed to MS.[68]

Suggestions that pregnant women take vitamin D during their pregnancy, especiallyduring winter months, is beginning to show merit to lessen the likelihood of the

development of MS later in life.[69][70]

CancerThe vitamin D hormone, calcitriol, has been found to induce death of cancer cells invitro and in vivo. The anti-cancer activity of vitamin D is thought to result from its role asa nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a

wide range of cellular mechanisms central to the development of cancer.[71] These

effects may be mediated through vitamin D receptors expressed in cancer cells.[16]

A search of primary and review medical literature published between 1970 and 2007found an increasing body of research supporting the hypothesis that the active form ofvitamin D has significant, protective effects against the development of cancer.Epidemiological studies show an inverse association between sun exposure, serumlevels of 25(OH)D, and intakes of vitamin D and risk of developing and/or survivingcancer. In 2005, scientists released a metastudy which demonstrated a beneficialcorrelation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's

colon cancer risk by 50%, and breast and ovarian cancer risks by 30%.[72][73][74] Ascientific review undertaken by the National Cancer Institute found that vitamin D wasbeneficial in preventing colorectal cancer, which showed an inverse relationship withblood levels of 80 nmol/L or higher associated with a 72% risk reduction. However, thesame study found no link between baseline vitamin D status and overall cancer

mortality.[75]

A 2006 study using data on over 4 million cancer patients from 13 different countriesshowed a marked difference in cancer risk between countries classified as sunny and

countries classified as less–sunny for a number of different cancers.[76] Research hasalso suggested that cancer patients who have surgery or treatment in the summer —and therefore make more endogenous vitamin D — have a better chance of survivingtheir cancer than those who undergo treatment in the winter when they are exposed to

less sunlight.[77] Another 2006 study found that taking the U.S. RDA of vitamin D (400IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000

people from two long-term health surveys.[78][79] A randomized intervention studyinvolving 1,200 women, published in June 2007, reports that vitamin D supplementation(1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence,during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed afterthe first year (and therefore excluding those cancers more likely to have originated prior

to the vitamin D intervention).[80][81] Research has also indicated beneficial effects of

high levels of calcitriol on patients with advanced prostate cancer.[82]

Low levels of vitamin D in serum have also been correlated with breast cancer disease

progression and bone metastases,[83] and studies suggest that increased intake of

vitamin D reduces the risk of breast cancer in premenopausal women.[84]

Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an

increased risk of breast cancer.[83] Impairment of the VDR-mediated gene expression isthought to alter mammary gland development or function and may predispose cells tomalignant transformation. Women with homozygous FOK1 mutations in the VDR genehad an increased risk of breast cancer compared with the women who did not. FOK1mutation has also been associated with decreasing bone mineral density which in turn

may be associated with an increase in the risk of breast cancer.[85]

The Canadian Cancer Society was the first to recommend, in 2007, that all of its adultcitizens begin taking 1,000(IU) per day of vitamin D. The country's northern latitude wasa factor in the decision, as was the growing body of evidence showing the vitamin's

effectiveness in lowering instances of cancer.[86][87]

Cardiovascular diseaseResearch indicates that vitamin D may play a role in preventing or reversing coronary

disease.[88][89] Vitamin D deficiency is associated with an increase in high blood

pressure and cardiovascular risk. Numerous observational studies show this link, but no

randomized trial has proven the impact of vitamin D supplementation.[90] The precisemechanism for cardiovascular regulation is still under investigation; possibilities includeblood pressure regulation through the renin-angiotensin system, parathyroid hormonelevels, direct impact on heart muscle function, inflammation, and vascular

calcification.[91]

When researchers monitored the vitamin D levels, blood pressure and othercardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years,they found that those people with low levels of vitamin D had a 62% higher risk of a

cardiovascular event than those with normal vitamin D levels.[92] Low levels of vitamin Dhave also been implicated in hypertension, elevated VLDL triglycerides, and impaired

insulin metabolism.[93]

A report from the National Health and Nutrition Examination Survey (NHANES) involvingnearly 5,000 participants found that low levels of vitamin D were associated with anincreased risk of peripheral artery disease (PAD). The incidence of PAD was 80%

higher in participants with the lowest vitamin D levels (<17.8 ng/mL).[42] Cholesterol

levels were found to be reduced in gardeners in the UK during the summer months.[94]

Heart attacks peak in winter and decline in summer in temperate[95] but not tropical

latitudes.[96]

The issue of vitamin D in heart health has not yet been settled. Exercise may accountfor some of the benefit attributed to vitamin D, since vitamin D levels are generally

higher in physically active persons.[97] Moreover, there may be an upper limit afterwhich cardiac benefits decline. One study found an elevated risk of ischaemic heartdisease in Southern India in individuals whose vitamin D levels were above 89

ng/mL.[57] These sun-living groups results do not generalize to sun-deprived urbandwellers. Among a group with heavy sun exposure, taking supplemental vitamin D isunlikely to result in blood levels over the ideal range, while urban dwellers not takingsupplemental vitamin D may fall under the levels recognized as ideal.

MortalityUsing information from the National Health and Nutrition Examination Survey a group ofresearchers concluded that having low levels of vitamin D (<17.8 ng/ml) wasindependently associated with an increase in all-cause mortality in the general

population.[98] The study evaluated whether low serum vitamin D levels wereassociated with all-cause mortality, cancer, and cardiovascular disease (CVD) mortalityamong 13,331 diverse American adults who were 20 years or older. Vitamin D levels ofthese participants were collected over a 6-year period (from 1988 through 1994), andindividuals were passively followed for mortality through the year 2000.

Among many factors that may be responsible for vitamin D's apparent beneficial effecton all-cause mortality is its effect on telomeres and its potential effect on slowing aging.Shortening of leukocyte telomeres is a marker of aging. Leukocyte telomere length(LTL) predicts the development of aging-related disease, and length of these telomeresdecreases with each cell division and with increased inflammation (more common in theelderly). Research indicates that vitamin D is a potent inhibitor of the proinflammatoryresponse and slows the turnover of leukocytes. Higher vitamin D levels were alsoassociated with longer leukocyte telomere length, indicating that vitamin D sufficiency

may play a role in preventing age-related diseases.[99]

See alsoVitamin D and influenzaEffect of sunlight on mushrooms - article about how ultraviolet light boosts vitaminD levels in mushrooms.

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46. ↑ "RODENTICIDES, source: Journal of Veterinary Medicine, archives, vol. 27, May, 1998". IPM Of Alaska,Solving Pest Problems Sensibly. http://www.homestead.com/ipmofalaska/files/rodenticides.html. Retrieved2006-07-07.

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49. ↑ http://www.crnusa.org/who_omc.html

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51. ↑ US Environmental Protection Agency. Cholecalciferol (Vitamin D3) Chemical Profile 12/84 . Chemical FactSheet Number 42. Washington, DC. December 1, 1984.

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54. ↑ 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure SurveillanceSystem.

55. ↑ "Complete Guide to Vitamins, Minerals ans Supplements", Fisher Books, Tucsan AZ, 1988, p42

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69. ↑ Vitamin D helps control MS gene. BBC News. 5 February 2009.

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74. ↑ Garland CF, Mohr SB, Gorham ED et al. (2006). "Role of ultraviolet B irradiance and vitamin D inprevention of ovarian cancer." Am J Prev Med. 31 :512-514.

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80. ↑ Martin Mittelstaedt (28 April 2007). "Vitamin D casts cancer prevention in new light". Global and Mail.http://www.theglobeandmail.com/servlet/story/RTGAM.20070428.wxvitamin28/BNStory/specialScienceandHealth/home. Retrieved 2007-04-28.

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85. ↑ Chen WY, Bertone-Johnson ER, Hunter DJ, Willett WC, Hankinson SE. Associations BetweenPolymorphisms in the Vitamin D Receptor and Breast Cancer Risk. Cancer Epidemiology, Biomarkers, &Prevention. 2005; 14(10):2335-2339.

86. ↑ Canadian Cancer Society announces Vitamin D recommendation, 08 June 2007.

87. ↑ Canadian Cancer Society recommends vitamin D. CTV.ca News Staff

88. ↑ Lack of vitamin D may increase heart disease risk http://www.americanheart.org/presenter.jhtml?identifier=3052800 American Heart Association rapid access journal report 01/07/2008

89. ↑ Newswise: Men with Low Vitamin D May Have Increased Risk of Heart Attack Retrieved on June 9,2008.

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92. ↑ Wang TJ, Pencina MJ, Booth SL, et al. (January 2008). "[Expression error: Missing operand for >Vitamin D deficiency and risk of cardiovascular disease]". Circulation 117 (4): 503–11.doi:10.1161/CIRCULATIONAHA.107.706127. PMID 18180395.

93. ↑ Lind L, Hänni A, Lithell H, Hvarfner A, Sörensen OH, Ljunghall S (September 1995). "[Expression error:Missing operand for > Vitamin D is related to blood pressure and other cardiovascular risk factors inmiddle-aged men]". Am. J. Hypertens. 8 (9): 894–901. doi:10.1016/0895-7061(95)00154-H. PMID8541004.

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95. ↑ Spencer FA, Goldberg RJ, Becker RC, Gore JM. (1998). "[Expression error: Missing operand for >Seasonal distribution of acute myocardial infarction in the second National Registry of MyocardialInfarction]". J Am Coll Cardiol. 31 (6): 1226–33. doi:10.1016/S0735-1097(98)00098-9. PMID 9581712.

96. ↑ Ku CS, Yang CY, Lee WJ, Chiang HT, Liu CP, Lin SL. (1998). "[Expression error: Missing operandfor > Absence of a seasonal variation in myocardial infarction onset in a region without temperatureextremes]". Cardiology. 89 (4): 277–82. doi:10.1159/000006800. PMID 9643275.

97. ↑ Scragg R, Holdaway I, Singh V, Metcalf P, Baker J, Dryson E (1995). "[Expression error: Missingoperand for > Serum 25-hydroxyvitamin D3 is related to physical activity and ethnicity but not obesity in amulticultural workforce]". Aust N Z J Med 25 (3): 218–23. PMID 7487689.

98. ↑ Melamed ML, Michos ED, Post W, Astor B (August 2008). "[Expression error: Missing operand for >25-hydroxyvitamin D levels and the risk of mortality in the general population]". Arch. Intern. Med. 168 (15):1629–37. doi:10.1001/archinte.168.15.1629 (inactive 2009-11-17). PMID 18695076.

99. ↑ Richards JB, Valdes AM, Gardner JP, et al. (November 2007). "Higher serum vitamin D concentrationsare associated with longer leukocyte telomere length in women". Am. J. Clin. Nutr. 86 (5): 1420–5. PMID17991655. PMC 2196219. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=17991655.

External linksVitamin D Fact Sheet from the U.S.National Institutes of HealthVitamin D at the Open Directory Project

Vitamins (A11)

Endocrine system: hormones (Peptide hormones · Steroid hormones)

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Vitamin C

Systematic (IUPAC) name2-oxo-L-threo-hexono-1,4- lactone-2,3-enediol

or(R)-3,4-dihydroxy-5-((S)- 1,2-dihydroxyethyl)furan-2(5H)-one

IdentifiersCAS number 50-81-7

ATC code A11G

PubChem 5785

Chemical dataFormula C6H8O6

Mol. mass 176.14 grams per mol

Synonyms L-ascorbate

Physical dataMelt. point 190–192 °C (374–378 °F)

decomposes

Pharmacokinetic dataBioavailability rapid & complete

Protein binding negligible

Metabolism ?

Half life 30 minutes

Excretion renal

Therapeutic considerationsPregnancy cat. A

Legal status general public availability

Routes oral

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REFERENCE » WIKIPEDIA ARTICLES

Vitamin Cview original wikipedia article

Not to be confused with Citric acid.

This article is about the nutrient. For the chemical compound, see ascorbic acid.

For other uses, see Vitamin C (disambiguation).

Vitamin C or L-ascorbic acid is anessential nutrient for humans, in which itfunctions as a vitamin. Ascorbate (an ion ofascorbic acid) is required for a range ofessential metabolic reactions in all animalsand plants. It is made internally by almostall organisms; notable mammalianexceptions are most or all of the orderchiroptera (bats), and the entire suborderAnthropoidea (Haplorrhini) (tarsiers,monkeys and apes). It is also needed byguinea pigs and some species of birds andfish. Deficiency in this vitamin causes the

disease scurvy in humans.[1][2][3] It is also

widely used as a food additive.[4]

The pharmacophore of vitamin C is theascorbate ion. In living organisms,ascorbate is an anti-oxidant, since itprotects the body against oxidative

stress,[5] and is a cofactor in several vital

enzymatic reactions.[6]

Scurvy has been known since ancienttimes. People in many parts of the worldassumed it was caused by a lack of freshplant foods. The British Navy started givingsailors lime juice to prevent scurvy in

1795.[7] Ascorbic acid was finally isolatedin 1933 and synthesized in 1934. The usesand recommended daily intake of vitamin Care matters of on-going debate, with RDIranging from 45 to 95 mg/day. Proponentsof megadosage propose from 200 toupwards of 2000 mg/day. A recent meta-analysis of 68 reliable antioxidantsupplementation experiments, involving atotal of 232,606 individuals, concluded thatconsuming additional ascorbate fromsupplements may not be as beneficial as

thought.[8]

Biological significanceFurther information: ascorbic acidVitamin C is purely the L-enantiomer of ascorbate; theopposite D-enantiomer has no physiologicalsignificance. Both forms are mirror images of the samemolecular structure. When L-ascorbate, which is astrong reducing agent, carries out its reducing function,it is converted to its oxidized form, L-

dehydroascorbate.[6] L-dehydroascorbate can then bereduced back to the active L-ascorbate form in the body

[9]

ascorbic acid(reduced form)

overview outline images locations

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Vitamin C

Images

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Vitamin CBiological significance

Biosynthesis

Vitamin C in evolution

Absorption, transport, and disposal

Deficiency

History of human understanding

Discovery of ascorbic acid

Physiological function

Collagen, carnitine, and tyrosinesynthesis, and microsomal metabolism

Antioxidant

Pro-oxidant

Daily requirements

Government recommended intakes

Alternative recommendations on intak

Therapeutic uses

Vitamin C megadosage

Testing for ascorbate levels in the body

Adverse effects

Common side-effects

Possible side-effects

Chance of overdose

Natural and artificial dietary sources

Plant sources

Animal sources

Food preparation

Vitamin C supplements

Artificial modes of synthesis

Food Fortification

References

Further reading

External links

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by enzymes and glutathione. During this processsemidehydroascorbic acid radical is formed. Ascorbatefree radical reacts poorly with oxygen, and thus, will notcreate a superoxide. Instead two semidehydroascorbateradicals will react and form one ascorbate and onedehydroascorbate. With the help of glutathione,

dehydroxyascorbate is converted back to ascorbate.[10]

The presence of glutathione is crucial since it sparesascorbate and improves antioxidant capacity of

blood.[11] Without it dehydroxyascorbate could notconvert back to ascorbate.

L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurseither attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming amineral ascorbate.

BiosynthesisThe vast majority of animals and plants are able tosynthesize their own vitamin C, through a sequenceof four enzyme-driven steps, which convert glucose

to vitamin C.[6] The glucose needed to produceascorbate in the liver (in mammals and perchingbirds) is extracted from glycogen; ascorbatesynthesis is a glycogenolysis-dependent

process.[12] In reptiles and birds the biosynthesis iscarried out in the kidneys.

Among the animals that have lost the ability tosynthesise vitamin C are simians (specifically thesuborder haplorrhini, which includes humans),guinea pigs, a number of species of passerinebirds (but not all of them—there is some suggestion

that the ability was lost separately a number of times in birds), and many (probably all)major families of bats, including major insect and fruit-eating bat families. These animalsall lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last stepof vitamin C synthesis, because they have a defective form of the gene for the enzyme

(Pseudogene ΨGULO).[13] Some of these species (including humans) are able to make

do with the lower levels available from their diets by recycling oxidised vitamin C.[14]

Most simians consume the vitamin in amounts 10 to 20 times higher than that

recommended by governments for humans.[15] This discrepancy constitutes much of thebasis of the controversy on current recommended dietary allowances. It is countered byarguments that humans are very good at conserving dietary vitamin C, and are able tomaintain blood levels of vitamin C comparable with other simians, on a far smallerdietary intake.

An adult goat, a typical example of a vitamin C-producing animal, will manufacturemore than 13 g of vitamin C per day in normal health and the biosynthesis will increase

"many fold under stress".[16] Trauma or injury has also been demonstrated to use up

large quantities of vitamin C in humans.[17] Some microorganisms such as the yeastSaccharomyces cerevisiae have been shown to be able to synthesize vitamin C from

simple sugars.[18][19]

Vitamin C in evolution

Venturi and Venturi[20][21] suggested that the antioxidant action of ascorbic aciddeveloped firstly in plant kingdom when, about 500 Mya, plants began to adapt tomineral deficient fresh-waters of estuary of rivers. Some biologists suggested that manyvertebrates had developed their metabolic adaptive strategies in estuary

environment.[22] In this theory, some 400-300 million years ago when living plants andanimals first began the move from the sea to rivers and land, environmental iodine

deficiency was a challenge to the evolution of terrestrial life.[23] In plants, animals andfishes, the terrestrial diet became deficient in many essential marine micronutrients,including iodine, selenium, zinc, copper, manganese, iron, etc. Freshwater algae andterrestrial plants, in replacement of marine antioxidants, slowly optimized the productionof other endogenous antioxidants such as ascorbic acid, polyphenols, carotenoids,

dehydroascorbic acid(oxidized form)

Model of a vitamin C molecule.Black is carbon, red is oxygen,

and white is hydrogen

flavonoids, tocopherols etc., some of which became essential “vitamins” in the diet ofterrestrial animals (vitamins C, A, E, etc.).

Ascorbic acid or vitamin C is a common enzymatic cofactor in mammals used in thesynthesis of collagen. Ascorbate is a powerful reducing agent capable of rapidlyscavenging a number of reactive oxygen species (ROS). Freshwater teleost fishes alsorequire dietary vitamin C in their diet or they will get scurvy (Hardie et al.,1991). Themost widely recognized symptoms of vitamin C deficiency in fishes are scoliosis,lordosis and dark skin coloration. Freshwater salmonids also show impaired collagenformation, internal/fin haemorrhage, spinal curvature and increased mortality. If thesefishes are housed in seawater with algae and phytoplankton, then vitaminsupplementation seems to be less important, presumably because of the availability of

other, more ancient, antioxidants in natural marine environment.[24]

Some scientists have suggested that the loss of human ability to make vitamin C may

have caused a rapid simian evolution into modern man.[25][26][27] However, the loss ofability to make vitamin C in simians must have occurred much further back inevolutionary history than the emergence of humans or even apes, since it evidentlyoccurred sometime after the split in the Haplorrhini (which cannot make vitamin C) andits sister clade which retained the ability, the Strepsirrhini ("wet-nosed" primates). Thesetwo branchs parted ways about 63 million years ago (Mya). Approximately 5 millionyears later (58 Mya), only a short time afterward from an evolutionary perspective, theinfraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae),branched off from the other haplorrhines. Since tarsiers also cannot make vitamin C,this implies the mutation had already occurred, and thus must have occurred betweenthese two marker points (63 to 58 Mya).

It has been noted that the loss of the ability to synthesize ascorbate strikingly parallelsthe evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate areboth strong reducing agents. This has led to the suggestion that in higher primates, uric

acid has taken over some of the functions of ascorbate.[28]

Absorption, transport, and disposalAscorbic acid is absorbed in the body by both active transport and simple diffusion.Sodium Dependent Active Transport - Sodium-Ascorbate Co-Transporters (SVCTs) andHexose transporters (GLUTs) are the two transporters required for absorption. SVCT1

and SVCT2 imported the reduced form of ascorbate across plasma membrane.[29]

GLUT1 and GLUT3 are the two glucose transporters and only transfer dehydroascorbic

acid form of Vitamin C.[30] Although dehydroascorbic acid is absorbed in higher ratethan ascorbate, the amount of dehydroascorbic acid found in plasma and tissues undernormal conditions is low, as cells rapidly reduce dehydroascorbic acid to

ascorbate.[31][32] Thus, SVCTs appear to be the predominant system for vitamin Ctransport in the body.

SVCT2 is involved in vitamin C transport in almost every tissue,[29] the notable

exception being red blood cells which lose SVCT proteins during maturation.[33]

Knockout animals for SVCT2 die shortly after birth,[34] suggesting that SVCT2-mediatedvitamin C transport is necessary for life.

With regular intake the absorption rate varies between 70 to 95%. However, the degreeof absorption decreases as intake increases. At high intake (12g), fractional humanabsorption of ascorbic acid may be as low as 16%; at low intake (<20 mg) the

absorption rate can reach up to 98%.[35] Ascorbate concentrations over renal re-absorption threshold pass freely into the urine and are excreted. At high dietary doses(corresponding to several hundred mg/day in humans) ascorbate is accumulated in thebody until the plasma levels reach the renal resorption threshold, which is about 1.5mg/dL in men and 1.3 mg/dL in women. Concentrations in the plasma larger than thisvalue (thought to represent body saturation) are rapidly excreted in the urine with a half-life of about 30 minutes; concentrations less than this threshold amount are activelyretained by the kidneys, and half-life for the remainder of the vitamin C store in thebody increases greatly, with the half-life lengthening as the body stores are

depleted.[36]

Although the body's maximal store of vitamin C is largely determined by the renalthreshold for blood, there are many tissues which maintain vitamin C concentrations farhigher than in blood. Biological tissues that accumulate over 100 times the level inblood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and

retina.[37] Those with 10 to 50 times the concentration present in blood plasma include

the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa,leukocytes, pancreas, kidney and salivary glands.

Ascorbic acid can be oxidized (broken down) in the human body by the enzyme L-ascorbate oxidase. Ascorbate which is not directly excreted in the urine as a result ofbody saturation or destroyed in other body metabolism is oxidized by this enzyme andremoved.

DeficiencyMain article: ScurvyScurvy is an avitaminosis resulting from lack of vitamin C, since without this vitamin, thesynthesised collagen is too unstable to perform its function. Scurvy leads to theformation of liver spots on the skin, spongy gums, and bleeding from all mucousmembranes. The spots are most abundant on the thighs and legs, and a person withthe ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvythere are open, suppurating wounds and loss of teeth and, eventually, death. The

human body can store only a certain amount of vitamin C,[38] and so the body soondepletes itself if fresh supplies are not consumed.

It has been shown that smokers who have diets poor in vitamin C are at a higher risk oflung-borne diseases than those smokers who have higher concentrations of vitamin C

in the blood.[39]

Nobel prize winner Linus Pauling and Dr. G. C. Willis have asserted that chronic longterm low blood levels of vitamin C (chronic scurvy) is a cause of atherosclerosis.

Western societies generally consume sufficient Vitamin C to prevent scurvy. In 2004 aCanadian Community health survey reported that Canadians of 19 years and abovehave intakes of vitamin C from food of, 133 mg/d for males and 120 mg/d for

females,[40] which is higher than the RDA recommendation. In human dietary studies,all obvious symptoms of scurvy previously induced by extremely low vitamin C intake,can be reversed by vitamin C supplementation as small as 10 mg a day. However,needed vitamin C intake for dealing with infection or large amounts of tissue repair(such as in burns) is much higher than the minimal dose needed to reverse scurvy.

History of human understandingThe need to include fresh plant food or raw animalflesh in the diet to prevent disease was knownfrom ancient times. Native peoples living inmarginal areas incorporated this into theirmedicinal lore. For example, spruce needles wereused in temperate zones in infusions, or the leavesfrom species of drought-resistant trees in desertareas. In 1536, the French explorer JacquesCartier, exploring the St. Lawrence River, used thelocal natives' knowledge to save his men who weredying of scurvy. He boiled the needles of the arborvitae tree to make a tea that was later shown to

contain 50 mg of vitamin C per 100 grams.[41][42]

Throughout history, the benefit of plant food tosurvive long sea voyages has been occasionallyrecommended by authorities. John Woodall, thefirst appointed surgeon to the British East IndiaCompany, recommended the preventive andcurative use of lemon juice in his book "TheSurgeon's Mate", in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firmopinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, andgreens; which is alone the primary cause of the disease."

While the earliest documented case of scurvy was described by Hippocrates around theyear 400 BC, the first attempt to give scientific basis for the cause of this disease wasby a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common amongthose with poor access to fresh fruit and vegetables, such as remote, isolated sailorsand soldiers. While at sea in May 1747, Lind provided some crew members with twooranges and one lemon per day, in addition to normal rations, while others continued oncider, vinegar, sulfuric acid or seawater, along with their normal rations. In the history ofscience this is considered to be the first occurrence of a controlled experiment

James Lind, a British Royal Navysurgeon who, in 1747, identifiedthat a quality in fruit prevented

the disease of scurvy in what wasthe first recorded controlled

experiment.

comparing results on two populations of a factor applied to one group only with all otherfactors the same. The results conclusively showed that citrus fruits prevented the

disease. Lind published his work in 1753 in his Treatise on the Scurvy.[43]

Lind's work was slow to be noticed, partly becausehis Treatise was not publish until six years after hisstudy, and also because he recommended a lemon

juice extract known as "rob".[44] Fresh fruit wasvery expensive to keep on board, whereas boiling itdown to juice allowed easy storage but destroyedthe vitamin (especially if boiled in copper

kettles).[45] Ship captains concluded wrongly thatLind's other suggestions were ineffective becausethose juices failed to prevent or cure scurvy.

It was 1795 before the British navy adopted lemonsor lime as standard issue at sea. Limes were morepopular as they could be found in British WestIndian Colonies, unlike lemons which weren't foundin British Dominions, and were therefore more

expensive. This practice led to the American use of the nickname "limey" to refer to theBritish. Captain James Cook had previously demonstrated and proven the principle ofthe advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian

Islands and beyond without losing any of his men to scurvy.[46] For this otherwiseunheard of feat, the British Admiralty awarded him a medal.

The name "antiscorbutic" was used in the eighteenth and nineteenth centuries asgeneral term for those foods known to prevent scurvy, even though there was nounderstanding of the reason for this. These foods included but were not limited to:lemons, limes, and oranges; sauerkraut, cabbage, malt, and portable soup.

In 1907, Axel Holst and Theodor Frølich, two Norwegian physicians studying beribericontracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small testmammal to substitute for the pigeons they used. They fed guinea pigs their test diet,which had earlier produced beriberi in their pigeons, and were surprised when scurvyresulted instead. Until that time scurvy had not been observed in any organism apartfrom humans, and had been considered an exclusively human disease.

Discovery of ascorbic acidIn 1912, the Polish-American biochemist CasimirFunk, while researching deficiency diseases,developed the concept of vitamins to refer to thenon-mineral micro-nutrients which are essential tohealth. The name is a blend of "vital", due to thevital role they play biochemically, and "amines"because Funk thought that all these materials werechemical amines. One of the "vitamines" wasthought to be the anti-scorbutic factor, longthought to be a component of most fresh plantmaterial.

In 1928 the Arctic anthropologist VilhjalmurStefansson attempted to prove his theory of howthe Eskimos are able to avoid scurvy with almostno plant food in their diet, despite the diseasestriking European Arctic explorers living on similarhigh-meat diets. Stefansson theorised that thenatives get their vitamin C from fresh meat that isminimally cooked. Starting in February 1928, forone year he and a colleague lived on anexclusively minimally-cooked meat diet while undermedical supervision; they remained healthy. (Laterstudies done after vitamin C could be quantified inmostly-raw traditional food diets of the Yukon,Inuit, and Métís of the Northern Canada, showedthat their daily intake of vitamin C averagedbetween 52 and 62 mg/day, an amount approximately the dietary reference intake

(DRI), even at times of the year when little plant-based food were eaten.)[47]

From 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert

Citrus fruits were one of the firstsources of vitamin C available to

ship's surgeons.

Albert Szent-Györgyi, picturedhere in 1948, was awarded the

1937 Nobel Prize in Medicine "forhis discoveries in connection with

the biological combustionprocesses, with special referenceto vitamin C and the catalysis offumaric acid". He also identifiedmany components and reactions

of the citric acid cycleindependently from Hans Adolf

Krebs.

Szent-Györgyi and, independently, the American Charles Glen King, first isolated theanti-scorbutic factor, calling it "ascorbic acid" for its vitamin activity. Ascorbic acid turnedout not to be an amine, nor even to contain any nitrogen. For their accomplishment,Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine "for his discoveries inconnection with the biological combustion processes, with special reference to vitamin C

and the catalysis of fumaric acid".[48]

Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and SirEdmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded insynthesizing the vitamin, making it the first to be artificially produced. This madepossible the cheap mass-production of what was by then known as vitamin C. OnlyHaworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the"Reichstein process" retained Reichstein's name.

In 1933 Hoffmann–La Roche became the first pharmaceutical company to mass-produce synthetic vitamin C, under the brand name of Redoxon.

In 1957 the American J.J. Burns showed that the reason some mammals weresusceptible to scurvy was the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes which synthesize

vitamin C.[49][50] American biochemist Irwin Stone was the first to exploit vitamin C forits food preservative properties. He later developed the theory that humans possess amutated form of the L-gulonolactone oxidase coding gene.

In 2008 researchers at the University of Montpellier discovered that in humans and otherprimates the red blood cells have evolved a mechanism to more efficiently utilize thevitamin C present in the body by recycling oxidized L-dehydroascorbic acid (DHA) backinto ascorbic acid which can be reused by the body. The mechanism was not found to

be present in mammals that synthesize their own vitamin C.[51]

Physiological functionIn humans, vitamin C is essential to a healthy diet as well as being a highly effective

antioxidant, acting to lessen oxidative stress; a substrate for ascorbate peroxidase;[3]

and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C

acts as an electron donor for important enzymes:[52]

Collagen, carnitine, and tyrosine synthesis, and microsomal metabolism

This article may be confusing or unclear to readers. Please help clarify the article;suggestions may be found on the talk page. (May 2009)

Ascorbic acid performs numerous physiological functions in human body. Thesefunctions include the synthesis of collagen, carnitine and neurotransmitters, the

synthesis and catabolism of tyrosine and the metabolism of microsome.[53] Ascorbateacts as a reducing agent (i.e. electron donor, anti-oxidant) in the above-describedsyntheses, maintaining iron and copper atoms in their reduced states.

Vitamin C acts as an electron donor for eight different enzymes:[52]

Three participate in collagen hydroxylation.[54][55][56] These reactions addhydroxyl groups to the amino acids proline or lysine in the collagen molecule viaprolyl hydroxylase and lysyl hydroxylase, both requiring vitamin C as a cofactor.Hydroxylation allows the collagen molecule to assume its triple helix structure andmaking vitamin C essential to the development and maintenance of scar tissue,

blood vessels, and cartilage.[38]

2 are necessary for synthesis of carnitine.[57][58] Carnitine is essential for thetransport of fatty acids into mitochondria for ATP generation.

The remaining three have the following functions in common but do not alwaysdo this:

dopamine beta hydroxylase participates in the biosynthesis of

norepinephrine from dopamine.[59][60]

another enzyme adds amide groups to peptide hormones, greatly

increasing their stability.[61][62]

one modulates tyrosine metabolism.[63][64]

United States vitamin C recommendations[73]

Recommended Dietary Allowance (adult male) 90 mg per dayRecommended Dietary Allowance (adult female) 75 mg per dayTolerable Upper Intake Level (adult male) 2,000 mg per dayTolerable Upper Intake Level (adult female) 2,000 mg per day

AntioxidantAscorbic acid is well known for its antioxidant activity. Ascorbate acts as a reducingagent to reverse oxidation in aqueous solution. When there are more free radicals(Reactive oxygen species) in the body versus antioxidant, a human is under the

condition called Oxidative stress.[65] Oxidative stress induced diseases encompasscardiovascular diseases, hypertension, chronic inflammatory diseases and

diabetes[66][67][68][69] The plasma ascorbate concentration in oxidative stress patient

(less than 45 µmol/L) measured is lower than healthy individual (61.4-80 µmol/L)[70]

According to McGregor and Biesalski (2006).[65] increasing plasma ascorbate level mayhave therapeutic effects in oxidative stress individual. Individuals with oxidative stressand healthy individuals have different pharmacokinetics of ascorbate.

Pro-oxidant

Ascorbic acid behaves not only as antioxidant but also as pro-oxidant.[65] Ascorbic acid

reduced transition metals, such as cupric ions (Cu2+) to cuprous (Cu1+) and ferric ions

(Fe3+) to ferrous (Fe2+) during conversion from ascorbate to dehydroxyascorbate In

Vitro.[71] This reaction can generate superoxide and other ROS. However, in the body,free transition elements are unlikely to be present while iron and copper is bound to

diverse proteins.[65] Recent studies show that intravenous injection of 7.5g of ascorbate

daily for six days did not increase pro-oxidant markers;[72] thus, ascorbate as a pro-oxidant is unlikely to convert metals to create ROS in vivo.

Daily requirementsThe North American Dietary Reference Intake recommends 90 milligrams per day and

no more than 2 grams per day (2000 milligrams per day).[73] Other related speciessharing the same inability to produce vitamin C and requiring exogenous vitamin C

consume 20 to 80 times this reference intake.[74][75] There is continuing debate withinthe scientific community over the best dose schedule (the amount and frequency of

intake) of vitamin C for maintaining optimal health in humans.[76] It is generally agreedthat a balanced diet without supplementation contains enough vitamin C to preventscurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or

are under stress require slightly more.[73]

High doses (thousands of milligrams) may result in diarrhea in healthy adults.

Proponents of alternative medicine (specifically orthomolecular medicine)[77] claim theonset of diarrhea to be an indication of where the body’s true vitamin C requirementlies, because this is the point where body uses vitamin's water solubility to simply flushout the unusable portion, as the diarrhea length/intensity is directly correlated to thequantity of the overdose, though this has yet to be clinically verified.

GovernmentrecommendedintakesRecommendationsfor vitamin Cintake have been set by various national agencies:

75 milligrams per day: the United Kingdom's Food Standards Agency[1]

45 milligrams per day: the World Health Organization[78]

60 mg/day: Health Canada 2007[79]

60–95 milligrams per day: United States' National Academy of Sciences.[73]

The United States defined Tolerable Upper Intake Level for a 25-year-old male is 2,000milligrams per day.

Alternative recommendations on intakesSome independent researchers have calculated the amount needed for an adult humanto achieve similar blood serum levels as vitamin C synthesising mammals as follows:

400 milligrams per day: the Linus Pauling Institute.[80]

500 milligrams per 12 hours: Professor Roc Ordman, from research into biological

free radicals.[81]

3,000 milligrams per day (or up to 30,000 mg during illness): the Vitamin C

Foundation.[82]

6,000–12,000 milligrams per day: Thomas E. Levy, Colorado Integrative Medical

Centre.[83]

6,000–18,000 milligrams per day: Linus Pauling's personal use.[84]

Therapeutic usesVitamin C is necessary for the treatment and prevention of scurvy. Scurvy is commonlycomorbid with other diseases of malnutrition; sufficient vitamin C to prevent scurvy

occurs in most diets in industrialized nations.[85][86][87]

Vitamin C functions as an antioxidant. Adequate intake is necessary for health, but

supplementation is probably not necessary in most cases.[88][89][90][91]

Based on animal and epidemiological models, high doses of vitamin C may have

"protective effects" on lead-induced nerve and muscle abnormalities,[92] especially in

smokers.[93][94]

Dehydroascorbic acid, the main form of oxidized vitamin C in the body, may reduceneurological deficits and mortality following stroke due to its ability to cross the blood-brain barrier, while "the antioxidant ascorbic acid (AA) or vitamin C does not penetrate

the blood-brain barrier".[95]

Vitamin C's effect on the common cold has been extensively researched.

Vitamin C megadosageMain article: Vitamin C megadosageSeveral individuals and organizations advocate large doses of vitamin C based on in

vitro and retrospective studies,[96] although large, randomized clinical trials on theeffects of high doses on the general population have never taken place. Individuals whohave recommended intake well in excess of the current Dietary Reference Intake (DRI)include Robert Cathcart, Ewan Cameron, Steve Hickey, Irwin Stone, Matthias Rath andLinus Pauling. Arguments for megadosage are based on the diets of closely relatedapes and the likely diet of pre-historical humans, and that most mammals synthesizevitamin C rather than relying on dietary intake.

Stone[97] and Pauling[75] calculated, based on the diet of primates[74] (similar to whatour common ancestors are likely to have consumed when the gene mutated), that theoptimum daily requirement of vitamin C is around 2,300 milligrams for a humanrequiring 2,500 kcal a day. Pauling also criticized the established RDA as sufficient to

prevent scurvy, but not necessarily the dosage for optimal health.[84]

Higher vitamin C intake reduces serum uric acid levels, and is associated with lower

incidence of gout.[98]

Vitamin C has also been promoted as efficacious against a vast array of diseases andsyndromes. Research has been done on the effects of Vitamin C on a variety of

disorders and diseases including the following:the common cold,[99][100]

pneumonia,[101] heart disease,[100][102] AIDS,[103][104] autism,[105] low sperm

count,[106] age-related macular degeneration,[107][108] altitude sickness,[109] pre-

eclampsia,[110] amyotrophic lateral sclerosis,[111] heroin addiction,[112] asthma,[113]

tetanus,[114] and cancer.[115][116][117][118] These uses are poorly supported by the

evidence, and sometimes contraindicated.[119][120][121][122][123]

Testing for ascorbate levels in the bodySimple tests use DCPIP to measure the levels of vitamin C in the urine and in serum orblood plasma. However these reflect recent dietary intake rather than the level of

vitamin C in body stores.[6] Reverse phase high performance liquid chromatography isused for determining the storage levels of vitamin C within lymphocytes and tissue.

It has been observed that while serum or blood plasma levels follow the circadianrhythm or short term dietary changes, those within tissues themselves are more stableand give a better view of the availability of ascorbate within the organism. However,very few hospital laboratories are adequately equipped and trained to carry out suchdetailed analyses, and require samples to be analyzed in specialized

laboratories.[124][125]

Adverse effects

Common side-effectsRelatively large doses of vitamin C may cause indigestion, particularly when taken onan empty stomach.

When taken in large doses, vitamin C causes diarrhea in healthy subjects. In one trial,doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschooland school age, and 20 adults for more than 1400 days. With the higher doses, toxicmanifestations were observed in five adults and four infants. The signs and symptomsin adults were nausea, vomiting, diarrhoea, flushing of the face, headache, fatigue and

disturbed sleep. The main toxic reactions in the infants were skin rashes.[126]

Possible side-effects

As vitamin C enhances iron absorption,[127] iron poisoning can become an issue topeople with rare iron overload disorders, such as haemochromatosis. A geneticcondition that results in inadequate levels of the enzyme glucose-6-phosphatedehydrogenase (G6PD) can cause sufferers to develop hemolytic anemia after ingesting

specific oxidizing substances, such as very large dosages of vitamin C.[128]

There is a longstanding belief among the mainstream medical community that vitamin C

causes kidney stones, which is based on little science.[129] Although recent studies

have found a relationship,[130] a clear link between excess ascorbic acid intake and

kidney stone formation has not been generally established.[131] Some case reports existfor patients with oxalate deposits and a history of high dose vitamin C usage.

Discussions of a possible link are given in articles such as [132].

In a study conducted on rats, during the first month of pregnancy, high doses of vitamin

C may suppress the production of progesterone from the corpus luteum.[133]

Progesterone, necessary for the maintenance of a pregnancy, is produced by thecorpus luteum for the first few weeks, until the placenta is developed enough to produceits own source. By blocking this function of the corpus luteum, high doses of vitamin C(1000+ mg) are theorized to induce an early miscarriage. In a group of spontaneouslyaborting women at the end of the first trimester, the mean values of vitamin C weresignificantly higher in the aborting group. However, the authors do state: 'This could not

be interpreted as an evidence of causal association.'[134] However, in a previous studyof 79 women with threatened, previous spontaneous, or habitual abortion, Javert andStander (1943) had 91% success with 33 patients who received vitamin C together withbioflavonoids and vitamin K (only three abortions), whereas all of the 46 patients who

did not receive the vitamins aborted.[135]

Recent rat and human studies suggest that adding Vitamin C supplements to anexercise training program can cause a decrease in mitochondria production, hampering

endurance capacity.[136]

Chance of overdoseAs discussed previously, vitamin C exhibits remarkably low toxicity. The LD50 (the dose

that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per

kilogram of body weight when taken orally.[45] The LD50 in humans remains unknown,

owing to medical ethics that preclude experiments which would put patients at risk ofharm. However, as with all substances tested in this way, the LD50 is taken as a guide

to its toxicity in humans and no data to contradict this has been found.

Plant source Amount(mg / 100g)

Kakadu plum 3100Camu Camu 2800Rose hip 2000Acerola 1600Seabuckthorn 695Jujube 500Indian gooseberry 445Baobab 400Blackcurrant 200Red pepper 190Parsley 130Guava 100Kiwifruit 90Broccoli 90Loganberry 80Redcurrant 80Brussels sprouts 80Wolfberry (Goji) 73 †Lychee 70Cloudberry 60Elderberry 60Persimmon 60

† average of 3 sources; dried

Plant source Amount(mg / 100g)

Papaya 60Strawberry 60Orange 50Lemon 40Melon, cantaloupe 40Cauliflower 40Garlic 31Grapefruit 30Raspberry 30Tangerine 30Mandarin orange 30Passion fruit 30Spinach 30Cabbage raw green 30Lime 30Mango 28Blackberry 21Potato 20Melon, honeydew 20Cranberry 13Tomato 10Blueberry 10Pineapple 10Pawpaw 10

Plant source Amount(mg / 100g)

Grape 10Apricot 10Plum 10Watermelon 10

Natural and artificial dietary sourcesThe richest natural sources are fruits andvegetables, and of those, the Kakadu plum andthe camu camu fruit contain the highestconcentration of the vitamin. It is also present insome cuts of meat, especially liver. Vitamin C isthe most widely taken nutritional supplement andis available in a variety of forms, including tablets,drink mixes, crystals in capsules or naked crystals.

Vitamin C is absorbed by the intestines using asodium-ion dependent channel. It is transportedthrough the intestine via both glucose-sensitiveand glucose-insensitive mechanisms. Thepresence of large quantities of sugar either in the

intestines or in the blood can slow absorption.[137]

Plant sourcesWhile plants are generally a good source of vitamin C, the amount in foods of plantorigin depends on: the precise variety of the plant, the soil condition, the climate inwhich it grew, the length of time since it was picked, the storage conditions, and the

method of preparation.[138]

The following table is approximate and shows the relative abundance in different raw

plant sources.[139][140][141] As some plants were analyzed fresh while others were dried(thus, artifactually increasing concentration of individual constituents like vitamin C), thedata are subject to potential variation and difficulties for comparison. The amount isgiven in milligrams per 100 grams of fruit or vegetable and is a rounded average frommultiple authoritative sources:

Rose hips are a particularly richsource of vitamin C

Banana 9Carrot 9Avocado 8Crabapple 8Persimmon - fresh 7Cherry 7Peach 7Apple 6Asparagus 6Beetroot 5Chokecherry 5Pear 4Lettuce 4Cucumber 3Eggplant 2Raisin 2Fig 2Bilberry 1Horned melon 0.5Medlar 0.3

Animal Source Amount(mg / 100g)

Calf liver (raw) 36Beef liver (raw) 31Oysters (raw) 30Cod roe (fried) 26Pork liver (raw) 23Lamb brain (boiled) 17Chicken liver (fried) 13

Animal Source Amount(mg / 100g)

Lamb liver (fried) 12Calf adrenals (raw) 11[145]

Lamb heart (roast) 11Lamb tongue (stewed) 6Human milk (fresh) 4Goat milk (fresh) 2Cow milk (fresh) 2

Animal sourcesThe overwhelming majority of species of animalsand plants synthesise their own vitamin C, makingsome, but not all, animal products, sources ofdietary vitamin C.

Vitamin C is most present in the liver and leastpresent in the muscle. Since muscle provides themajority of meat consumed in the western humandiet, animal products are not a reliable source ofthe vitamin. Vitamin C is present in mother's milkand, in lower amounts, in raw cow's milk, withpasteurized milk containing only trace

amounts.[144] All excess vitamin C is disposed ofthrough the urinary system.

The following table shows the relative abundanceof vitamin C in various foods of animal origin,given in milligram of vitamin C per 100 grams of food:

Food preparationVitamin C chemically decomposes under certain conditions, many of which may occurduring the cooking of food. Vitamin C concentrations in various food substances

decrease with time in proportion to the temperature they are stored at[146] and cookingcan reduce the Vitamin C content of vegetables by around 60% possibly partly due toincreased enzymatic destruction as it may be more significant at sub-boiling

temperatures.[147] Longer cooking times also add to this effect, as will copper food

vessels, which catalyse the decomposition.[45]

Another cause of vitamin C being lost from food is leaching, where the water-solublevitamin dissolves into the cooking water, which is later poured away and not consumed.However, vitamin C doesn't leach in all vegetables at the same rate; research shows

Goats, like almost all animals,make their own vitamin C. Anadult goat, weighting approx.

70kg, will manufacture more than13,000 mg of vitamin C per day in

normal health, and levelsmanyfold higher when faced with

stress.[142][143]

broccoli seems to retain more than any other.[148] Research has also shown that fresh-cut fruits don't lose significant nutrients when stored in the refrigerator for a few

days.[149]

Vitamin C supplementsVitamin C is the most widely taken dietary

supplement.[150] It is available in many formsincluding caplets, tablets, capsules, drink mixpackets, in multi-vitamin formulations, in multipleantioxidant formulations, and crystalline powder.Timed release versions are available, as areformulations containing bioflavonoids such asquercetin, hesperidin and rutin. Tablet and capsulesizes range from 25 mg to 1500 mg. Vitamin C (asascorbic acid) crystals are typically available inbottles containing 300 g to 1 kg of powder (ateaspoon of vitamin C crystals equals 5,000 mg).

Artificial modes of synthesisVitamin C is produced from glucose by two mainroutes. The Reichstein process, developed in the1930s, uses a single pre-fermentation followed by a purely chemical route. The moderntwo-step fermentation process, originally developed in China in the 1960s, usesadditional fermentation to replace part of the later chemical stages. Both processes yield

approximately 60% vitamin C from the glucose feed.[151]

Research is underway at the Scottish Crop Research Institute in the interest of creatinga strain of yeast that can synthesise vitamin C in a single fermentation step from

galactose, a technology expected to reduce manufacturing costs considerably.[18]

World production of synthesised vitamin C is currently estimated at approximately110,000 tonnes annually. Main producers have been BASF/Takeda, DSM, Merck andthe China Pharmaceutical Group Ltd. of the People's Republic of China. China is slowlybecoming the major world supplier as its prices undercut those of the US and European

manufacturers.[152] By 2008 only the DSM plant in Scotland remained operational

outside the strong price competition from China.[153] The world price of vitamin C rosesharply in 2008 partly as a result of rises in basic food prices but also in anticipation ofa stoppage of the two Chinese plants, situated at Shijiazhuang near Beijing, as part of ageneral shutdown of polluting industry in China over the period of the Olympic

games.[154]

Food FortificationHealth Canada evaluated the effect of fortification of foods with abscorbate in the

guidance document, Addition of Vitamins and Minerals to Food, 2005.[155] HealthCanada categorized abscorbate as a ‘Risk Category A nutrients’. This means it is eithera nutrient for which an upper limit for intake is set but allows a wide margin of intakethat has a narrow margin of safety but non-serious critical adverse effects. HealthCanada recommended a minimum of 3 mg or 5 % of RDI in order for the food to claimto be a source of Vitamin C and maximum fortification of 12 mg (20 % of RDI) in orderto be claimed "Excellent Source".

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76. ↑ "Linus Pauling Vindicated; Researchers Claim RDA For Vitamin C is Flawed". PR Newswire. 6 July 2004.http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/07-06-2004/0002204911.Retrieved 2007-02-20.

77. ↑ Cathcart, Robert (1994). "Vitamin C, Titrating To Bowel Tolerance, Anascorbemia, and Acute InducedScurvy". Orthomed. http://www.orthomed.com/titrate.htm. Retrieved 2007-02-22.

78. ↑ "Vitamin and mineral requirements in human nutrition, 2nd edition" (PDF). World Health Organization.2004. http://whqlibdoc.who.int/publications/2004/9241546123_chap7.pdf. Retrieved 2007-02-20.

79. ↑ http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_vitamin_c_e.html hc-sc.gc.ca

80. ↑ Higdon, Jane. "Linus Pauling Institute Recommendations". Oregon State University.http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/index.html#lpi_recommend. Retrieved 2007-04-11.

81. ↑ Roc Ordman. "The Scientific Basis Of The Vitamin C Dosage Of Nutrition Investigator". Beloit College.http://www.beloit.edu/~nutritio/vitCdose.htm. Retrieved 2007-02-22.

82. ↑ "Vitamin C Foundation's RDA". http://www.vitamincfoundation.org/vitcrda.htm. Retrieved 2007-02-12.

83. ↑ Levy, Thomas E. (2002). Vitamin C Infectious Diseases, & Toxins. Xlibris. ISBN 1401069630. OCLC123353969. Chapter 5 - Vitamin C optidosing.

84. ↑ 84.0 84.1 Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN0-380-70289-4. OCLC 154663991 15690499.

85. ↑ WHO (June 4, 2001) (PDF). Area of work: nutrition. Progress report 2000.http://www.who.int//mipfiles/2299/MIP_01_APR_SDE_3.en.pdf.

86. ↑ Olmedo JM, Yiannias JA, Windgassen EB, Gornet MK (August 2006). "[Expression error: Missingoperand for > Scurvy: a disease almost forgotten]". Int. J. Dermatol. 45 (8): 909–13. doi:10.1111/j.1365-4632.2006.02844.x. PMID 16911372.

87. ↑ Velandia B, Centor RM, McConnell V, Shah M (August 2008). "[Expression error: Missing operand for> Scurvy is still present in developed countries]". J Gen Intern Med 23 (8): 1281–4. doi:10.1007/s11606-008-0577-1. PMID 18459013.

88. ↑ Shenkin A (2006). "[Expression error: Missing operand for > The key role of micronutrients]". Clin Nutr25 (1): 1–13. doi:10.1016/j.clnu.2005.11.006. PMID 16376462.

89. ↑ Woodside J, McCall D, McGartland C, Young I (2005). "[Expression error: Missing operand for >Micronutrients: dietary intake v. supplement use]". Proc Nutr Soc 64 (4): 543–53.doi:10.1079/PNS2005464. PMID 16313697.

90. ↑ Stanner SA, Hughes J, Kelly CN, Buttriss J (2004). "[Expression error: Missing operand for > A reviewof the epidemiological evidence for the 'antioxidant hypothesis']". Public Health Nutr 7 (3): 407–22.doi:10.1079/PHN2003543. PMID 15153272.

91. ↑ Rivers, Jerry M (1987). "[Expression error: Missing operand for > Safety of High-level Vitamin CIngestion]". Annals of the New York Academy of Sciences 498: 445. doi:10.1111/j.1749-6632.1987.tb23780.x. PMID 3304071.

92. ↑ Hasan MY, Alshuaib WB, Singh S, Fahim MA (2003). "[Expression error: Missing operand for > Effectsof ascorbic acid on lead induced alterations of synaptic transmission and contractile features in murinedorsiflexor muscle]". Life Sci. 73 (8): 1017–25. doi:10.1016/S0024-3205(03)00374-6. PMID 12818354.

93. ↑ Dawson E, Evans D, Harris W, Teter M, McGanity W (1999). "[Expression error: Missing operand for> The effect of ascorbic acid supplementation on the blood lead levels of smokers]". J Am Coll Nutr 18 (2):166–70. PMID 10204833.

94. ↑ Simon JA, Hudes ES (1999). "[Expression error: Missing operand for > Relationship of ascorbic acidto blood lead levels]". JAMA 281 (24): 2289–93. doi:10.1001/jama.281.24.2289. PMID 10386552.

95. ↑ Huang J, Agus DB, Winfree CJ, Kiss S, Mack WJ, McTaggart RA, Choudhri TF, Kim LJ, Mocco J, PinskyDJ, Fox WD, Israel RJ, Boyd TA, Golde DW, Connolly ES Jr. (2001). "[Expression error: Missingoperand for > Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potentcerebroprotection in experimental stroke]". Proceedings of the National Academy of Sciences 98 (20):11720–4. doi:10.1073/pnas.171325998. PMID 11573006.

96. ↑ Douglas, RM; Hemilä, H (2005). "[Expression error: Missing operand for > Vitamin C for Preventingand Treating the Common Cold]". PLoS Medicine 2 (6): e168. doi:10.1371/journal.pmed.0020168. PMID15971944.

97. ↑ Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease . Grosset and Dunlap. ISBN 0-448-11693-6. OCLC 3967737. http://www.vitamincfoundation.org/stone/.

98. ↑ Choi, MD, DrPH, HK; Gao, X; Curhan, G (March 9, 2009). "Vitamin C Intake and the Risk of Gout inMen". Archives of Internal Medicine. 169 (5): 502–507. doi:10.1001/archinternmed.2008.606. PMID19273781. PMC 2767211. http://archinte.ama-assn.org/cgi/content/abstract/169/5/502.

99. ↑ Douglas RM, Hemilä H, Chalker E, Treacy B (2007). "[Expression error: Missing operand for > VitaminC for preventing and treating the common cold]". Cochrane Database Syst Rev (3): CD000980.doi:10.1002/14651858.CD000980.pub3. PMID 17636648.

100. ↑ 100.0 100.1 Rath MW, Pauling LC. U.S. Patent 5,278,189 Prevention and treatment of occlusivecardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein(a). USPTO. 11Jan 1994.

101. ↑ Hemilä H, Louhiala P (2007). "[Expression error: Missing operand for > Vitamin C for preventing andtreating pneumonia]". Cochrane Database Syst Rev (1): CD005532.doi:10.1002/14651858.CD005532.pub2. PMID 17253561.

102. ↑ Vitamin and Mineral Supplements from the American Heart Association

103. ↑ "Nigeria: Vitamin C Can Suppress HIV/Aids Virus". allAfrica.com. 2006-05-22.http://allafrica.com/stories/200605220885.html. Retrieved 2006-06-16.

104. ↑ Boseley, Sarah (2005-05-14). "Discredited doctor's 'cure' for Aids ignites life-and-death struggle in SouthAfrica". The Guardian. http://www.guardian.co.uk/aids/story/0,7369,1483821,00.html. Retrieved 2007-02-21.

105. ↑ Levy SE, Hyman SL (2005). "[Expression error: Missing operand for > Novel treatments for autisticspectrum disorders]". Ment Retard Dev Disabil Res Rev 11 (2): 131–42. doi:10.1002/mrdd.20062. PMID15977319.

106. ↑ Akmal M, Qadri J, Al-Waili N, Thangal S, Haq A, Saloom K (2006). "[Expression error: Missingoperand for > Improvement in human semen quality after oral supplementation of vitamin C]". J Med Food9 (3): 440–2. doi:10.1089/jmf.2006.9.440. PMID 17004914.

107. ↑ Evans JR; Evans, Jennifer R (2006). "[Expression error: Missing operand for > Antioxidant vitamin andmineral supplements for slowing the progression of age-related macular degeneration]". Cochrane

Database Syst Rev (2): CD000254. doi:10.1002/14651858.CD000254.pub2. PMID 16625532.

108. ↑ Evans J (June 2008). "[Expression error: Missing operand for > Antioxidant supplements to prevent orslow down the progression of AMD: a systematic review and meta-analysis]". Eye 22 (6): 751–60.doi:10.1038/eye.2008.100. PMID 18425071.

109. ↑ Baillie JK, Thompson AA, Irving JB, et al. (March 2009). "[Expression error: Missing operand for >Oral antioxidant supplementation does not prevent acute mountain sickness: double blind, randomizedplacebo-controlled trial]". QJM 102 (5): 341–8. doi:10.1093/qjmed/hcp026. PMID 19273551.

110. ↑ Rumbold A, Duley L, Crowther CA, Haslam RR (2008). "[Expression error: Missing operand for >Antioxidants for preventing pre-eclampsia]". Cochrane Database Syst Rev (1): CD004227.doi:10.1002/14651858.CD004227.pub3. PMID 18254042.

111. ↑ Orrell RW, Lane RJ, Ross M (2007). "[Expression error: Missing operand for > Antioxidant treatmentfor amyotrophic lateral sclerosis / motor neuron disease]". Cochrane Database Syst Rev (1): CD002829.doi:10.1002/14651858.CD002829.pub4. PMID 17253482.

112. ↑ Libby, Alfred F. & Stone, Irwin (1977-07-16), The Hypoascorbemia-Kwashiorkor Approach to DrugAddiction Therapy: A Pilot Study, http://www.seanet.com/~alexs/ascorbate/197x/libby-af-orthomol_psych-1977-v6-n4-p300.htm

113. ↑ Kaur B, Rowe BH, Arnold E (2009). "[Expression error: Missing operand for > Vitamin Csupplementation for asthma]". Cochrane Database Syst Rev (1): CD000993.doi:10.1002/14651858.CD000993.pub3. PMID 19160185.

114. ↑ Hemilä H, Koivula TT (2008). "[Expression error: Missing operand for > Vitamin C for preventing andtreating tetanus]". Cochrane Database Syst Rev (2): CD006665. doi:10.1002/14651858.CD006665.pub2.PMID 18425960.

115. ↑ High Doses of Vitamin C Are Not Effective as a Cancer Treatment

116. ↑ "FDA OKs vitamin C trial for cancer". Physorg.com. January 12, 2007.http://www.physorg.com/news87833644.html. Retrieved 2007-04-06. "Federal approval of a clinical trial onintravenous vitamin C as a cancer treatment lends credence to alternative cancer care, U.S. researcherssaid."

117. ↑ Yeom CH, Jung GC, Song KJ (2007). "[Expression error: Missing operand for > Changes of terminalcancer patients' health-related quality of life after high dose vitamin C administration]". J. Korean Med. Sci.22 (1): 7–11. doi:10.3346/jkms.2007.22.1.7. PMID 17297243.

118. ↑ http://www.sciencedaily.com/releases/2008/08/080804190645.htm from Science News, Vitamin CInjections Slow Tumor Growth In Mice as reported in ScienceDaily Aug. 5, 2008, retrieved August 5, 2008

119. ↑ "Vitamin C (Ascorbic acid)". MedLine Plus. National Institute of Health. 2006-08-01.http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitaminc.html. Retrieved 2007-08-03.

120. ↑ Vitamin C by the American Cancer Society

121. ↑ Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008). "[Expression error: Missingoperand for > Antioxidant supplements for prevention of mortality in healthy participants and patients withvarious diseases]". Cochrane Database Syst Rev (2): CD007176. doi:10.1002/14651858.CD007176. PMID18425980.

122. ↑ Huang HY, Caballero B, Chang S, et al. (May 2006). "Multivitamin/mineral supplements and prevention ofchronic disease". Evid Rep Technol Assess (Full Rep) (139): 1–117. PMID 17764205.http://www.ahrq.gov/downloads/pub/evidence/pdf/multivit/multivit.pdf.

123. ↑ Brzozowska A, Kaluza J, Knoops KT, de Groot LC (April 2008). "[Expression error: Missing operandfor > Supplement use and mortality: the SENECA study]". Eur J Nutr 47 (3): 131–7. doi:10.1007/s00394-008-0706-y. PMID 18414768.

124. ↑ Emadi-Konjin P, Verjee Z, Levin A, Adeli K (2005). "Measurement of intracellular vitamin C levels inhuman lymphocytes by reverse phase high performance liquid chromatography (HPLC)" (PDF). ClinicalBiochemistry 38 (5): 450–6. doi:10.1016/j.clinbiochem.2005.01.018. PMID 15820776.http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TDD-4FMHSY9-2-1&_cdi=5196&_user=308069&_orig=search&_coverDate=05%2F31%2F2005&_sk=999619994&view=c&wchp=dGLzVzz-zSkWW&md5=05a80321d3767c0cdfd386ef7121a781&ie=/sdarticle.pdf.

125. ↑ Yamada H, Yamada K, Waki M, Umegaki K. (2004). "Lymphocyte and Plasma Vitamin C Levels in Type2 Diabetic Patients With and Without Diabetes Complications" (PDF). Diabetes Care 27 (10): 2491–2.doi:10.2337/diacare.27.10.2491. PMID 15451922. http://care.diabetesjournals.org/cgi/reprint/27/10/2491.pdf.

126. ↑ "Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants,emulsifiers and thickening agents". World Health Organization. 4 July 1973.http://www.inchem.org/documents/jecfa/jecmono/v05je20.htm. Retrieved 2007-04-13.

127. ↑ Fleming DJ, Tucker KL, Jacques PF, Dallal GE, Wilson PW, Wood RJ (2002). "Dietary factors associatedwith the risk of high iron stores in the elderly Framingham Heart Study cohort" (PDF). Am. J. Clin. Nutr. 76(6): 1375–84. PMID 12450906. http://www.ajcn.org/cgi/reprint/76/6/1375.pdf.

128. ↑ Cook JD, Reddy MB (2001). "Effect of ascorbic acid intake on nonheme-iron absorption from a completediet" (PDF). Am. J. Clin. Nutr. 73 (1): 93–8. PMID 11124756. http://www.ajcn.org/cgi/reprint/73/1/93.pdf.

129. ↑ Goodwin JS, Tangum MR (November 1998). "Battling quackery: attitudes about micronutrientsupplements in American academic medicine". Arch. Intern. Med. 158 (20): 2187–91.doi:10.1001/archinte.158.20.2187. PMID 9818798. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=9818798.

130. ↑ Massey LK, Liebman M, Kynast-Gales SA (2005). "Ascorbate increases human oxaluria and kidneystone risk" (PDF). J. Nutr. 135 (7): 1673–7. PMID 15987848. http://jn.nutrition.org/cgi/reprint/135/7/1673.pdf.

131. ↑ Naidu KA (2003). "Vitamin C in human health and disease is still a mystery? An overview" (PDF). J.Nutr. 2 (7): 7. doi:10.1186/1475-2891-2-7. PMID 14498993. PMC 201008.http://www.nutritionj.com/content/pdf/1475-2891-2-7.pdf.

132. ↑ S. Mashour, MD, J. F. Turner Jr., MD, FCCP, and R. Merrell, MD (2000). "Acute Renal Failure, Oxalosis,and Vitamin C Supplementation* A Case Report and Review of the Literature". Chest 118: 561.doi:10.1378/chest.118.2.561. http://www.chestjournal.org/content/118/2/561.long.

133. ↑ Ovcharov R, Todorov S (1974). "[Expression error: Missing operand for > [The effect of vitamin C onthe estrus cycle and embryogenesis of rats]]" (in Bulgarian). Akusherstvo i ginekologiia 13 (3): 191–5.PMID 4467736.

134. ↑ Vobecky JS, Vobecky J, Shapcott D, Cloutier D, Lafond R, Blanchard R (1976). "[Expression error:Missing operand for > Vitamins C and E in spontaneous abortion]". International journal for vitamin andnutrition research. Internationale Zeitschrift für Vitamin- und Ernährungsforschung. Journal international devitaminologie et de nutrition 46 (3): 291–6. PMID 988001.

135. ↑ Javert CT, Stander HJ (1943). "[Expression error: Missing operand for > Plasma Vitamin C andProthrombin Concentration in Pregnancy and in Threatened, Spontaneous, and Habitual Abortion]".Surgery, Gynecology, and Obstetrics 76 : 115–122.

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136. ↑ Mari-Carmen Gomez-Cabrera et al. (2008-01). "[Expression error: Missing operand for > Oraladministration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-inducedadaptations in endurance performance]". American Journal of Clinical Nutrition 87 (1): 142–9. PMID18175748.

137. ↑ Wilson JX (2005). "[Expression error: Missing operand for > Regulation of vitamin C transport]". Annu.Rev. Nutr. 25 : 105–25. doi:10.1146/annurev.nutr.25.050304.092647. PMID 16011461.

138. ↑ "The vitamin and mineral content is stable". Danish Veterinary and Food Administration.http://www.uk.foedevarestyrelsen.dk/Nutrition/Vitamin_mineral_content_is_stable/forside.htm. Retrieved2007-03-07.

139. ↑ "National Nutrient Database". Nutrient Data Laboratory of the US Agricultural Research Service.http://www.nal.usda.gov/fnic/foodcomp/search/. Retrieved 2007-03-07.

140. ↑ "Vitamin C Food Data Chart". Healthy Eating Club. http://www.healthyeatingclub.com/info/books-phds/books/foodfacts/html/data/data4i.html. Retrieved 2007-03-07.

141. ↑ "Natural food-Fruit Vitamin C Content". The Natural Food Hub.http://www.naturalhub.com/natural_food_guide_fruit_vitamin_c.htm. Retrieved 2007-03-07.

142. ↑ Chatterjee, IB (1973). "[Expression error: Missing operand for > Evolution and the Biosynthesis ofAscorbic Acid]". Science 182 (118): 1271–1272. doi:10.1126/science.182.4118.1271. PMID 4752221.

143. ↑ Irwin Stone, PC-A (1979). "Eight Decades of Scurvy". Orthomolecular Psychiatry 8, (2): 58–62.http://www.seanet.com/~alexs/ascorbate/197x/stone-i-orthomol_psych-1979-v8-n2-p58.htm.

144. ↑ Clark, Stephanie, Ph. D (8 January 2007). "Comparing Milk: Human, Cow, Goat & Commercial InfantFormula". Washington State University. http://www.saanendoah.com/compare.html. Retrieved 2007-02-28.

145. ↑ Toutain, P. L.; D. Béchu, and M. Hidiroglou (November 1997). "Ascorbic acid disposition kinetics in theplasma and tissues of calves". Am J Physiol Regul Integr Comp Physiol 273, (5, R1585-R1597): 1585.PMID 9374798. http://ajpregu.physiology.org/cgi/content/full/273/5/R1585.

146. ↑ Roig MG, Rivera ZS, Kennedy JF. A model study on rate of degradation of L-ascorbic acid duringprocessing using home-produced juice concentrates. Int J Food Sci Nutr. 1995 May;46(2):107-15.

147. ↑ Allen MA, Burgess SG.The Losses of Ascorbic Acid during the Large-scale Cooking of Green Vegetablesby Different Methods. British Journal of Nutrition (1950), 4 : 95-100

148. ↑ Combs GF. The Vitamins, Fundamental Aspects in Nutrition and Health. 2nd ed. San Diego, CA:Academic Press, 2001:245–272

149. ↑ Hitti, Miranda (2 June 2006). "Fresh-Cut Fruit May Keep Its Vitamins". WebMD.http://www.webmd.com/content/article/123/115022.htm. Retrieved 2007-02-25.

150. ↑ The Diet Channel Vitamin C might be the most widely known and most popular vitamin purchased as asupplement.

151. ↑ "The production of vitamin C" (PDF). Competition Commission. 2001. http://www.competition-commission.org.uk/rep_pub/reports/2001/fulltext/456a4.2.pdf. Retrieved 2007-02-20.

152. ↑ Patton, Dominique (2005-10-20). "DSM makes last stand against Chinese vitamin C". nutraingredients.http://www.nutraingredients.com/news/ng.asp?n=63349-dsm-vitamin-c. Retrieved 2007-02-20.

153. ↑ DSM vitamin plant gains green thumbs-up Shane Starling,Decision News Media SAS , 26-Jun-2008.Accessed July 2008

154. ↑ Vitamin C: Distruptions to Production in China to Maintain Firm Market FLEXNEWS, 30/06/2008,Accessed July 2008

155. ↑ Addition of Vitamins and Minerals to Food, 2005

Further readingBooks

Pauling, Linus (1976). Vitamin C, the Common Cold, and theFlu. W H Freeman & Co. ISBN 0716703610. OCLC 2388395.Cameron, Ewan; Linus Pauling, (1979). Cancer and Vitamin C.Pauling Institute of Science and Medicine.ISBN 0393500004. OCLC 5788147.Clemetson, C.A.B (1989). Vitamin C. Boca Raton, Florida: CRC Press. ISBN 0-8493-4841-2. OCLC 165609070 17918592. Monograph - Volumes I, II, III.

External linksJane Higdon, "Vitamin C", Micronutrient Information Center, Linus PaulingInstituteU.S. Patent 5,278,189 — "Prevention and treatment of occlusive cardiovasculardisease with ascorbate and substances that inhibit the binding of lipoprotein (a)",Inventors: Matthias W. Rath and Linus C. Paulingvitamin C at United Kingdom Food Standards AgencyNaidu KA (2003). "Vitamin C in human health and disease is still a mystery? Anoverview". Nutrition journal 2: 7. doi:10.1186/1475-2891-2-7. PMID 14498993.PMC 201008. http://www.nutritionj.com/content/2/1/7.Vitamin C Requirements: Optimal Health Benefits vs Overdose — a moderatedose advocacy siteVitamin C information from U.S. MedlinePlus Health Information

Vitamins (A11)

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Vitamin B6view original wikipedia article

Vitamin B6 is a water-soluble vitamin and is part

of the vitamin B complex group. Pyridoxalphosphate (PLP) is the active form and is acofactor in many reactions of amino acidmetabolism, including transamination, deamination,and decarboxylation. PLP also is necessary for theenzymatic reaction governing the release ofglucose from glycogen.

HistoryVitamin B6 is a water-soluble compound that was

discovered in the 1930s during nutrition studies onrats. In 1934, a Hungarian physician, Paul Gyorgydiscovered a substance that was able to cure askin disease in rats (dermititis acrodynia), thissubstance he named vitamin B6. In 1938,Lepkovsky isolated vitamin B6 from rice bran.Harris and Folkers in 1939 determined the structure of pyridoxine, and, in 1945, Snellwas able to show that there are two forms of vitamin B6, pyridoxal and pyridoxamine.Vitamin B6 was named pyridoxine to indicate its structural homology to pyridine. Allthree forms of vitamin B6 are precursors of an activated compound known as pyridoxal

5'-phosphate (PLP), which plays a vital role as the cofactor of a large number ofessential enzymes in the human body.

Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involvingamino acids. The reactions carried out by the PLP-dependent enzymes that act onamino acids include transfer of the amino group, decarboxylation, racemization, andbeta- or gamma-elimination or replacement. Such versatility arises from the ability ofPLP to covalently bind the substrate, and then to act as an electrophilic catalyst, therebystabilizing different types of carbanionic reaction intermediates.

Overall, the Enzyme Commission (EC; http://www.chem.qmul.ac.uk/iubmb/enzyme/ ) hascatalogued more than 140 PLP-dependent activities, corresponding to ~4% of allclassified activities.

The effectiveness as treatment for PMS, PMDD, and clinical depression is

debatable.[1][2] B6 is also considered an experimental but potentially effective treatmentfor schizophrenia and autism.

FormsSeven forms of this vitamin are known:

pyridoxine (PN). PN is the form that is given as vitamin B6 supplement.

pyridoxine 5'-phosphate (PNP).pyridoxal (PL).pyridoxal 5'-phosphate (PLP). PLP is the metabolically active form.pyridoxamine (PM).pyridoxamine 5'-phosphate (PMP).4-pyridoxic acid (PA). PA is the catabolite which is excreted in the urine.

All forms except PA can be interconverted.

FunctionsPyridoxal phosphate, the metabolically active form of vitamin B6, is involved in many

aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis,

Pyridoxine

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Functions

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Gluconeogenesis

Lipid metabolism

Metabolic functions

Amino acid metabolism

Gluconeogenesis

Neurotransmitter synthesis

Histamine synthesis

Hemoglobin synthesis and function

Gene expression

Dietary reference intakes

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Absorption

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Clinical assessment of vitamin B6

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hemoglobin synthesis and function and gene expression. Pyridoxal phosphate generallyserves as a coenzyme for many reactions and can help facilitate decarboxylation,transamination, racemization, elimination, replacement and beta-group interconversion

reactions[3]. The liver is the site for vitamin B6 metabolism.

Amino acid metabolismPyridoxal phosphate (PLP) is a cofactor in transaminases that can catabolize aminoacids. PLP is also an essential component of two enzymes that converts methionine tocysteine via two reactions. Low vitamin B6 status will result in decreased activity of

these enzymes. PLP is also an essential cofactor for enzymes involved in themetabolism of selenomethionine to selenohomocysteine and then fromselenohomocysteine to hydrogen selenide. Vitamin B6 is also required for the

conversion of tryptophan to niacin and low vitamin B6 status will impair this

conversion[3]. PLP is also used to create physiologically active amines bydecarboxylation of amino acids. Some notable examples of this include: histidine tohistamine, tryptophan to serotonin, glutamate to GABA (gamma-aminobutyric acid), anddihydroxyphenylalanine to dopamine.

GluconeogenesisVitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze

transamination reactions that are essential for the providing amino acids as a substratefor gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen

phosphorylase[3], the enzyme that is necessary for glycogenolysis to occur.

Lipid metabolismVitamin B6 is an essential component of enzymes that facilitate the biosynthesis of

sphingolipids[3]. Particularly, the synthesis of ceramide requires PLP. In this reactionserine is decarboxylated and combined with palmitoyl-CoA to form sphinganine which iscombined with a fatty acyl CoA to form dihydroceramide. Dihydroceramide is thenfurther desaturated to form ceramide. In addition, the breakdown of sphingolipids is alsodependent on vitamin B6 since S1P Lyase, the enzyme responsible for breaking down

sphingosine-1-phosphate, is also PLP dependent.

Metabolic functionsThe primary role of vitamin B6 is to act as a coenzyme to many other enzymes in the

body that are involved predominantly in metabolism. This role is performed by the activeform, pyridoxal phosphate. This active form is converted from the two other naturalforms founds in food: pyridoxal, pyridoxine and pyridoxamine.

Vitamin B6 is involved in the following metabolic processes:

amino acid, glucose and lipid metabolismneurotransmitter synthesishistamine synthesishemoglobin synthesis and functiongene expression

Amino acid metabolismPyridoxal phosphate is involved in almost all amino acid metabolism, from synthesis tobreakdown.

1. Transamination: transaminase enzymes needed to break down amino acids aredependent on the presence of pyridoxal phosphate. The proper activity of theseenzymes are crucial for the process of moving amine groups from one amino acid toanother.

2. Transsulfuration: Pyridoxal phosphate is a coenzyme needed for the proper functionof the enzymes cystathionine synthase and cystathionase. These enzymes work totransform methionine into cysteine.

3. Selenoamino acid metabolism: Selenomethionine is the primary dietary form ofselenium. Pyridoxal phosphate is needed as a cofactor for the enzymes that allow

selenium to be used from the dietary form. Pyridoxal phosphate also plays a cofactorrole in releasing selenium from selenohomocysteine to produce hydrogen selenide. This

hydrogen selenide can then be used to incorporate selenium into selenoproteins.[3]

4. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin

B6 status will impair this conversion[3].

GluconeogenesisVitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze

transamination reactions that are essential for providing amino acids as a substrate forgluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen

phosphorylase[3], the enzyme that is necessary for glycogenolysis to occur.

Neurotransmitter synthesisPyridoxal phosphate-dependent enzymes play a role in the biosynthesis of fourimportant neurotransmitters: serotonin, epinephrine, norepinephrine and gamma-

aminobutyric acid[3]. Serine racemase, which synthesizes the neuromodulator D-serine,is also a pyridoxal phosphate-dependent enzyme.

Histamine synthesis

Pyridoxal phosphate is involved in the metabolism of histamine[3].

Hemoglobin synthesis and functionPyridoxal phosphate aids in the synthesis of heme and can also bind to two sites on

hemoglobin to enhance the oxygen binding of hemoglobin[3].

Gene expressionIt transforms homocysteine in then cistation then in cysteine, leading indirectly toepigenetics phenomena of nature is still not certain; for this reason, Pyridoxal phosphateshould be used in the next experiments about epigenetics. Pyridoxal phosphate hasbeen implicated in increasing or decreasing the expression of certain genes. Increasedintracellular levels of the vitamin will lead to a decrease in the transcription ofglucocorticoid hormones. Also, vitamin B6 deficiency will lead to the increased

expression of albumin mRNA. Also, pyridoxal phosphate will influence gene expressionof glycoprotein IIb by interacting with various transcription factors. The result is inhibition

of platelet aggregation.[3]

Dietary reference intakesLife Stage Group RDA/AI* ULInfants0–6 months7–12 months

(mg/day)0.1*0.3*

(mg/day)NDND

Children1-3 yrs4-8 yrs

0.50.6

3040

Males9-13 yrs14-18 yrs19-50 yrs50- >70 yrs

1.01.31.31.7

6080100100

Females9-13 yrs13-18 yrs19-50 yrs50- >70 yrs

1.01.21.31.5

6080100100

Pregnancy<18 yrs19-50 yrs

1.91.9

80100

Lactation<18 yrs19-50 yrs

2.02.0

80100

The Institute of Medicine notes that "No adverse effects associated with Vitamin B6

from food have been reported. This does not mean that there is no potential for adverseeffects resulting from high intakes. Because data on the adverse effects of Vitamin B6

are limited, caution may be warranted. Sensory neuropathy has occurred from high

intakes of supplemental forms."[4] See the full Dietary Reference Intake table from theInstitute of Medicine's.

Food sourcesVitamin B6 is widely distributed in foods in both its free and bound forms. Good sources

include meats, whole grain products, vegetables, and nuts. Cooking, storage and

processing losses of vitamin B6 vary and in some foods may be more than 50%,[5]

depending on the form of vitamin present in the food. Plant foods lose the least duringprocessing as they contain mostly pyridoxine which is far more stable than the pyridoxalor pyridoxamine found in animal foods. For example, milk can lose 30-70% of its

vitamin B6 content when dried.[3] Vitamin B6 is found in the germ and aleurone layer of

grains and milling results to the reduction of this vitamin in white flour. Freezing andcanning are other food processing methods that results in the loss of vitamin B6 in

foods.[6]

AbsorptionVitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity

for absorption being so great, animals are able to absorb quantities much greater thanwhat is needed for physiological demands. The absorption of pyridoxal phosphate andpyridoxamine phosphate involves their dephosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in thedigestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in thejejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal

phosphate in the tissue.[3]

ExcretionThe products of vitamin B6 metabolism are excreted in the urine; the major product of

which is 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6 is

oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid isundetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical

marker to assess the vitamin B6 status of an individual.[3] Other products of vitamin

B6metabolism that are excreted in the urine when high doses of the vitamin have been

given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. A smallamount of vitamin B6 is also excreted in the feces.

DeficienciesThe classic clinical syndrome for B6 deficiency is a seborrhoeic dermatitis-like eruption,

atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and

neurologic symptoms of somnolence, confusion, and neuropathy.[7]

While severe vitamin B6 deficiency results in dermatologic and neurologic changes, less

severe cases present with metabolic lesions associated with insufficient activities of thecoenzyme pyridoxal phosphate. The most prominent of the lesions is due to impairedtryptophan-niacin conversion. This can be detected based on urinary excretion ofxanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result

from impaired transsulfuration of methionine to cysteine. The pyridoxal phosphate-dependent transaminases and glycogen phosphorylase provide the vitamin with its rolein gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose

tolerance.[3]

A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association

with other vitamins of the B complex. The elderly and alcoholics have an increased risk

of vitamin B6 deficiency, as well as other micronutrient deficiencies.[8] Renal patients

undergoing dialysis may experience vitamin B6 deficiency. The availability of vitamin B6to the body can be affected by certain drugs such as anticonvulsants and

corticosteriods.[9]

Clinical assessment of vitamin B6Pyridoxal phosphate in the plasma is considered to be one of the best indicator ofvitamin B6 status in the body. When plasma pyridoxal phosphate is less than 10nmol/L,

it is indicative of vitamin B6 deficiency.[10] Urinary 4-pyridoxic acid is also an indicator ofvitamin B6 deficiency. Urinary 4-pyridoxic of less than 3.0 mmol/day is suggestive of

vitamin B6 deficiency.[11]

ToxicityAn overdose of pyridoxine can cause a temporary deadening of certain nerves such asthe proprioceptory nerves; causing a feeling of disembodiment common with the loss of

proprioception. This condition is reversible when supplementation is stopped.[12]

Because adverse effects have only been documented from vitamin B6 supplements and

never from food sources, this article only discusses the safety of the supplemental formof vitamin B6 (pyridoxine). Although vitamin B6 is a water-soluble vitamin and is

excreted in the urine, very high doses of pyridoxine over long periods of time may resultin painful neurological symptoms known as sensory neuropathy. Symptoms include painand numbness of the extremities, and in severe cases difficulty walking. Sensoryneuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day.However, there have been a few case reports of individuals who developed sensoryneuropathies at doses of less than 500 mg daily over a period of months. None of thestudies, in which an objective neurological examination was performed, found evidenceof sensory nerve damage at intakes of pyridoxine below 200 mg/day. In order to preventsensory neuropathy in virtually all individuals, the Food and Nutrition Board of theInstitute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100mg/day for adults. Because placebo-controlled studies have generally failed to showtherapeutic benefits of high doses of pyridoxine, there is little reason to exceed the ULof 100 mg/day.

Preventive roles and therapeutic usesAt least one preliminary study has found that this vitamin may increase dream vividness

or the ability to recall dreams.[13] It is thought that this effect may be due to the role this

vitamin plays in the conversion of tryptophan to serotonin.[13]

The intake of vitamin B, from either diet or supplements, could cut the risk ofParkinson’s disease by half according to a prospective study from the Netherlands."Stratified analyses showed that this association was restricted to smokers," wrote the

authors.[14]

Pyridoxine has a role in preventing heart disease. Without enough pyridoxine, acompound called homocysteine builds up in the body. Homocysteine damages bloodvessel linings, setting the stage for plaque buildup when the body tries to heal thedamage.Vitamin B6 prevents this buildup, thereby reducing the risk of heart attack.Pyridoxine lowers blood pressure and blood cholesterol levels and keeps blood platelets

from sticking together. All of these properties work to keep heart disease at bay.[15]

Nutritional supplementation with high dose vitamin B6 and magnesium is one of the

most popular alternative medicine choices for autism.[16][17]

Some studies suggest that the B6-magnesium combination can also help attentiondeficit disorder, citing improvements in hyperactivity, hyperemotivity/aggressiveness and

improved school attention. [18]

A lack of the vitamin may play a role in sensitivity to monosodium glutamate (MSG), aflavor enhancer. This sensitivity can cause headaches, pain and tingling of the upperextremities, nausea, and vomiting. In both of these syndromes, supplementation ofpyridoxine alleviates symptoms only when people were deficient in the vitamin to begin

with.[15]

If people are marginally deficient in vitamin B6, they may be more susceptible to carpal

tunnel syndrome. Carpal tunnel syndrome is characterized by pain and tingling in thewrists after performing repetitive movements or otherwise straining the wrist on a

regular basis.[15] Vitamin B6 has been shown in at least two small-scale clinical studies[19][20] to have a beneficial effect on carpal tunnel syndrome, particularly in cases whereno trauma or overuse etiology for the CTS is known.

Vitamin B6 has long been publicized as a cure for premenstrual syndrome (PMS). Studyresults conflict as to which symptoms are eased, but most of the studies confirm thatwomen who take B6 supplements have reductions in bloating, breast pain, andpremenstrual acne flare, a condition in which pimples break out about a week before awoman's period begins.There is strong evidence that pyridoxine supplementation,starting ten days before the menstrual period, prevents most pimples from forming. Thiseffect is due to the vitamin's role in hormone and prostaglandin regulation. Skinblemishes are typically caused by a hormone imbalance, which vitamin B6 helps to

regulate.[15]

Mental depression is another condition which may result from low vitamin B6 intake.Because of pyridoxine's role in serotonin and other neurotransmitter production,supplementation often helps depressed people feel better, and their mood improves

significantly. It may also help improve memory in older adults.[15]

It is also suggested that ingestion of vitamin B6 can alleviate some of the manysymptoms of an alcoholic hangover and morning sickness from pregnancy. This might

be due to B6's mild diuretic effect.[21] Though the mechanism is not known, resultsshow that pyridoxamine has a therapeutic effects in clinical trials for diabetic

nephropathy.[22]

References1. ↑ Vitamin Pills: Popping Too Many?, WebMD

2. ↑ "Vitamin B6 Therapy for PMDD", Complementary and Alternative Medicine, Creighton University School ofMedicine

3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Combs, G.F. The Vitamins: FundamentalAspects in Nutrition and Health. 2008. San Diego: Elsevier

4. ↑ Food and Nutrition Board. Institute of Medicine. "Dietary Reference Intakes: Vitamins". NationalAcademies, 2001.

5. ↑ McCormick, D. B. Vitamin B6 In: Present Knowledge in Nutrition (Bowman, B. A. and Russell, R. M.,

eds), 9th edition, vol. 2, p.270. Washington, D.C.: International Life Sciences Institute, 2006.

6. ↑ Sauberlich H. Vitamins -how much is for keeps? Nutr Today 1987;22:20-28

7. ↑ Andrews' Diseases of the Skin, 10th Edition, Elsevier.

8. ↑ Bowman, B.A., Russell, R. M. Present Knowledge in Nutrition. 9th Edition. Washington, DC: ILSI Press;2006; pg.273

9. ↑ Sauberlich H. Vitamins -how much is for keeps? Nutr Today 1987; 22:20-28

10. ↑ Lui A., Lumeng L. Aronoff G., Li T-K. Relationship between body store of vitamin B6 and plasmapyridoxal-P clearance; metabolic balance studies in humans. J Lab Clin Med 1985;106:491-97

11. ↑ Leklem J. Vitamin B6: a status report. J. Nutr 1990;120:1503-7

12. ↑ Vitamin and Mineral Supplement Fact Sheets Vitamin B6

13. ↑ 13.0 13.1 Ebben, M., Lequerica, A., & Spielman A. (2002). Effects of pyridoxine on dreaming: a preliminarystudy. Perceptual & Motor Skills, 94(1), 135–140.

14. ↑ "Increased intake of vitamin B6Sheet". http://www.nutraingredients.com/news/ng.asp?n=69580-vitamin-b-folate-parkinson-s-disease. Retrieved 2006-08-11.

15. ↑ 15.0 15.1 15.2 15.3 15.4 http://recipes.howstuffworks.com/vitamin-b62.htm

16. ↑ Efficacy of vitamin B6 and magnesium in the treatm...[J Autism Dev Disord. 1995] - PubMed Result

17. ↑ Angley M, Semple S, Hewton C, Paterson F, McKinnon R (2007). "Children and autism—part 2—management with complementary medicines and dietary interventions" (PDF). Aust Fam Physician 36 (10):827–30. PMID 17925903.http://www.racgp.org.au/Content/NavigationMenu/Publications/AustralianFamilyPhys/2007issues/afp200710/200710angley.pdf.

18. ↑ Mousain-Bosc M et al. (2006). "[Expression error: Missing operand for > Improvement ofneurobehavioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficithyperactivity disorders.]". Magnesium Research 19 (1): 46–52. PMID 16846100.

19. ↑ Ellis J et al: Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnelsyndrome. Am J Clin Nutr. 1979 Oct;32(10):2040-6.

20. ↑ Kasdan ML, Janes C.: Carpal tunnel syndrome and vitamin B6. Plast Reconstr Surg. 1987 Mar;79(3):456-62.

21. ↑ THE MYSTERIOUS VITAMIN B6. By Dr. Russ Ebbets. Off The Road Column

22. ↑ Sergi V.C., Wenhui Zhang, Billy G.H., Anthony S.S., Paul A.V. Pyridoxamine protects proteins fromfunctional damage by 3-Deoxyglucosone; mechanism of action of pyridoxamine. Biochemistry 2008,47,997-1006.

External linksFacts about Vitamin B6 from Office of Dietary Supplements at National Institutes

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of HealthThe B6 database A database of B6-dependent enzymes at University of ParmaVitamin B6 Information Sheet from the Linus Pauling Institute at Oregon StateUniversityVitamin B6 (and magnesium) in the treatment of autism from the Autism ResearchInstituteCOT statement on vitamin B6 (pyridoxine) toxicity (June 1997) (Committee onToxicity of Chemicals in Food, Consumer Products and the Environment (COT))MeSH Vitamin+B6

Vitamins (A11)

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Pantothenic acid

IUPAC name 3-[(2,4-dihydroxy-3,3-dimethylbutanoyl)amino]propanoic acid

IdentifiersCAS number 137-08-6 PubChem 988SMILES CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O

PropertiesMolecularformula

C9H17NO5

Molar mass 219.23 g mol−1

Supplementary data pageStructure andproperties

n, εr, etc.

Thermodynamicdata

Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for materials

in their standard state (at 25 °C, 100 kPa)Infobox references

REFERENCE » WIKIPEDIA ARTICLES

Pantothenic acidview original wikipedia article

Pantothenic acid, also calledvitamin B5 (a B vitamin), is a

water-soluble vitamin required tosustain life (essential nutrient).Pantothenic acid is needed to formcoenzyme-A (CoA), and is critical inthe metabolism and synthesis ofcarbohydrates, proteins, and fats. Inchemical structure, it is the amidebetween D-pantoate and beta-alanine. Its name is derived fromthe Greek pantothen (πάντοθεν)meaning "from everywhere" andsmall quantities of pantothenic acidare found in nearly every food, withhigh amounts in whole-graincereals, legumes, eggs, meat, androyal jelly. It is commonly found asits alcohol analog, the provitaminpanthenol, and as calciumpantothenate. Pantothenic acid isan ingredient in some hair and skincare products.

Biological roleOnly the dextrorotatory (D) isomer of pantothenic acid possesses biologic activity.[1]

The levorotatory (L) form may antagonize the effects of the dextrorotatory isomer.[2]

Pantothenic acid is used in the synthesis of coenzyme A (CoA). Coenzyme A may actas an acyl group carrier to form acetyl-CoA and other related compounds; this is a way

to transport carbon atoms within the cell.[3] CoA is important in energy metabolism forpyruvate to enter the tricarboxylic acid cycle(TCA cycle) as acetyl-CoA, and for α-

ketoglutarate to be transformed to succinyl-CoA in the cycle.[4] CoA is also important inthe biosynthesis of many important compounds such as fatty acids, cholesterol, and

acetylcholine.[5] CoA is incidentally also required in the formation of ACP[6], which is

also required for fatty acid synthesis in addition to CoA.[7]

Pantothenic acid in the form of CoA is also required for acylation and acetylation, which,for example, are involved in signal transduction and enzyme activation and deactivation,

respectively.[8]

Since pantothenic acid participates in a wide array of key biological roles, it is essential

to all forms of life.[9] As such, deficiencies in pantothenic acid may have numerouswide-ranging effects, as discussed below.

Sources

Dietary

Small quantities of pantothenic acid are found in most foods.[10] The major food sourceof pantothenic acid is in meats, although the concentration found in food animals'muscles is only about half that in humans' muscles. [2] Whole grains are another goodsource of the vitamin, but milling often removes much of the pantothenic acid, as it is

found in the outer layers of whole grains[11]. Vegetables, such as broccoli and

avocados, also have an abundance of the acid.[12] In animal feeds, the most important

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Pantothenic acid

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Pantothenic acidBiological role

Sources

Dietary

Supplementation

Daily requirement

Absorption

Deficiency

Toxicity

Uses

Testicular Torsion

Diabetic Ulceration

Hypolipidemic Effects

Wound Healing

Hair care

Acne

Diabetic peripheral polyneuropathy

Ruminant Nutrition

Synonyms

See also

Enzymes

References

External links

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sources of the vitamin are rice, wheat brans, alfalfa, peanut meal, molasses, yeasts,and condensed fish solutions. The most significant sources of pantothenic acid in nature

are coldwater fish ovaries and royal jelly.[13]

A recent study also suggests that gut bacteria in humans can generate pantothenic

acid, but this has not yet been proven.[14]

SupplementationThe derivative of pantothenic acid, pantothenol, is a more stable form of the vitamin and

is often used as a source of the vitamin in multivitamin supplements.[15] Anothercommon supplemental form of the vitamin is calcium pantothenate. Calciumpantothenate is often used in dietary supplements because as a salt, it is more stablethan pantothenic acid in the digestive tract allowing for better absorption.

Possible benefits of supplementation: Doses of 2g/day of calcium pantothenate mayreduce the duration of morning stiffness, degree of disability, and pain severity inrheumatoid arthritis patients. Although the results are inconsistent, supplementation may

improve oxygen utilization efficiency and reduce lactic acid accumulation in athletes. [16]

Daily requirementPantothenate in the form of 4'phosphopantetheine is considered to be the more activeform of the vitamin in the body; however, any derivative must be broken down to

pantothenic acid before absorption[17]. Ten Mg of calcium pantothenate is equivalent to9.2 mg of pantothenic acid.

Age group Age Requirements[18]

Infants 0–6 months 1.7 MgInfants 7–12 months 1.8 MgChildren 1–3 years 2 MgChildren 4–8 years 3 MgChildren 9–12 years 4 MgAdult men and women 13+ years 5 MgPregnant women (vs. 5) 6 MgBreastfeeding women (vs. 5) 7 Mg

United Kingdom RDA: 6 mg/day

AbsorptionWithin most foods, pantothenic acid is in the form of CoA or Acyl Carrier Protein (ACP).In order for the intestinal cells to absorb this vitamin it must be converted into free

pantothenic acid[19]. Within the lumen of the intestine, CoA and ACP are hydrolyzed

into 4'-phosphopantetheine[20]. 4'-phosphopantetheine is then dephosphorylated into

pantetheine[21]. Pantetheinase, an intestinal enzyme, then hydrolyzes pantetheine into

free pantothenic acid[22].

Free pantothenic acid is absorbed into intestinal cells via a saturable, sodium-

dependent active transport system[23]. At high levels of intake, when this mechanism is

saturated, some pantothenic acid may also be absorbed via passive diffusion.[24]

However, as intake increases 10-fold, absorption rate decreases to 10%[25].

DeficiencyPantothenic acid deficiency is exceptionally rare and has not been thoroughly studied. Inthe few cases where deficiency has been seen (victims of starvation and limitedvolunteer trials), nearly all symptoms can be reversed with the return of pantothenic

acid[26].

Symptoms of deficiency are similar to other vitamin B deficiencies. There is impairedenergy production, due to low CoA levels, which could cause symptoms of irritability,

fatigue, and apathy[27]. Acetylcholine synthesis is also impaired, therefore, neurological

symptoms can also appear in deficiency[28]. They include numbness, paresthesia, and

muscle cramps[29]. Deficiency in pantothenic acid can also cause hypoglycemia, or an

increased sensitivity to insulin[30]. Insulin receptors are acylated with palmitic acid when

they do not want to bind with insulin[31]. Therefore, more insulin will bind to receptors

when acylation decreases, causing hypoglycemia[32]. Additional symptoms couldinclude: restlessness, malaise, sleep disturbances, nausea, vomiting, and abdominal

cramps[33]. In a few rare circumstances more serious (but reversible) conditions havebeen seen, such as adrenal insufficiency and hepatic encephalopathy.

It has been noted that painful burning sensations of the feet were reported in testsconducted on volunteers. Deficiency of pantothenic acid may explain similar sensations

reported in malnourished prisoners of war.[9]

Deficiency symptoms in other non-ruminant animals include disorders of the nervous,gastrointestinal, and immune systems, reduced growth rate, decreased food intake, skin

lesions and changes in hair coat, alterations in lipid and carbohydrate metabolism.[34]

ToxicityToxicity of pantothenic acid is unlikely. In fact, no Tolerable Upper Level Intake (UL) has

been established for the vitamin[35]. Large doses of the vitamin, when ingested, haveno reported side effects and massive doses (e.g. 10 g/day) may only yield mild intestinal

distress and diarrhea at worst[36].

There are also no adverse reactions known following parenteral or topical application of

the vitamin.[37]

However, a large dosis of vitamin B5 (e.g: 5 - 9 gram) is known to cause nausea and alack of fatigue.

UsesGiven pantothenic acid's prevalence among living things and the limited body of studiesin deficiency, many uses of pantothenic acid have been the subject of research.

Testicular Torsion

Testicular torsion can severely affect fertility if it occurs[38]. One study on a rat modelindicated that a treatment of 500 mg of dexpanthenol/kg body weight 30 minutes prior to

detorsion can greatly decrease the risk of infertility after torsion[39]. Pantothenic acid

has the ability to spare reduced glutathione levels[40]. Reactive oxygen species play a

role in testicular atrophy, which the glutathione can 'fight' against[41].

Diabetic UlcerationFoot ulceration is a problem commonly associated with diabetes, which often leads to

amputation[42]. A preliminary study completed by Abdelatif, Yakoot and Etmaanindicated that perhaps a royal jelly and panthenol ointment can help cure the

ulceration[43]. People studied with foot ulceration or deep tissue infection had a 96%

and 92% success rate of recovery[44]. However, as this was a pilot study, it was not a

randomized placebo-controlled double-blinded study[45]. While these results appearpromising, they need to be validated.

Hypolipidemic EffectsPantothenic acid derivatives, panthenol, phosphopantethine and pantethine, have also

been seen to improve the lipid profile in the blood and liver[46]. In a mouse model, they

injected 150 mg of the derivative/kg body weight[47]. All three derivatives were able toeffectively lower low-density lipoprotein (LDL) as well as triglyceride (TG) levels,panthenol was able to lower total cholesterol and pantethine was able to lower LDL-

cholesterol in the serum[48]. The decrease in LDL-cholesterol is significant, as it will

decrease the risk of heart attack and stroke[49]. In the liver, panthenol was the most

effective, as it lowered TG, T-chol, free cholesterol and cholesterol-ester levels[50].

Wound HealingA study in 1999 showed that pantothenic acid has an effect on wound healing in

vitro[51]. Wiemann and Hermann found that cell cultures with a concentration of100μg/mL calcium D-pantothenate increased migration, and the fibres ran directionallywith several layers, whereas the cell cultures without pantothenic acid healed in no

orderly motion, and with fewer layers[52]. Cell proliferation, or cell multiplication was

found to increase with pantothenic acid supplementation[53]. Finally, there wereincreased concentrations of two proteins, both of which have still to be been identified,

that was found in the supplemented culture, but not on the control[54]. Further studiesare needed to determine whether these effects will stand in vivo.

Hair careMouse models identified skin irritation and loss of hair color as possible results ofsevere pantothenic acid deficiency. As a result, the cosmetic industry began addingpantothenic acid to various cosmetic products, including shampoo. These products,however, showed no benefits in human trials. Despite this, many cosmetic products still

advertise pantothenic acid additives. [55][56][57][58][59][60]

AcneFollowing from discoveries in mouse trials, in the late 1990s a small study waspublished promoting the use of pantothenic acid to treat acne vulgaris.

According to a study published in 1995 by Dr. Lit-Hung Leung,[61] high doses of VitaminB5 resolved acne and decreased pore size. Dr. Leung also proposes a mechanism,

stating that CoA regulates both hormones and fatty-acids, and without sufficientquantities of pantothenic acid, CoA will preferentially produce androgens. This causesfatty acids to build up and be excreted through sebaceous glands, causing acne.Leung's study gave 45 Asian males and 55 Asian females varying doses of 10-20g ofpantothenic acid (100000% of the US Daily Value), 80% orally and 20% through topicalcream. Leung noted improvement of acne within one week to one month of the start ofthe treatment.

Diabetic peripheral polyneuropathy28 out of 33 patients (84.8%) previously treated with alpha-lipoic acid for peripheralpolyneuropathy reported further improvement after combination with pantothenic acid.The theoretical basis for this is that both substances intervene at different sites inpyruvate metabolism and are thus more effective than one substance alone. Additionalclinical findings indicated that diabetic neuropathy may occur in association with a latentprediabetic metabolic disturbance, and that the symptoms of neuropathy can befavourably influenced by the described combination therapy, even in poorly controlled

diabetes.[62]

Ruminant NutritionNo dietary requirement for pantothenic acid has been established as synthesis ofpantothenic acid by ruminal microorganisms appears to be 20 to 30 times more thandietary amounts. Net microbial synthesis of pantothenic acid in the rumen of steercalves has been estimated to be 2.2 mg/kg of digestible organic matter consumed perday. The degradation of dietary intake of pantothenic acid is considered to be 78percent. Supplementation of pantothenic acid at 5 to 10 times theoretic requirements did

not improve performance of feedlot cattle [63]

SynonymsPantothenateVitamin B5

See also

Coenzyme APanthenolRoger J. Williams (discoverer of pantothenic acid)Acyl carrier protein (ACP)

EnzymesKetopantoate hydroxymethyltransferase

References1. ↑ MedlinePlus. "Pantothenic acid (Vitamin-B5), Dexpanthenol". Natural Standard Research Collaboration.

U.S. National Library of Medicine. Last accessed 4 Jan 2007. [1]

2. ↑ Kimura S, Furukawa Y, Wakasugi J, Ishihara Y, Nakayama A. Antagonism of L(-)pantothenic acid on lipidmetabolism in animals. J Nutr Sci Vitaminol (Tokyo). 1980;26(2):113-7. PMID 7400861.

3. ↑ Voet, D., Voet, J.G., Pratt, C.W. (2006). Fundamentals of Biochemistry: Life at the Molecular Level, 2nded. Hoboken, NJ: John Wiley & Sons, Inc.

4. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

5. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

6. ↑ Sweetman, L. (2005). Pantothenic Acid. Encyclopedia of Dietary Supplements. 1: 517-525.

7. ↑ Voet, D., Voet, J.G., Pratt, C.W. (2006). Fundamentals of Biochemistry: Life at the Molecular Level, 2nded. Hoboken, NJ: John Wiley & Sons, Inc.

8. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning

9. ↑ 9.0 9.1 Jane Higdon, "Pantothenic Acid", Micronutrient Information Center, Linus Pauling Institute

10. ↑ "Nutrient Data Products and Services, Nutrient Data : Reports by Single Nutrients".http://www.ars.usda.gov/Services/docs.htm?docid=9673. Retrieved 2007-08-12.

11. ↑ Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, PantothenicAcid, Biotin, and Choline. National Academy Press, 2000 http://books.nap.edu/catalog/6015.html

12. ↑ Otten, J. J., Hellwig, J. P., Meyers, L. D. (2008). Dietary reference intakes: The essential guid to nutrientrequirements. Washington, DC: The National Academies Press

13. ↑ Combs,G. F. Jr. The vitamins: Fundamental Aspects in Nutrition and Health. 3rd Edition. Ithaca, NY:Elsevier Academic Press; 2008; pg.346

14. ↑ Said H, Ortiz A, McCloud E, Dyer D, Moyer M, Rubin S (1998). "[Expression error: Missing operandfor > Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared withpantothenic acid.]". Am J Physiol 275 (5 Pt 1): C1365–71. PMID 9814986.

15. ↑ Combs,G. F. Jr. The vitamins: Fundamental Aspects in Nutrition and Health. 3rd Edition. Ithaca, NY:Elsevier Academic Press; 2008; pg.347

16. ↑ Combs, Gerald. The Vitamins: Fundamental Aspects in Nutrition and Health. Burlington: ElsevierAcademic Press, 2008.

17. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

18. ↑ Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, PantothenicAcid, Biotin, and Choline. National Academy Press, 2000 http://books.nap.edu/catalog/6015.html

19. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

20. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

21. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

22. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

23. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

24. ↑ Combs GF. The vitamins: fundamental aspects in nutrition and health. 3rd ed. Boston: Elsevier, 2008.

25. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

26. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

27. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

28. ↑ Otten, J. J., Hellwig, J. P., Meyers, L. D. (2008). Dietary reference intakes: The essential guid to nutrientrequirements. Washington, DC: The National Academies Press

29. ↑ Otten, J. J., Hellwig, J. P., Meyers, L. D. (2008). Dietary reference intakes: The essential guid to nutrientrequirements. Washington, DC: The National Academies Press

30. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

31. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

32. ↑ Voet, D., Voet, J.G., Pratt, C.W. (2006). Fundamentals of Biochemistry: Life at the Molecular Level, 2nd

ed. Hoboken, NJ: John Wiley & Sons, Inc.

33. ↑ Otten, J. J., Hellwig, J. P., Meyers, L. D. (2008). Dietary reference intakes: The essential guid to nutrientrequirements. Washington, DC: The National Academies Press

34. ↑ Smith, C. M. and W. O. Song. 1996. Comparative nutrition of pantothenic acid. Nutr. Biochem. 7:312-321.

35. ↑ Trumbo, P. R. (2006). Pantothenic Acid. In Shils, M. E., Shike, M., Ross, A. C., Caballero, B., Cousins, R.J. (Eds) Modern Nutrition in Health and Disease. 10th ed. (pp.462-467) Philadelphia, PA: LippincottWilliams & Wilkins.

36. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

37. ↑ Combs, G. F. Jr. The Vitamins: Fundamental Aspects in Nutrition and Health. 2nd Edition. Ithaca, NY:Elsevier Academic Press; 1998; pg.374

38. ↑ Etensel, B., Özkıscık, S., Özkara, E., Serbest, Y. A., Yazıcı, M., Gürsoy, H. (2007). The protective effectof dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion. PediatricSurgery International. 23: 271-275.

39. ↑ Etensel, B., Özkıscık, S., Özkara, E., Serbest, Y. A., Yazıcı, M., Gürsoy, H. (2007). The protective effectof dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion. PediatricSurgery International. 23: 271-275.

40. ↑ Etensel, B., Özkıscık, S., Özkara, E., Karul, A., Öztan, O., Yazıcı, M., Gürsoy, H. (2007). Dexpanthenolattenuates lipid peroxidation and testicular damage at experimental ischemia and reperfusion injury.Pediatric Surgery International. 23: 177-181.

41. ↑ Etensel, B., Özkıscık, S., Özkara, E., Serbest, Y. A., Yazıcı, M., Gürsoy, H. (2007). The protective effectof dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion. PediatricSurgery International. 23: 271-275.

42. ↑ Abdelatif, M., Yakoot, M., Etmaan, M. (2008). Safety and efficacy of a new honey ointment on diabeticfoot ulcers: a prospective pilot study. Journal of Wound Care. 17.3:108-110.

43. ↑ Abdelatif, M., Yakoot, M., Etmaan, M. (2008). Safety and efficacy of a new honey ointment on diabeticfoot ulcers: a prospective pilot study. Journal of Wound Care. 17.3:108-110.

44. ↑ Abdelatif, M., Yakoot, M., Etmaan, M. (2008). Safety and efficacy of a new honey ointment on diabeticfoot ulcers: a prospective pilot study. Journal of Wound Care. 17.3:108-110.

45. ↑ Abdelatif, M., Yakoot, M., Etmaan, M. (2008). Safety and efficacy of a new honey ointment on diabeticfoot ulcers: a prospective pilot study. Journal of Wound Care. 17.3:108-110.

46. ↑ Naruta, E., Buko, V. (2001). Hypolipidemic effect of pantothenic acid derivatives in mice withhypothalamic obesity induced by aurothioglucose. Experimental and Toxologic Pathology. 53: 393-398.

47. ↑ Naruta, E., Buko, V. (2001). Hypolipidemic effect of pantothenic acid derivatives in mice withhypothalamic obesity induced by aurothioglucose. Experimental and Toxologic Pathology. 53: 393-398.

48. ↑ Naruta, E., Buko, V. (2001). Hypolipidemic effect of pantothenic acid derivatives in mice withhypothalamic obesity induced by aurothioglucose. Experimental and Toxologic Pathology. 53: 393-398.

49. ↑ Gropper, S. S, Smith, J. L., Groff, J. L. (2009). Advanced nutrition and human metabolism. Belmont, CA:Wadsworth, Cengage learning.

50. ↑ Naruta, E., Buko, V. (2001). Hypolipidemic effect of pantothenic acid derivatives in mice withhypothalamic obesity induced by aurothioglucose. Experimental and Toxologic Pathology. 53: 393-398.

51. ↑ Weimann, B. J., Hermann, D. (1999). Studies on wound healing: Effects of calcium D-pantothenate onthe migration, proliferation and protein synthesis of human dermal fibroblasts in culture. InternationalJournal for Vitamin and Nutrition Research. 69.2: 113-119.

52. ↑ Weimann, B. J., Hermann, D. (1999). Studies on wound healing: Effects of calcium D-pantothenate onthe migration, proliferation and protein synthesis of human dermal fibroblasts in culture. InternationalJournal for Vitamin and Nutrition Research. 69.2: 113-119.

53. ↑ Weimann, B. J., Hermann, D. (1999). Studies on wound healing: Effects of calcium D-pantothenate onthe migration, proliferation and protein synthesis of human dermal fibroblasts in culture. InternationalJournal for Vitamin and Nutrition Research. 69.2: 113-119.

54. ↑ Weimann, B. J., Hermann, D. (1999). Studies on wound healing: Effects of calcium D-pantothenate onthe migration, proliferation and protein synthesis of human dermal fibroblasts in culture. InternationalJournal for Vitamin and Nutrition Research. 69.2: 113-119.

55. ↑ G. David Novelli (1953). "[Expression error: Missing operand for > Metabolic Functions of PantothenicAcid]". Physiol Rev 33 (4): 525–43. PMID 13100068.

56. ↑ Schalock PC, Storrs FJ, Morrison L. (2000). "[Expression error: Missing operand for > Contact urticariafrom panthenol in hair conditioner]". Contact Dermatitis 43 (4): 223. doi:10.1034/j.1600-0536.2000.043004223.x. PMID 11011922.

57. ↑ D.W. Woolley (1941). "[Expression error: Missing operand for > Identification of the mouseantialopecia factor]". J. Biol. Chem. 139 (1): 29–34.

58. ↑ Shun Ishibashi , Margrit Schwarz , Philip K. Frykman , Joachim Herz and David W. Russell (1996)."[Expression error: Missing operand for > Disruption of Cholesterol 7-Hydroxylase Gene in Mice, I.Postnatal lethality reversed by bile acid and vitamin supplementation]". J. Biol. Chem. 271 (30): 18017–18023. doi:10.1074/jbc.271.30.18017. PMID 8663429.

59. ↑ C. Smith, W. Song (1996). "[Expression error: Missing operand for > Comparative nutrition ofpantothenic acid]". The Journal of Nutritional Biochemistry 7 (6): 312–321. doi:10.1016/0955-2863(96)00034-4.

60. ↑ Paul F. Fenton2, George R. Cowgill, Marie A. Stone and Doris H. Justice (1950). "[Expression error:Missing operand for > The Nutrition of the Mouse, VIII. Studies on Pantothenic Acid, Biotin, Inositol andP-Aminobenzoic Acid]". Journal of Nutrition 42 (2): 257–269. PMID 14795275.

61. ↑ Leung L (1995). "[Expression error: Missing operand for > Pantothenic acid deficiency as thepathogenesis of acne vulgaris]". Med Hypotheses 44 (6): 490–2. doi:10.1016/0306-9877(95)90512-X.PMID 7476595.

62. ↑ Münchener Medizinische Wochenschrift (Germany), 1997, 139/12 (34-37)

63. ↑ National Research Council. 2001. Nutrient Requirements of Dairy Cattle. 7th rev. ed. Natl. Acad. Sci.,Washington, DC.

External linksPDRhealth.com - Pantothenic acid

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Niacin

IUPAC name nicotinic acidOther names pyridine-3-carboxylic

acid, nicotinic acid,nicotinamide,niacinamide, vitamin B3

IdentifiersCAS number 59-67-6 PubChem 938MeSH NiacinSMILES C1=CC(=CN=C1)C(=O)OChemSpider ID 913

PropertiesMolecular formula C6H5NO2

Molar mass 123.11 g/molMelting point 236.6 °C, 510 K, 458 °F

Boiling point decomposes

Supplementary data pageStructure and properties n, εr, etc.

Thermodynamic data Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for

materials in their standard state (at 25 °C, 100kPa)

Infobox references

REFERENCE » WIKIPEDIA ARTICLES

Niacinview original wikipedia article

This article is about the organic compound and vitamin. For the band, see Niacin(band).

Niacin, also known as vitamin B3 or

nicotinic acid, is an organic compoundwith the formula C5H4NCO2H. This

colourless, water-soluble solid is aderivative of pyridine, with a carboxylgroup (COOH) at the 3-position. Otherforms of vitamin B3 include the

corresponding amide, nicotinamide("niacinamide"), where the carboxyl grouphas been replaced by a carboxamide group(CONH2), as well as more complex amides

and a variety of esters. The terms niacin,nicotinamide, and vitamin B3 are often

used interchangeably to refer to anymember of this family of compounds, sincethey have the same biochemical activity.

Niacin is converted to nicotinamide andthen to NAD and NADP in vivo. Althoughthe two are identical in their vitaminactivity, nicotinamide does not have thesame pharmacological effects as niacin,which occur as side-effects of niacin'sconversion. Nicotinamide does not reduce

cholesterol or cause flushing.[1]

Nicotinamide may be toxic to the liver at

doses exceeding 3 g/day for adults.[2]

Niacin is a precursor to NADH, NAD+,

NADP+ and NADPH, which play essential

metabolic roles in living cells.[3] Niacin isinvolved in both DNA repair, and theproduction of steroid hormones in theadrenal gland.

Niacin is one of five vitamins associated with a pandemic deficiency disease: these areniacin (pellagra), vitamin C (scurvy), thiamin (beriberi), vitamin D (rickets), and vitaminA deficiency, a syndrome which has no common name but is one of the most commonsymptomatic deficiencies worldwide. In larger doses, niacin can reverse atherosclerosisby lowering low density lipoprotein (LDL) and favorably affecting other compounds.

HistoryNiacin was first described by Hugo Weidel in 1873 in his studies of nicotine.[4] The

original preparation remains useful: the oxidation of nicotine using nitric acid.[5] Niacinwas extracted from livers by Conrad Elvehjem who later identified the active ingredient,

then referred to as the "pellagra-preventing factor" and the "anti-blacktongue factor."[6]

When the biological significance of nicotinic acid was realized, it was thoughtappropriate to choose a name to dissociate it from nicotine, to avoid the perception thatvitamins or niacin-rich food contains nicotine, or that cigarettes contain vitamins. Theresulting name 'niacin' was derived from nicotinic acid + vitamin.

Carpenter found in 1951 that niacin in corn is biologically unavailable, and can only be

released in very alkaline lime water of pH 11.[7] This process is known as

nixtamalization.[8]

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Niacin

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NiacinHistory

Dietary needs

Lipid modifying effects

Anti-Alzheimer's symptomatic effects

Toxicity

Inositol hexanicotinate

Biosynthesis and chemical synthesis

Receptor

Food sources

References

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Niacin is referred to as Vitamin B3 because it was the third of the B vitamins to be

discovered. It has historically been referred to as "vitamin PP."

Dietary needsMain article: PellagraDepending on the definition used, niacin is one of between 40 to 80 essential humannutrients.

Currently, niacin deficiency is rarely seen in developed countries and is usually apparent

in conditions of poverty and malnutrition and chronic alcoholism[9]. Alcoholic patientstypically experience increased intestinal permeability leading to negative healthoutcomes. Studies have indicated that in patients with alcoholic pellagra, niacindeficiency may be an important factor influencing both the onset and severity of thiscondition . Severe deficiency of niacin in the diet causes the disease pellagra. Pellagrais characterized by diarrhea, dermatitis and dementia as well as “necklace” lesions onthe lower neck, hyperpigmentation, thickening of the skin, inflammation of the mouthand tongue, digestive disturbances, amnesia, delirium, and eventually death, if left

untreated[10]. Common psychiatric symptoms of niacin deficiency include irritability, poor

concentration, anxiety, fatigue, restlessness, apathy, and depression[11]. Mild niacindeficiency has been shown to slow metabolism, causing decreased tolerance to thecold. Dietary niacin deficiency tends to occur in areas where people eat maize ("corn")as a staple food. Maize is the only grain low in niacin, and nixtamalization is needed toincrease the bioavaiability of niacin during meal/flour production. Nixtamalization refersto the process of cooking maize with alkaline lime. This is the primary processing stepduring the manufacture of maize products, including chips, tortillas, and taco shells. Thebasic pre-Columbian technique involves cooking whole maize in water for 12–16 hoursin large tanks. The steeped maize is referred to as nixtamal, and the cooked liquid isnejayote. This process functions to soften the pericarp of the maize, and allows theendosperm to absorb water, enabling its milling. The nixtamal is washed and thenstone-ground to produce masa, which is used to produce a variety of products withimproved bioavailability of niacin (Sefa-Dedeh et al., 2004).

The recommended daily allowance of niacin is 2–12 mg/day for children, 14 mg/day for

women, 16 mg/day for men, and 18 mg/day for pregnant or breast-feeding women.[12]

The upper limit for adult men and women is 35 mg/day which is based on flushing asthe critical adverse effect, this dose-dependent flushing effect consists of a singleepisode 10 to 20 minutes after niacin is taken.

Hartnup’s disease is a hereditary nutritional disorder resulting in niacin deficiency[13].This condition was first identified in the 1950’s by the Hartnup family in London. It isdue to a deficit in the intestines and kidneys, making it difficult for the body to breakdown and absorb dietary tryptophan. The resulting condition is similar to pellagra,including symptoms of red, scaly rash and sensitivity to sunlight. Oral niacin is given asa treatment for this condition in doses ranging from 40-200 mg with a good prognosis if

identified and treated early[14]. Niacin synthesis is also deficient in carcinoid syndrome,because of metabolic diversion of its precursor, tryptophan, to form serotonin.

Niacin status is generally tested through urinary biomarkers,[15] which are believed to

be more reliable than plasma levels.[16]

Lipid modifying effectsIn pharmacological doses, niacin has been proven to reverse atherosclerosis byreducing total cholesterol, triglyceride, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL); and increasing high-density lipoprotein (HDL).

Niacin, prescribed in doses between 1000 and 2000 mg two to three times daily,[17]

blocks the breakdown of fats in adipose tissue, more specifically the very-low-densitylipoprotein (VLDL), precursor of low-density lipoprotein (LDL) or "bad" cholesterol.Because niacin blocks breakdown of fats, it causes a decrease in free fatty acids in theblood and, as a consequence, decreased secretion of VLDL and cholesterol by the

liver.[18]

By lowering VLDL levels, niacin also increases the level of high-density lipoprotein(HDL) or "good" cholesterol in blood, and therefore it is sometimes prescribed for

patients with low HDL, who are also at high risk of a heart attack.[19][20]

The ARBITER 6-HALTS study, reported at the 2009 annual meeting of the American

Heart Association and in the New England Journal of Medicine[21] concluded that, whenadded to statins, 2000 mg/day slow-release niacin was more effective than Ezetimibe

(Zetia) in reducing atherosclerosis.[22]

As of August 2008, a combination of niacin with laropiprant is tested in a clinical trial.

Laropiprant reduces facial flushes induced by niacin. [23] Taking 650 mg of aspirin 20-30 minutes prior to taking niacin has also been proven to prevent flushing in 90% ofpatients, presumably by suppressing prostaglandin synthesis,[2] and while this regimenalso increases the risk of gastrointestinal bleeding,[3] the increased risk is less than 1percent. [4]

Anti-Alzheimer's symptomatic effectsVitamin B3 has been reported to prevent Alzheimer's-like symptoms in a mouse model

of the disease.[24]

ToxicityPharmacological doses of niacin (1.5 - 6 g per day) often lead to side-effects that caninclude dermatological complaints such as skin flushing and itching, dry skin, skinrashes including acanthosis nigricans. Gastrointestinal complaints, such as dyspepsia(indigestion) and liver toxicity (fulminant hepatic failure) have also been reported. Sideeffects of hyperglycemia, cardiac arrhythmias and birth defects have also been

reported.[25][26] The flush lasts for about 15 to 30 minutes, and is sometimesaccompanied by a prickly or itching sensation, particularly in areas covered by clothing.This effect is mediated by prostaglandin and can be blocked by taking 300 mg of aspirinhalf an hour before taking niacin, or by taking one tablet of ibuprofen per day. Takingthe niacin with meals also helps reduce this side effect. After several weeks of a

consistent dose, most patients no longer flush.[27] Slow- or "sustained"-release forms of

niacin have been developed to lessen these side-effects.[18][28] One study showed the

incidence of flushing was significantly lower with a sustained release formulation[29]

though doses above 2 g per day have been associated with liver damage, particularly

with slow-release formulations.[25] Flushing is often thought to involve histamine, but

histamine has been shown not to be involved in the reaction.[30] Prostaglandin (PGD2)

is the primary cause of the flushing reaction, with serotonin appearing to have a

secondary role in this reaction.[30]

High-dose niacin may also elevate blood sugar, thereby worsening diabetes mellitus.[25]

Hyperuricemia is another side-effect of taking high-dose niacin, and may exacerbate

gout.[31]

Niacin at doses used in lowering cholesterol has been associated with birth defects inlaboratory animals, with possible consequences for infant development in pregnant

women.[25]

Niacin at extremely high doses can have life-threatening acute toxic reactions.[32]

Extremely high doses of niacin can also cause niacin maculopathy, a thickening of themacula and retina which leads to blurred vision and blindness. This maculopathy is

reversible after stopping niacin intake.[33]

Inositol hexanicotinateOne popular form of dietary supplement is inositol hexanicotinate, usually sold as "flush-free" or "no-flush" niacin in units of 250, 500 or 1000 mg/tablet or capsule. While thisform of niacin does not cause the flushing associated with the immediate releaseproducts, the evidence that it has lipid modifying functions is contradictory, at best. Asthe clinical trials date from the early 1960s (Dorner, Welsh) or the late 1970s (Ziliotto,

Kruse, Agusti) it is difficult to assess them by today's standards.[34] A more recentplacebo-controlled trial was small (n=11/group), but results after three months at 1500mg/day showed no trend for improvements in total cholesterol, LDL-C, HDL-C ortriglycerides (AM Benjo; Atherosclerosis 2006;187:116-122). Thus, so far there is notenough evidence to recommend inositol hexanicotinate to treat dyslipidemia.Furthermore, the American Heart Association and the National Cholesterol EducationProgram both take the position that only prescription niacin should be used to treat

dyslipidemias, and only under the management of a physician. The reason given is thatniacin at effective intakes of 1500-3000 mg/day can also potentially have severeadverse effects. Monitoring of liver enzymes is necessary.

Biosynthesis and chemical synthesisThe liver cansynthesizeniacin fromthe essentialamino acidtryptophan,requiring 60mg oftryptophan tomake one mg

of niacin.[35]

The 5-memberedaromaticheterocycleof tryptophanis cleavedandrearrangedwith thealpha aminogroup oftryptophaninto the 6-memberedaromaticheterocycleof niacin.

Severalmillionkilograms ofniacin aremanufacturedeach year,starting from3-

methylpyridine.

ReceptorThe receptor for niacin is a G protein-coupled receptor called HM74A.[36] It couples to

Gi alpha subunit.[37]

Food sourcesNiacin is found in variety of foods including liver, chicken, beef, fish, cereal, peanuts andlegumes and is also synthesized from tryptophan, which is found in meat, dairy andeggs. In order to convert 1 mg of niacin, 60 mg of tryptophan is required.

Animal products:

liver, heart and kidneychickenbeeffish: tuna, salmonmilkeggs

Biosynthesis: Tryptophan → kynurenine → niacin

Biosynthesis

Fruits and vegetables:

avocadosdatestomatoesleaf vegetablesbroccolicarrotssweet potatoesasparagus

Seeds:

nutswhole grain productslegumessaltbush seeds

Fungi:

mushroomsbrewer's yeast

References1. ↑ Jaconello P (October 1992). "[Expression error: Missing operand for > Niacin versus niacinamide]".

CMAJ 147 (7): 990. PMID 1393911.

2. ↑ Knip M, Douek IF, Moore WP, et al. (2000). "[Expression error: Missing operand for > Safety of high-dose nicotinamide: a review]". Diabetologia 43 (11): 1337–45. doi:10.1007/s001250051536. PMID11126400.

3. ↑ Cox, Michael; Lehninger, Albert L; Nelson, David R. (2000). Lehninger principles of biochemistry . NewYork: Worth Publishers. ISBN 1-57259-153-6.

4. ↑ Weidel, H (1873). "[Expression error: Missing operand for > Zur Kenntniss des Nicotins]". JustusLiebig's Annalen der Chemie und Pharmacie 165: 330–349. doi:10.1002/jlac.18731650212.

5. ↑ Samuel M. McElvain (1941), "Nicotinic Acid", Org. Synth.,http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=CV1P0385.pdf; Coll. Vol. 1: 385

6. ↑ Elvehjem, C.A.; Madden, R.J.; Strongandd, F.M.. "[Expression error: Missing operand for > W.WOOLLEY 1938 The isolation and identification of the anti-blacktongue factor J]". J. Biol. Chem 123: 137.

7. ↑ LAGUNA J, CARPENTER KJ (September 1951). "Raw versus processed corn in niacin-deficient diets".J. Nutr. 45 (1): 21–8. PMID 14880960. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=14880960.

8. ↑ "Vitamin B3". University of Maryland Medical Center. 2002-01-04.http://www.umm.edu/altmed/articles/vitamin-b3-000335.htm. Retrieved 2008-03-31.

9. ↑ Pitsavas, Stergios; Christina Andreou, Franzesca Bascialla, Vasilis P. Bozikas, Athanasios Karavatos(2004). "Pellagra Encephalopathy Following B-Complex Vitamin Treatment without Niacin". InternationalJournal of Psychiatry in Medicine 31 (1): 91-96. http://baywood.metapress.com/link.asp?id=29xv1gg1u17krgjh. Retrieved 2009-11-27.

10. ↑ Prakash, Ravi; Sachin Gandotra, Lokesh Kumar Singh, Basudeb Das, Anuja Lakra. "Rapid resolution ofdelusional parasitosis in pellagra with niacin augmentation therapy". General Hospital Psychiatry 30 (6):581-584. doi:10.1016/j.genhosppsych.2008.04.011. http://www.sciencedirect.com/science/article/B6T70-4T24FKB-D/2/f619871a3d1f1d626b775c84523d6d94. Retrieved 2009-11-27.

11. ↑ Prakash, Ravi; Sachin Gandotra, Lokesh Kumar Singh, Basudeb Das, Anuja Lakra. "Rapid resolution ofdelusional parasitosis in pellagra with niacin augmentation therapy". General Hospital Psychiatry 30 (6):581-584. doi:10.1016/j.genhosppsych.2008.04.011. http://www.sciencedirect.com/science/article/B6T70-4T24FKB-D/2/f619871a3d1f1d626b775c84523d6d94. Retrieved 2009-11-27.

12. ↑ United States Department of Agriculture, National Agriculture Library, Food and Nutrition InformationCenter, Dietary Reference Intakes: Recommended Intakes for Individuals, Vitamins [1]

13. ↑ Prakash, Ravi; Sachin Gandotra, Lokesh Kumar Singh, Basudeb Das, Anuja Lakra. "Rapid resolution ofdelusional parasitosis in pellagra with niacin augmentation therapy". General Hospital Psychiatry 30 (6):581-584. doi:10.1016/j.genhosppsych.2008.04.011. http://www.sciencedirect.com/science/article/B6T70-4T24FKB-D/2/f619871a3d1f1d626b775c84523d6d94. Retrieved 2009-11-27.

14. ↑ Prakash, Ravi; Sachin Gandotra, Lokesh Kumar Singh, Basudeb Das, Anuja Lakra. "Rapid resolution ofdelusional parasitosis in pellagra with niacin augmentation therapy". General Hospital Psychiatry 30 (6):581-584. doi:10.1016/j.genhosppsych.2008.04.011. http://www.sciencedirect.com/science/article/B6T70-4T24FKB-D/2/f619871a3d1f1d626b775c84523d6d94. Retrieved 2009-11-27.

15. ↑ Institute of Medicine. (2006). Dietary Reference Intakes Research Synthesis: Workshop Summary, p. 37.National Academies Press.

16. ↑ Jacob RA, Swendseid ME, McKee RW, Fu CS, Clemens RA (April 1989). "Biochemical markers forassessment of niacin status in young men: urinary and blood levels of niacin metabolites". J. Nutr. 119 (4):591–8. PMID 2522982. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=2522982.

17. ↑ Marks, Jay W. (2005). "Niacin Monograph". MedicineNet, Inc..

18. ↑ 18.0 18.1 Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill MedicalPublishing Division. ISBN 0071451536. http://www.medicinenet.com/niacin/article.htm.

19. ↑ McGovern ME (2005). "[Expression error: Missing operand for > Taking aim at HDL-C. Raising levelsto reduce cardiovascular risk]". Postgrad Med 117 (4): 29–30, 33–5, 39 passim. PMID 15842130.

20. ↑ Canner PL, Berge KG, Wenger NK, et al. (1986). "[Expression error: Missing operand for > Fifteenyear mortality in Coronary Drug Project patients: long-term benefit with niacin]". J. Am. Coll. Cardiol. 8 (6):1245–55. PMID 3782631.

21. ↑ N Engl J Med 361:2113

22. ↑ Singer, Natasha (November 15, 2009). "Study Raises Questions About Cholesterol Drug’s Benefit". The

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New York Times. http://www.nytimes.com/2009/11/16/health/research/16heart.html. Retrieved November16, 2009.

23. ↑ Paolini JF, Bays HE, Ballantyne CM, et al. Extended-release niacin/laropiprant: reducing niacin-inducedflushing to better realize the benefit of niacin in improving cardiovascular risk factors. Cardiol Clin. 2008Nov;26(4):547-60.

24. ↑ Green, Kim N.; Joan S. Steffan, Hilda Martinez-Coria, Xuemin Sun, Steven S. Schreiber, Leslie MichelsThompson, and Frank M. LaFerla (November 5, 2008). "Nicotinamide Restores Cognition in Alzheimer'sDisease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau". The Journal of Neuroscience 28 (45): 11500–11510. doi:10.1523/JNEUROSCI.3203-08.2008. PMID 18987186. PMC 2617713. http://www.jneurosci.org/cgi/content/abstract/28/45/11500.Retrieved January 20, 2009.

25. ↑ 25.0 25.1 25.2 25.3 Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred(2006). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill. ISBN0071422803.

26. ↑ McGee, W (2007-02-01). "Medical Encyclopedia: Niacin". MedlinePlus.http://www.nlm.nih.gov/medlineplus/ency/article/002409.htm. Retrieved 2008-03-31.

27. ↑ "Guidelines for Niacin Therapy For the Treatment of Elevated Lipoprotein a (Lpa)". Rush Hemophilia &Thrombophilia Center. August 15, 2002, Revised July 27, 2005.http://www.rush.edu/Rush_Document/Niacin%20therapy%20for%20elevated%20Lpa,0.pdf. Retrieved 20November 2009. "facial flushing is a common side effect of niacin therapy that usually subsides afterseveral weeks of consistent niacin use"

28. ↑ Barter, P (2006). "[Expression error: Missing operand for > Options for therapeutic intervention: Howeffective are the different agents?]". European Heart Journal Supplements 8 (F): F47–F53.doi:10.1093/eurheartj/sul041.

29. ↑ Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C (2004). "[Expression error: Missingoperand for > Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role ofnicotinic acid--a position paper developed by the European Consensus Panel on HDL-C]". Curr Med ResOpin 20 (8): 1253–68. doi:10.1185/030079904125004402. PMID 15324528.

30. ↑ 30.0 30.1 "[Expression error: Missing operand for > Niacin-induced "Flush" Involves Release ofProstaglandin D2 from Mast Cells and Serotonin from Platelets: Evidence from Human Cells in Vitro and anAnimal Model]". Journal of Pharmacology and Experimental Therapeutics. 2008.

31. ↑ Capuzzi DM, Morgan JM, Brusco OA, Intenzo CM (2000). "[Expression error: Missing operand for >Niacin dosing: relationship to benefits and adverse effects]". Curr Atheroscler Rep 2 (1): 64–71.doi:10.1007/s11883-000-0096-y. PMID 11122726.

32. ↑ Mittal MK, Florin T, Perrone J, Delgado JH, Osterhoudt KC (2007). "[Expression error: Missing operandfor > Toxicity from the use of niacin to beat urine drug screening]". Ann Emerg Med 50 (5): 587–90.doi:10.1016/j.annemergmed.2007.01.014. PMID 17418450.

33. ↑ Gass JD (2003). "[Expression error: Missing operand for > Nicotinic acid maculopathy. 1973]". Retina(Philadelphia, Pa.) 23 (6 Suppl): 500–10. PMID 15035390.

34. ↑ Taheri, R (2003-01-15). "No-Flush Niacin for the Treatment of Hyperlipidemia". Medscape.http://www.medscape.com/viewarticle/447528. Retrieved 2008-03-31.

35. ↑ Jacobson, EL (2007). "Niacin". Linus Pauling Institute.http://lpi.oregonstate.edu/infocenter/vitamins/niacin/. Retrieved 2008-03-31.

36. ↑ Zhang Y, Schmidt RJ, Foxworthy P, et al. (2005). "[Expression error: Missing operand for > Niacinmediates lipolysis in adipose tissue through its G-protein coupled receptor HM74A]". Biochem. Biophys.Res. Commun. 334 (2): 729–32. doi:10.1016/j.bbrc.2005.06.141. PMID 16018973.

37. ↑ Zellner C, Pullinger CR, Aouizerat BE, et al. (2005). "[Expression error: Missing operand for >Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors]". Hum. Mutat. 25 (1): 18–21. doi:10.1002/humu.20121. PMID 15580557.

Vitamins (A11)

Categories:

Articles containing potentially dated statements from August 2008 | All articles containingpotentially dated statements | Hypolipidemic agents | B vitamins | Pyridines | Carboxylicacids | Inositol

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Riboflavin

IUPAC name 7,8-dimethyl- 10-((2R,3R,4S)- 2,3,4,5- tetrahydroxypentyl)benzo [g] pteridine- 2,4 (3H,10H)- dione

IdentifiersCAS number 83-88-5 PubChem 1072MeSH RiboflavinSMILES Cc1cc2c(cc1C)n(c-

3nc(=O)[nH]c(=O)c3n2)C[C@@H]([C@@H]([C@@H](CO)O)O)OProperties

Molecular formula C17H20N4O6

Molar mass 376.36 g/molMelting point 290 °C (dec.)

Supplementary data pageStructure andproperties

n, εr, etc.

Thermodynamicdata

Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for materials in their standard state (at

25 °C, 100 kPa)Infobox references

REFERENCE » WIKIPEDIA ARTICLES

Riboflavinview original wikipedia article

Riboflavin

(E101[1]),also knownas vitaminB2, is an

easilyabsorbedmicronutrientwith a keyrole inmaintaininghealth inhumans andanimals. It isthe centralcomponent ofthe cofactorsFAD andFMN, and isthereforerequired byallflavoproteins.As such,vitamin B2 is

required for awide varietyof cellular processes. Like the other B vitamins, it plays a key role in energymetabolism, and is required for the metabolism of fats, ketone bodies, carbohydrates,and proteins.

Milk, cheese, leafy green vegetables, liver, kidneys, legumes such as mature

soybeans,[2] yeast, mushrooms and almonds[3] are good sources of vitamin B2, but

exposure to light destroys riboflavin.

The name "riboflavin" comes from "ribose" and "flavin".

DiscoveryVitamin B was originally considered to have twocomponents, a heat-labile vitamin B1 and a heat-stable vitamin B2 (1). In the 1920s, vitamin B2 wasthought to be the factor necessary for preventingpellagra. In 1923, Paul Gyorgi in Heidelberg wasinvestigating egg white injury in rats, the curativefactor for this condition was called vitamin H. Sinceboth pellagra and vitamin H deficiency wereassociated with dermatitis, Gyorgi decided to testthe effect of vitamin B2 on vitamin H deficiency inrat. He enlisted the service of Wagner-Jauregg in Kuhan’s laboratory (1). In 1933, Kuhn,Gyorgy, and Wagner found that thiamin-free extracts of yeast, liver, or rice branprevented the growth failure of rats fed a thiamin supplemented diet. Further, they notedthat a yellow-green fluorescence in each extract promoted rat growth, and that theintensity of fluorescence was proportional to the effect on growth. This observationenabled them to develop a rapid chemical and bioassay to isolate the factor from eggwhite in 1933, they called it Ovoflavin. The same group then isolated the samepreparation (a growth-promoting compound with yellow-green fluorescence) from wheyusing the same procedure (lactoflavin). In 1934 Kuhan’s group identified the structure ofso-called flavin and synthesised vitamin B2 (1).

Fluorescent spectra of Riboflavin

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Riboflavin

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RiboflavinDiscovery

Toxicity

Industrial synthesis

Riboflavin in food: Occurrence, sources stability

Nutrition-Recommended Dietary Allowan(RDA)

Recommended Dietary Allowance (RD

Riboflavin deficiency

Assessment of Riboflavin Status

Function

Mechanism of Action

Clinical uses

Industrial Uses

Good sources

See also

References

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ToxicityRiboflavin is not toxic when taken orally, as its low solubility keeps it from being

absorbed in dangerous amounts from the gut.[4] Although toxic doses can be

administered by injection,[4] any excess at nutritionally relevant doses is excreted in the

urine,[5] imparting a bright yellow color when in large quantities. In humans, there is noevidence for riboflavin toxicity produced by excessive intakes. Even when 400 mg/d ofriboflavin was given orally to subjects in one study for three months to investigate theefficacy of riboflavin in the prevention of migraine headache, no short-term side effects

were reported.[6][7]

Industrial synthesisVarious biotechnological processes have been developed for industrial scale riboflavinbiosynthesis using different microorganisms, including filamentous fungi such as Ashbyagossypii, Candida famata and Candida flaveri as well as the bacteria Corynebacterium

ammoniagenes and Bacillus subtilis.[8] The latter organism has been geneticallymodified to both increase the bacteria's production of riboflavin and to introduce anantibiotic (ampicillin) resistance marker, and is now successfully employed at acommercial scale to produce riboflavin for feed and food fortification purposes. Thechemical company BASF has installed a plant in South Korea, which is specialized onriboflavin production using Ashbya gossypii. The concentrations of riboflavin in theirmodified strain are so high, that the mycelium has a reddish / brownish color andaccumulates riboflavin crystals in the vacuoles, which will eventually burst themycelium.

Riboflavin in food: Occurrence, sources andstabilityRiboflavin is yellow or yellow-orange in color andin addition to being used as a food coloring, it isalso used to fortify some foods. It is used in babyfoods, breakfast cereals, pastas, sauces,processed cheese, fruit drinks, vitamin-enrichedmilk products, and some energy drinks. Regardingoccurrence and sources of vitamin B2, Yeastextract is considered to be exceptionally rich invitamin B2, and liver and kidney are also richsources. Wheat bran, eggs, meat, milk, andcheese are important sources in diets containingthese foods. Cereals grains contain relatively lowconcentrations of flavins, but are important sourcesin those parts of the world where cereals constitute

the staple diet.[9][10] The milling of cereals resultsin considerable loss (up to 60%) of vitamin B2, sowhite flour is enriched in some countries such asUSA by addition of the vitamin. The enrichment ofbread and ready-to-eat breakfast cerealscontributes significantly to the dietary supply ofvitamin B2. Polished rice is not usually enriched,because the vitamin’s yellow color would make therice visually unacceptable to the major rice-consumption populations. However, most of theflavins content of the whole brown rice is retained ifthe rice is steamed prior to milling. This processdrives the flavins in the germ and aleurone layers into the endosperm. Free riboflavin isnaturally present in foods along with protein-bound FMN and FAD. Bovine milk contains

mainly free riboflavin, with a minor contribution from FMN and FAD.[11] In whole milk,

14% of the flavins are bound noncovalently to specific proteins.[12] Egg white and eggyolk contain specialized riboflavin-binding proteins, which are required for storage offree riboflavin in the egg for use by the developing embryo.

It is difficult to incorporate riboflavin into many liquid products because it has poorsolubility in water. Hence the requirement for riboflavin-5'-phosphate (E101a), a more

Riboflavin powder.

A riboflavin solution.

expensive but more soluble form of riboflavin.

Riboflavin is generally stable during the heat processing and normal cooking of foods iflight is excluded. The alkaline conditions in which riboflavin is unstable are rarelyencountered in foodstuffs. Riboflavin degradation in milk can occur slowly in dark during

storage in the refrigerator.[13] (7).

Nutrition-Recommended Dietary Allowance(RDA)

Recommended Dietary Allowance (RDA)The latest (1998) RDA recommendation for vitamin B2 are similar to the 1989 RDA,which for adults, suggested a minimum intake of 1.2 mg for persons whose caloric

intake may be > 2,000 Kcal.[14] The current RDAs for Riboflavin for adult men andwomen are 1.3 mg/day and 1.1 mg/day, respectively; the estimated averagerequirement for adult men and women are 1.1 mg and 0.9 mg, respectively.Recommendations for daily riboflavin intake increase with pregnancy and lactation to1.4 mg and 1.6 mg, respectively (1in advanced). For infants the RDA is 0.3-0.4 mg/day

and for children it is 0.6-0.9 mg/day.[15]

Riboflavin deficiencyFurther information: Ariboflavinosis

Riboflavin is continuously excreted in the urine of healthy individuals,[2] makingdeficiency relatively common when dietary intake is insufficient. However, riboflavin

deficiency is always accompanied by deficiency of other vitamins.[2]

A deficiency of riboflavin can be primary - poor vitamin sources in one's daily diet - orsecondary, which may be a result of conditions that affect absorption in the intestine,the body not being able to use the vitamin, or an increase in the excretion of thevitamin from the body.

In humans, signs and symptoms of riboflavin deficiency (ariboflavinosis) include crackedand red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at thecorners of the mouth (angular cheilitis), and a sore throat. A deficiency may also causedry and scaling skin, fluid in the mucous membranes, and iron-deficiency anemia. Theeyes may also become bloodshot, itchy, watery and sensitive to bright light.

Riboflavin deficiency is classically associated with the oral-ocular-genital syndrome.Angular cheilitis, photophobia, and scrotal dermatitis are the classic remembered signs.

In animals, riboflavin deficiency results in lack of growth, failure to thrive, and eventualdeath. Experimental riboflavin deficiency in dogs results in growth failure, weakness,ataxia, and inability to stand. The animals collapse, become comatose, and die. Duringthe deficiency state, dermatitis develops together with hair-loss. Other signs includecorneal opacity, lenticular cataracts, hemorrhagic adrenals, fatty degeneration of thekidney and liver, and inflammation of the mucus membrane of the gastrointestinal tract.Post-mortem studies in rhesus monkeys fed a riboflavin-deficient diet revealed thatabout one-third the normal amount of riboflavin was present in the liver, which is themain storage organ for riboflavin in mammals. These overt clinical signs of riboflavindeficiency are rarely seen among inhabitants of the developed countries. However,

about 28 million Americans exhibit a common ‘sub-clinical’ stage.[16] characterized by achange in biochemical indices (e.g. reduced plasma erythrocyte glutathione reductaselevels). Although the effects of long-term sub-clinical riboflavin deficiency are unknown,in children this deficiency results in reduced growth. Subclinical riboflavin deficiency hasalso been observed in women taking oral contraceptives, in the elderly, in people witheating disorders, and in disease states such as HIV, inflammatory bowel disease,diabetes and chronic heart disease. The fact that riboflavin deficiency does notimmediately lead to gross clinical manifestations indicates that the systemic levels ofthis essential vitamin are tightly regulated.

Assessment of Riboflavin StatusBiochemical tests are essential for confirming clinical cases of riboflavin deficiency andfor establishing subclinical deficiencies. Among these tests:

Erythrocyte glutathione reductase activity:

Glutathione reductase is a nicotinamide adenine dinucleotide phosphate (NADPH), aFAD-dependent enzyme, and the major flavoproteins in erythrocyte. The measurementof the activity coefficient of erythrocyte glutathione reductase (EGR) is the preferred

method for assessing riboflavin status.[17] It provides a measure of tissue saturation andlong-term riboflavin status. In vitro enzyme activity in terms of activity coefficients (AC)is determined both with and without the addition of FAD to the medium. ACs representa ratio of the enzyme’s activity with FAD to the enzyme’s activity without FAD. An AC of1.2 to 1.4, riboflavin status is considered low when FAD is added to stimulate enzymeactivity. An AC > 1.4 suggests riboflavin deficiency. On the other hand, if FAD is added

and AC is < 1.2, then riboflavin status is considered acceptable.[18] Tillotson and Baker

(1972)[19] reported that a decrease in the intakes of riboflavin was associated withincrease in EGR AC. in the U.K. study of Norwich elderly (Bailey et al., 1997), initialEGR AC values for both males and females were significantly correlated with thosemeasured 2 years later, suggesting that EGR AC may be a reliable measure of long-term biochemical riboflavin status of individuals. These findings are consistent with

earlier studies (Rutishauser et al., 1979).[20]

Urinary riboflavin excretion:

Experimental balance studies indicate that urinary riboflavin excretion rates increaseslowly with increasing intakes, until intake level approach 1.0 mg/d, when tissue

saturation occurs. At higher intakes, the rate of excretion increases dramatically.[21]

Once intakes of 2.5 mg/d are reached, excretion becomes approximately equal to therate of absorption (Horwitt et al., 1950)(18). At such high intake a significant proportionof the riboflavin intake is not absorbed.If urinary riboflavin excretion is <19 µg/gcreatinine (without recent riboflavin intake) or < 40 µg per day are indicative ofdeficiency.

FunctionFMN and FAD function as coenzymes for a wide variety of oxidative enzymes andremain bound to the enzymes during the oxidation-reduction reactions. Flavins can actas oxidizing agents because of their ability to accept a pair of hydrogen atoms.Reduction of isoalloxazine ring (FAD, FMN oxidized form) yields the reduced forms ofthe flavoproteins (FMNH2 and FADH2)(5).

Mechanism of ActionFlavoproteins exhibit a wide range of redox potential and therefore can play a widevariety of roles in intermediary metabolism (5). Some of these roles are:

Flavoproteins play very important roles in the electron transport chain(5)Decarboxylation of pyruvate and α-Ketoglutarate requires FAD()Fatty acyl CoA dehydrogenase requires FAD in fatty acid oxidation (5)FAD is required to the production of pyridoxic acid from pyridoxal (vitamin B6)The primary coenzyme form of vitamin B6 (Pyridoxal phosphate) is FMNdependent(5)FAD is required to convert retinal (Vitamin A) to retinoic acidSynthesis of an active form of folate (5-methyl THF) is FADH2 dependentFAD is required to convert tryptophan to niacin (vitamin B3)Reduction of the oxidized form of glutathione (GSSG) to its reduced form (GSH) isalso FAD dependent (5)

Clinical usesRiboflavin has been used in several clinical and therapeutic situations. For over 30years, riboflavin supplements have been used as part of the phototherapy treatment ofneonatal jaundice. The light used to irradiate the infants breaks down not only the toxincausing the jaundice, but the naturally occurring riboflavin within the infant's blood aswell.

More recently there has been growing evidence that supplemental riboflavin may be a

useful additive along with beta-blockers in the prevention of migraine headaches.[22]

Development is underway to use riboflavin to improve the safety of transfused blood byreducing pathogens found in collected blood. Riboflavin attaches itself to the nucleicacids (DNA and RNA) in cells, and when light is applied, the nucleic acids are broken,

effectively killing those cells. The technology has been shown to be effective forinactivating pathogens in all three major blood components: (platelets, red blood cells,and plasma). It has been shown to inactivate a broad spectrum of pathogens, includingknown and emerging viruses, bacteria, and parasites.

Recently riboflavin has been used in a new treatment to slow or stop the progression ofthe corneal disorder keratoconus. This is called corneal collagen crosslinking (CXL). Incorneal crosslinking, riboflavin drops are applied to the patient’s corneal surface. Oncethe riboflavin has penetrated through the cornea, Ultraviolet A light therapy is applied.This induces collagen crosslinking, which increases the tensile strength of the cornea.The treatment has been shown in several studies to stabilize keratoconus.

Industrial UsesBecause riboflavin is fluorescent under UV light, dilute solutions (0.015-0.025% w/w)are often used to detect leaks or to demonstrate coverage in an industrial system sucha chemical blend tank or bioreactor. (See the ASME BPE section on Testing andInspection for additional details.)

Good sourcesRiboflavin is found naturally in asparagus, bananas, persimmons, okra, chard, cottagecheese, milk, yogurt, meat, eggs and fish, each of which contain at least 0.1 mg of thevitamin per 3–10.5 oz (85–300 g) serving.(5). Riboflavin is destroyed by exposure toultraviolet light, so milk sold in transparent (glass/plastic) bottles will likely contain lessriboflavin than milk sold in opaque containers.

See alsoAriboflavinosis (riboflavin deficiency)FlavinRiboflavin synthaseRiboflavin kinase

References1. ↑ "Current EU approved additives and their E Numbers". UK Food Standards

Agency. July 27, 2007.http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist.Retrieved December 3, 2009.

2. ↑ 2.0 2.1 2.2 Brody, Tom (1999). Nutritional Biochemistry. San Diego: AcademicPress. ISBN 0-12-134836-9. OCLC 162571066 212425693 39699995 51091036.

3. ↑ Higdon, Jane; Victoria J. Drake (2007). "Riboflavin". Micronutrient InformationCenter. Linus Pauling Institute at Oregon State University.http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/. Retrieved December 3,2009.

4. ↑ 4.0 4.1 Unna, Klaus and Greslin, Joseph G. (1942). "[Expression error:Missing operand for > Studies on the toxicity and pharmacology of riboflavin]". JPharmacol Exp Ther 76 (1): 75–80.

5. ↑ Zempleni, J and Galloway, JR and McCormick, DB (1996). "[Expression error:Missing operand for > Pharmacokinetics of orally and intravenously administeredriboflavin in healthy humans]". Am J Clin Nutr (The American Society for Nutrition)63 (1): 54–66. PMID 8604671.

6. ↑ Boehnke C., Reuter U., Flach U., and et al., High-dose riboflavin treatment isefficacious in migraine prophylaxis: an open study in a tertiary care centre 2004Jul;11(7):475-7

7. ↑ Gropper S.S., Smith J.L., and Groff J.L., Riboflavin, Chapter 9, in AdvancedNutrition and Human Metabolism, 5th ed. Wadsworth CENGAG Learning, 2009,P329-333

8. ↑ Stahmann KP, Revuelta JL and Seulberger H. (2000). "[Expression error:Missing operand for > Three biotechnical processes using Ashbya gossypii,Candida famata, or Bacillus subtilis compete with chemical riboflavin production]".Appl Microbiol Biotechnol 53 (5): 509–516. doi:10.1007/s002530051649.

9. ↑ Food Standards Agency, McCance and Widdowson’s The Composition ofFoods, 6th summary ed, Royal Society of Chemistry, Cambridge, 2002

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10. ↑ Ball F.M. George, Riboflavin in Vitamins in Foods, Analysis, Bioavailability, andStability. Taylor and Francis Group, New York, 2006. P168-175

11. ↑ Ball F.M. George, Riboflavin in Vitamins in Foods, Analysis, Bioavailability, andStability. Taylor and Francis Group, New York, 2006. P168-175

12. ↑ Kanno, C., Kanehara, N., Shirafuji, K., and et al. Binding Form of Vitamin B2 inBovine Milk: its concentration, distribution, and binding linkage, J. Nutr. Sci.Vitaminol., 37, 15, 1991

13. ↑ Faron G, Drouin R, Pedneault L, et al. Recurrent cleft lip and palate in siblingsof a patient with malabsorption syndrome, probably caused by hypovitaminosis Aassociated with folic acid and riboflavin deficiencies. Teratology 2001;63:161–3

14. ↑ National Research Council. RDAs, 10th ed. Washington, DC: National AcademyPress, 1989, PP.132-37

15. ↑ Gropper S.S., Smith J.L., and Groff J.L., Riboflavin, Chapter 9, in AdvancedNutrition and Human Metabolism, 5th ed. Wadsworth CENGAG Learning, 2009,P329-333

16. ↑ Powers J. Hilary. Riboflavin (vitamin B-2) and health, Review Article. Am J ClinNutr 2003;77:1352–60

17. ↑ 10. Gibson S. Rosalind, Riboflavin in Principles of Nutritional Assessment, 2nded. OXFORD university press, 2005

18. ↑ Gropper S.S., Smith J.L., and Groff J.L., Riboflavin, Chapter 9, in AdvancedNutrition and Human Metabolism, 5th ed. Wadsworth CENGAG Learning, 2009,P329-333

19. ↑ Tilloston JA, Bashor EM. An enzymatic measurement of the riboflavin status inman. American J. Of Clin. Nutr., 1972; 72:251-261

20. ↑ Rutishauser IHE, Bates CJ, Paul AA, and et al. Long term vitamin status anddietary intake of health elderly subjects. I. Riboflavin. British J. of Nutr. , 1979;42:33-42

21. ↑ Gibson S. Rosalind, Riboflavin in Principles of Nutritional Assessment, 2nd ed.OXFORD university press, 2005.

22. ↑ Sándor PS, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migrainewith beta-blockers and riboflavin: differential effects on the intensity dependenceof auditory evoked cortical potentials. Headache. 2000 Jan;40(1):30-5.

External linksJane Higdon, "Riboflavin", Micronutrient Information Center, Linus PaulingInstituteMirasol PRT includes a brief description of riboflavin as an agent to inactivatepathogens.

Vitamins (A11)

Categories:

Flavins | Vitamins | Coenzymes

HistoryView article history

All Wikipedia content is licensed under the GNU Free Document License or the CreativeCommons CC-BY-SA license or is otherwise used here in compliance with the Copyright Act

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Thiamine

IUPAC name 2-[3-[(4-amino- 2-methyl- pyrimidin-5-yl) methyl]- 4-methyl- thiazol- 5-yl]ethanol

Other names Aneurine hydrochloride, thiaminIdentifiers

CAS number 59-43-8 (Cl-) ,67-03-8 (Cl-.HClhydrochloride)

PubChem 1130MeSH ThiamineSMILES [Cl-].Cc1c(CCO)sc[n+]1Cc2cncnc2NChemSpider ID 5819

PropertiesMolecularformula

C12H17N4OS+Cl-.HCl

Molar mass 337.27Melting point 248-260 °C (hydrochloride salt)

HazardsMSDS External MSDSMain hazards Allergies

Supplementary data pageStructure andproperties

n, εr, etc.

Thermodynamicdata

Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS

(what is this?) (verify)Except where noted otherwise, data are given for

materials in their standard state (at 25 °C, 100 kPa)Infobox references

REFERENCE » WIKIPEDIA ARTICLES

Thiamineview original wikipedia article

Thiamine or thiamin,[1] sometimescalled aneurin, is a water-solublevitamin of the B complex (vitamin B1),

whose phosphate derivatives areinvolved in many cellular processes.The best characterized form is thiaminediphosphate (ThDP), a coenzyme inthe catabolism of sugars and aminoacids. In yeast, ThDP is also requiredin the first step of alcoholicfermentation.

Thiamine is synthesized in bacteria,fungi and plants. Animals must coverall their needs from their food andinsufficient intake results in a diseasecalled beriberi affecting the peripheralnervous system (polyneuritis) and/orthe cardiovascular system, with fataloutcome if not cured by thiamine

administration.[2] In less severedeficiency, nonspecific signs includemalaise, weight loss, irritability and

confusion.[3] Today, there is still a lot ofwork devoted to elucidating the exactmechanisms by which thiaminedeficiency leads to the specificsymptoms observed (see below).Finally, new thiamine phosphatederivatives have recently been

discovered,[4] emphasizing thecomplexity of thiamine metabolism andthe need for more research in the field.

History: Thediscovery of vitaminsand the biochemicallesionThiamine was the first of the water-soluble vitamins to be described,[2] leading to thediscovery of more such trace compounds essential for survival and to the notion ofvitamin. Chinese medical texts referred to beriberi (a thiamine deficiency disease) as

early as 2700 BC.[5] It was not until AD 1884 that Kanehiro Takaki (1849-1920), asurgeon general in the Japanese navy, rejected the previous germ theory and attributedthe disease to insufficient nitrogen intake (protein deficiency).

In 1897 Christiaan Eijkman (1858-1930), a military doctor in the Dutch Indies,discovered that fowl fed on a diet of cooked, polished rice developed paralysis, which

could be reversed by discontinuing rice polishing.[6] He attributed that to a nerve poisonin the endosperm of rice, from which the outer layers of the grain gave protection to thebody. Eijkman was awarded the Nobel Prize in Physiology and Medicine in 1929,because his observations led to the discovery of vitamins. An associate, Gerrit Grijns(1865-1944), correctly interpreted the connection between excessive consumption ofpolished rice and beriberi in 1901: he concluded that rice contained an essential nutrient

in the outer layers of the grain that was removed by polishing.[7]

In 1911 Casimir Funk isolated an antineuritic substance from rice bran that he called a

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Thiamine

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ThiamineHistory: The discovery of vitamins and thbiochemical lesion

Chemical properties

Biosynthesis

Nutrition

References

Reference Daily Intake and high doses

Antagonists

Absorption and transport

Absorption

Bound to serum proteins

Cellular uptake

Tissue distribution

Excretion

Thiamine phosphate derivatives and func

Thiamine monophosphate

Thiamine diphosphate

Thiamine triphosphate

Adenosine thiamine triphosphate

Adenosine thiamine diphosphate

Deficiency

Beriberi

Alcoholic brain disease

Thiamine deficiency in poultry

Thiamine deficiency in ruminants

Idiopathic paralytic disease in wild bir

Analysis and diagnostic testing

Genetic diseases

Research

Understanding the mechanism by whithiamine deficiency leads to selectiveneuronal death

Catalytic mechanisms in thiaminediphosphate-dependent enzymes

Non-cofactor roles of thiamine derivat

Persistent carbenes

See also

References

External links

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“vitamine” (on account of its containing an amino group). Dutch chemists, BarendCoenraad Petrus Jansen (1884-1962) and his closest collaborator Willem Frederik

Donath (1889-1957), went on to isolate and crystallize the active agent in 1926,[8]

whose structure was determined by Robert Runnels Williams (1886-1965), a USchemist, in 1934. Thiamine (“sulfur-containing vitamin”) was synthesized in 1936 by the

same group[9].

It was first named “aneurin” (for anti-neuritic vitamin).[10] Sir Rudolph Peters, in Oxford,introduced thiamine-deprived pigeons as a model for understanding how thiaminedeficiency can lead to the pathological-physiological symptoms of beriberi. Indeed,feeding the pigeons upon polished rice leads to an easily recognizable behavior of headretraction, a condition called opisthotonos. If not treated, the animal will die after a fewdays. Administration of thiamine at the stage of opithotonos will lead to a complete cureof the animal within 30 min. As no morphological modifications were observed in thebrain of the pigeons before and after treatment with thiamine, Peeters introduced the

concept of biochemical lesion[11]

When Lohman and Schuster (1937) showed that the diphosphorylated thiaminederivative (thiamine diphosphate, ThDP) was a cofactor required for the oxydative

decarboxylation of pyruvate,[12] (a reaction now known to be catalyzed by pyruvatedehydrogenase), the mechanism of action of thiamine in the cellular metabolismseemed to be elucidated. Presently, this view seems to be oversimplified: pyruvatedehydrogenase is only one of several enzymes requiring thiamine diphosphate as acofactor, moreover other thiamine phosphate derivatives have been discovered sincethen, and they may also contribute to the symptoms observed during thiaminedeficiency.

Finally, the mechanism by which the thiamine moiety of ThDP exerts its coenzymefunction by proton substitution on position 2 of the thiazolium ring was elucidated by

Ronald Breslow in 1958.[13]

Chemical propertiesThiamine is a colorless compound with a chemical formula C12H17N4OS. Its structure

contains a pyrimidine ring and a thiazole ring linked by a methylene bridge. Thiamine issoluble in water, methanol, and glycerol and practically insoluble in acetone, ether,chloroform, and benzene. It is stable at acidic pH, but is unstable in alkaline

solutions.[2][14] Thiamine is unstable to heat, but stable during frozen storage. It is

unstable when exposed to ultraviolet light[14] and gamma irradiation.[15][16] Thiamine

reacts strongly in Maillard-type reactions.[2]

BiosynthesisComplex thiamine biosynthetic pathways occur in

bacteria, some protozoans, plants and fungi.[17][18]

The thiazole and pyrimidine moieties aresynthesized separately and then assembled to formThMP by thiamine-phosphate synthase (EC2.5.1.3). The exact biosynthetic pathways maydiffer among organisms. In E. coli and otherenterobacteriaceae ThMP may be phosphorylatedto the cofactor ThDP by a thiamine-phosphatekinase (ThMP + ATP → ThDP + ADP, EC2.7.4.16). In most bacteria and in eukaryotes,ThMP is hydrolyzed to thiamine, that may then bepyrophosphorylated to ThDP by thiaminediphosphokinase (thiamine + ATP → ThDP + AMP,EC 2.7.6.2).

The biosynthetic pathways are regulated byriboswitches in all organisms that synthesisethiamine. If there is sufficient thiamine present inthe cell then the thiamine binds to the mRNAencoding genes required in the pathway preventingthe translation of the enzymes. If there is no thiamine present then there is no inhibitionand the enzymes required for the biosynthesis are produced. The specific riboswitch,the TPP riboswitch, is the only riboswitch that has been identified in both eukaryotic and

A 3D representation of the TPPriboswitch with thiamine bound

prokaryotic organisms.[19]

Nutrition

ReferencesThiamine is found in a wide variety of foods at low concentrations. Yeast and pork arethe most highly concentrated sources of thiamine. Cereal grains, however, are generallythe most important dietary sources of thiamine, by virtue of their ubiquity. Of these,whole grains contain more thiamine than refined grains, as thiamine is found mostly inthe outer layers of the grain and in the germ (which are removed during the refiningprocess). For example, 100 g of whole wheat flour contains 0.55 mg of thiamine, while100 g of white flour only contains 0.06 mg of thiamine. In the US, processed flour mustbe enriched with thiamine mononitrate (along with niacin, ferrous iron, riboflavin andfolic acid) to replace that lost in processing.

Some other foods rich in thiamine are oatmeal, flax and Sunflower seeds, brown rice,whole grain rye, asparagus, kale, cauliflower, potatoes, oranges, liver (beef, pork and

chicken) and eggs.[3]

Thiamine hydrochloride is a food additive used to add a brothy/meaty flavor to graviesor soups.

Reference Daily Intake and high dosesThe RDA in most countries is set at about 1.4 mg. However, tests on volunteers at daily

doses of about 50 mg have claimed an increase in mental acuity.[20] There are noreports available of adverse effects from consumption of excess thiamine by ingestion offood and supplements. Because the data are inadequate for a quantitative riskassessment, no Tolerable Upper Intake Level (UL) can be derived for thiamine.

AntagonistsThiamine in foods can be degraded in a variety of ways. Sulfites, which are added to

foods usually as a preservative,[21] will attack thiamine at the methylene bridge in the

structure, cleaving the pyrimidine ring from the thiazole ring.[3] The rate of this reactionis increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases

(present in raw fish and shellfish[2]). Some thiaminases are produced by bacteria.Bacterial thiaminases are cell surface enzymes that must dissociate from the membranebefore being activated; the dissociation can occur in ruminants under acidoticconditions. Rumen bacteria also reduce sulfate to sulfite, therefore high dietary intakesof sulfate can have thiamine-antagonistic activities.

Plant thiamine antagonists are heat stable and occur as both the ortho and parahydroxyphenols. Some examples of these antagonists are caffeic acid, chlorogenic acidand tannic acid. These compounds interact with the thiamine to oxidize the thiazolering, thus rendering it unable to be absorbed. Two flavonoids, quercetin and rutin, have

also been implicated as thiamine antagonists.[3]

Absorption and transport

AbsorptionThiamine is released by the action of phosphatase and pyrophosphatase in the uppersmall intestine. At low concentrations the process is carrier mediated and at higherconcentrations, absorption occurs via passive diffusion. Active transport is greatest in

the jejunum and ileum (it is inhibited by alcohol consumption and by folic deficiency.[2]

Decline in thiamine absorption occurs at intakes above 5 mg.[22] The cells of theintestinal mucosa have thiamine pyrophosphokinase activity, but it is unclear whetherthe enzyme is linked to active absorption. The majority of thiamine present in theintestine is in the pyrophosphorylated form ThDP, but when thiamine arrives on theserosal side of the intestine it is often in the free form. The uptake of thiamine by themucosal cell is likely coupled in some way to its phosphorylation/dephosphorylation. Onthe serosal side of the intestine, evidence has shown that discharge of the vitamin by

those cells is dependent on Na+-dependent ATPase.[3]

Bound to serum proteinsThe majority of thiamine in serum is bound to proteins, mainly albumin. Approximately90% of total thiamine in blood is in erythrocytes. A specific binding protein calledthiamine-binding protein (TBP) has been identified in rat serum and is believed to be a

hormonally regulated carrier protein that is important for tissue distribution of thiamine.[3]

Cellular uptakeUptake of thiamine by cells of the blood and other tissues occurs via active transport

and passive diffusion.[2] About 80% of intracellular thiamine is phosphorylated and mostis bound to proteins. In some tissues, thiamine uptake and secretion appears to be

mediated by a soluble thiamine transporter that is dependent on Na+ and a transcellular

proton gradient.[3]

Tissue distributionHuman storage of thiamine is about 25 to 30 mg with the greatest concentrations inskeletal muscle, heart, brain, liver, and kidneys. ThMP and free (unphosphorylated)thiamine is present in plasma, milk, cerebrospinal fluid, and likely all extracellular fluids.Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capableof crossing cell membranes. Thiamine contents in human tissues are less than those of

other species.[3][23]

ExcretionThiamine and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid and thiamine acetic acid) are excreted principally in the

urine.[14]

Thiamine phosphate derivatives and functionThiamine is mainly the transport form of the vitamin, while the active forms arephosphorylated thiamine derivatives. There are four known natural thiamine phosphatederivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), alsosometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and therecently discovered adenosine thiamine triphosphate (AThTP) and adenosine thiaminediphosphate (AThDP).

Thiamine monophosphateThere is no known physiological role of ThMP.

Thiamine diphosphateThe synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate(TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinaseaccording to the reaction thiamine + ATP → ThDP + AMP (EC 2.7.6.2). ThDP is acoenzyme for several enzymes that catalyze the transfer of two-carbon units and inparticular the dehydrogenation (decarboxylation and subsequent conjugation withcoenzyme A) of 2-oxoacids (alpha-keto acids). Examples include:

Present in most speciespyruvate dehydrogenase and 2-oxoglutarate dehydrogenase (also called α-ketoglutarate dehydrogenase)branched-chain α-keto acid dehydrogenase2-hydroxyphytanoyl-CoA lyasetransketolase

Present in some species:pyruvate decarboxylase (in yeast)several additional bacterial enzymes

The enzymes transketolase, pyruvate dehydrogenase (PDH) and 2-oxoglutaratedehydrogenase (OGDH) are all important in carbohydrate metabolism. The cytosolicenzyme transketolase is a key player in the pentose phosphate pathway, a major routefor the biosynthesis of the pentose sugars deoxyribose and ribose. The mitochondrialPDH and OGDH are part of biochemical pathways that result in the generation ofadenosine triphosphate (ATP), which is a major form of energy for the cell. PDH linksglycolysis to the citric acid cycle, while the reaction catalyzed by OGDH is a rate-limtingstep in the citric acid cycle. In the nervous system, PDH is also involved in the

production of acetylcholine, a neurotransmitter, and for myelin synthesis.[24]

Thiamine triphosphateThiamine triphosphate (ThTP) was long considered a specific neuroactive form ofthiamine. However, recently it was shown that ThTP exists in bacteria, fungi, plants and

animals suggesting a much more general cellular role.[25] In particular in E. coli, it

seems to play a role in response to amino acid starvation.[26]

Adenosine thiamine triphosphateAdenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate hasrecently been discovered in Escherichia coli where it accumulates as a result of carbon

starvation.[4] In E. coli, AThTP may account for up to 20 % of total thiamine. It also

exists in lesser amounts in yeast, roots of higher plants and animal tissue.[27]

Adenosine thiamine diphosphateAdenosine thiamine diphosphate (AThDP) or thiaminylated adenosine diphosphate

exists in small amounts in vertebrate liver, but its role remains unknown.[27]

DeficiencyThiamine derivatives and thiamine-dependent enzymes are present in all cells of thebody, thus, a thiamine deficiency would seem to adversely affect all of the organsystems. However, the nervous system and the heart are particularly sensitive tothiamine deficiency, because of their high oxidative metabolism.

Thiamine deficiency can lead to severe fatigue of eyes and myriad problems includingneurodegeneration, wasting and death. A lack of thiamine can be caused bymalnutrition, a diet high in thiaminase-rich foods (raw freshwater fish, raw shellfish,

ferns) and/or foods high in anti-thiamine factors (tea, coffee, betel nuts)[28] and bygrossly impaired nutritional status associated with chronic diseases, such as alcoholism,

gastrointestinal diseases, HIV-AIDS, and persistent vomiting.[29] It is thought that manypeople with diabetes have a deficiency of thiamine and that this may be linked to some

of the complications that can occur.[30][31]

Well-known syndromes caused by thiamine deficiency include beriberi and Wernicke-Korsakoff syndrome, diseases also common with chronic alcoholism.

BeriberiBeriberi is a neurological and cardiovascular disease. The three major forms of the

disorder are dry beriberi, wet beriberi, and infantile beriberi.[14]

Dry beriberi is characterized principally by peripheral neuropathy consisting ofsymmetric impairment of sensory, motor, and reflex functions affecting distal more

than proximal limb segments and causing calf muscle tenderness.[29]

Wet beriberi is associated with mental confusion, muscular wasting, edema,tachycardia, cardiomegaly, and congestive heart failure in addition to peripheral

neuropathy.[2]

Infantile beriberi occurs in infants breast-fed by thiamin-deficient mothers (whomay show no sign of thiamine deficiency). Infants may manifest cardiac, aphonic,or pseudomeningitic forms of the disorder. Infants with cardiac beriberi frequently

exhibit a loud piercing cry, vomiting, and tachycardia.[14] Convulsions are not

uncommon, and death may ensue if thiamine is not administered promptly.[29]

Following thiamine treatment, rapid improvement occurs generally within 24 hours.[14]

Improvements of peripheral neuropathy may require several months of thiamine

treatment.[32]

Alcoholic brain diseaseNerve cells and other supporting cells (such as glial cells) of the nervous system requirethiamine. Examples of neurologic disorders that are linked to alcohol abuse includeWernicke’s encephalopathy (WE, Wernicke-Korsakoff syndrome) and Korsakoff’spsychosis (alcohol amnestic disorder) as well as varying degrees of cognitive

impairment.[33]

Wernicke’s encephalopathy is the most frequently encountered manifestation of

thiamine deficiency in Western society,[34] though it may also occur in patients with

impaired nutrition from other causes, such as gastrointestinal disease,[34] those withHIV-AIDS, and with the injudicious administration of parenteral glucose or

hyperalimentation without adequate B-vitamin supplementation.[35] This is a strikingneuro-psychiatric disorder characterized by paralysis of eye movements, abnormal

stance and gait, and markedly deranged mental function.[36]

Alcoholics may have thiamine deficiency because of the following:

inadequate nutritional intake: alcoholics tend to intake less than therecommended amount of thiamine.decreased uptake of thiamine from the GI tract: active transport of thiamine intoenterocytes is disturbed during acute alcohol exposure.

liver thiamine stores are reduced due to hepatic steatosis or fibrosis.[37]

impaired thiamine utilization: magnesium, which is required for the binding ofthiamine to thiamine-using enzymes within the cell, is also deficient due tochronic alcohol consumption. The inefficient utilization of any thiamine that doesreach the cells will further exacerbate the thiamine deficiency.Ethanol per se inhibits thiamine transport in the gastrointestinal system and

blocks phosphorylation of thiamine to its cofactor form (ThDP).[38]

Korsakoff Psychosis is generally considered to occur with deterioration of brain

function in patients initially diagnosed with WE.[39]. This is an amnestic-confabulatorysyndrome characterized by retrograde and anterograde amnesia, impairment of

conceptual functions, and decreased spontaneity and initiative.<[29]

Following improved nutrition and the removal of alcohol consumption, some impairmentslinked with thiamine deficiency are reversed; particularly poor brain functionality,although in more severe cases, Wernicke-Korsakoff syndrome leaves permanentdamage. (See delirium tremens.)

Thiamine deficiency in poultryAs most feedstuffs used in poultry diets contain enough quantities of vitamins to meetthe requirements in this species, deficiencies in this vitamin does not occur with

commercial diets. This was, at least, the opinion in the 1960s.[40]

Mature chickens show signs 3 weeks after being fed a deficient diet. In young chicks, itcan appear before 2 weeks of age.

Onset is sudden in young chicks. There is anorexia and an unsteady gait. Later on,there are locomotor signs, beginning with an apparent paralysis of the flexor of the toes.The characteristic position is called "stargazing", meaning a chick "sitting on its hocksand the head in opisthotonos.

Response to administration of the vitamin is rather quick, occurring a few hours

later.[41][42]

Differential diagnosis include riboflavin deficiency and avian encephalomyelitis. Inriboflavin deficiency, the "curled toes" is a characteristic symptom. Muscle tremor istypical of avian encephalomyelitis. A therapeutic diagnosis can be tried bysupplementing Vitamin B1 only in the affected bird. If the animals do not respond in a

few hours, Vitamin B1 deficiency can be excluded.

Thiamine deficiency in ruminants

Polioencephalomalacia(PEM), is the most common thiamine deficiency disorder inyoung ruminant and nonruminant animals. Symptoms of PEM include a profuse, buttransient diarrhea, listlessness, circling movements, star gazing or opisthotonus (head

drawn back over neck), and muscle tremors.[43] The most common cause is high-carbohydrate feeds, leading to the overgrowth of thiaminase-producing bacteria, butdietary ingestion of thiaminase (e.g. in bracken fern), or inhibition of thiamine absorption

by high sulfur intake are also possible.[44]

Idiopathic paralytic disease in wild birdsRecently thiamine deficiency has been identified as the cause of a paralytic disease

affecting wild birds in the Baltic Sea area dating back to 1982.[45] In this condition,there is difficulty in keeping the wings folded along the side of the body when resting,loss of the ability to fly and voice with eventual paralysis of the wings and legs anddeath. It affects primarily 0.5–1 kg sized birds such as the herring gull (Larusargentatus), Common Starling (Sturnus vulgaris) and Common Eider (Somateriamollissima). Researches noted "Because the investigated species occupy a wide rangeof ecological niches and positions in the food web, we are open to the possibility that

other animal classes may suffer from thiamine deficiency as well."[45]p. 12006

Analysis and diagnostic testingA positive diagnosis test for thiamine deficiencycan be ascertained by measuring the activity of theenzyme transketolase in erythrocytes (ErythrocyteTransketolase Activation Assay). Thiamine, as wellas its phosphate derivatives, can also be detecteddirectly in whole blood, tissues, foods, animal feedand pharmaceutical preparations following theconversion of thiamine to fluorescent thiochromederivatives (Thiochrome Assay) and separation byhigh performance liquid chromatography

(HPLC).[46][47][48] In recent reports, a number of Capillary Electrophoresis (CE)techniques and in-capillary enzyme reaction methods have emerged as potential

alternative techniques for the determination and monitoring of thiamine in samples.[49]

Genetic diseasesGenetic diseases of thiamine transport are rare but serious. Thiamine Responsive

Megaloblastic Anemia with diabetes mellitus and sensorineural deafness (TRMA)[50] is

an autosomal recessive disorder caused by mutations in the gene SLC19A2,[51] a highaffinity thiamine transporter. TRMA patients do not show signs of systemic thiaminedeficiency, suggesting redundancy in the thiamine transport system. This has led to the

discovery of a second high affinity thiamine transporter, SLC19A3.[52][53] Leigh Disease(Subacute Necrotising Encephalomyelopathy) is an inherited disorder which affectsmostly infants in the first years of life and is invariably fatal. Pathological similaritiesbetween Leigh disease and WE led to the hypothesis that the cause was a defect inthiamine metabolism. One of the most consistent findings has been an abnormality of

the activation of the pyruvate dehydrogenase complex[54]

Other disorders in which a putative role for thiamine has been implicated includeSubacute Necrotizing Encephalomyelopathy, Opsoclonic Cerebellopathy (aparaneoplastic syndrome), and Nigerian Seasonal Ataxia. In addition, several inherited

disorders of ThDP-dependent enzymes have been reported,[55] which may respond to

thiamine treatment.[29]

ResearchResearch in the field mainly concerns the mechanisms by which thiamine deficiencyleads to neuronal death in relation to Wernicke Korsakoff Psychosis. Another importantfield concerns the understanding of the molecular mechanisms involved in ThDPcatalysis. More recently, research has been devoted to the understanding of thepossible non-cofactor roles of other derivatives such as ThTP and AThTP.

Oxidation of thiamine derivativesto fluorescent thiochromes bypotassium ferricyanide under

alkaline conditions

Understanding the mechanism by which thiamine deficiency leads toselective neuronal deathExperimentally induced beriberi polyneuropathy in chickens may be a good model for

studying these forms of neuropathy in view of diagnosis and treatment.[56] From studiesusing rat models, a link between thiamine deficiency and colon carcinogenesis was

suggested.[57] Rat model is used also in research of Wernicke's encephalopathy.[58]

Thiamine deprived mice are a classic model of systemic oxidative stress, used in

research of Alzheimer’s disease.[59]

Catalytic mechanisms in thiamine diphosphate-dependent enzymesA lot of work is devoted to the understanding of the interplay between ThDP and ThDP-

dependent enzymes in catalysis.[60][61]

Non-cofactor roles of thiamine derivativesThiamine compounds other than ThDP exist in most cells from many organisms,including bacteria, fungi, plants and animals. Among those compounds are thiaminetriphosphate (ThTP) and adenosine thiamine triphosphate (AThTP) are thought to havenon-cofactor roles, though at present it is not known to what extent they participate in

the symptoms [4][27][62][63]

Persistent carbenesThe production of furoin from furfural is catalyzed by thiamine through a relatively stablecarbene (organic radical). This reaction, studied in 1957 by R. Breslow, was the frstevidence for the existence of persistent carbenes.

See alsoThiamine oxidase, an enzyme for producing thiamine acetic acid.

References1. ↑ Thiamine is pronounced "Thigh-a-min".

2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Mahan LK, Escott-Stump S, editors. Krause's food, nutrition, & diet therapy.10th ed. Philadelphia: W.B. Saunders Company; 2000

3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Combs, G. F. Jr. The vitamins: Fundamental Aspects in Nutrition and Health.3rd Edition. Ithaca, NY: Elsevier Academic Press; 2008

4. ↑ 4.0 4.1 4.2 Bettendorff L, Wirtzfeld B, Makarchikov AF, Mazzucchelli G, Frédérich M, Gigliobianco T,Gangolf M, De Pauw E, Angenot L and Wins P (2007). "[Expression error: Missing operand for >Discovery of a natural thiamine adenine nucleotide]". Nature Chem. Biol. 3: 211–212.doi:10.1038/nchembio867.

5. ↑ McCollum EV. A History of Nutrition. Cambridge, MA: Riverside Press, Houghton Mifflin; 1957.

6. ↑ Eijkman, C. (1897). Eine Beriberiähnliche Krankheit der Hühner. Virchows Arch. Pathol. Anat. 148: 523.

7. ↑ Grijns, G. (1901) Over polyneuritis gallinarum. I. Geneesk. Tijdscht. Ned. Ind. 43, 3-110

8. ↑ Jansen, B.C.P. and Donath, W.F. (1926) On the isolation of antiberiberi vitamin. Proc. Kon. Ned. Akad.Wet. 29: 1390-1400.

9. ↑ Williams, R.R. and Cline, J.K. (1936). Synthesis of vitamin B1. J. Am. Chem. Soc. 58: 1504-1505.

10. ↑ Carpenter KJ. Beriberi, white rice, and vitamin B: a disease, a cause, and a cure. Berkeley, CA:University of California Press; 2000

11. ↑ Peters, R.A. (1936). The biochemical lesion in vitamin B1 deficiency. Application of modern biochemicalanalysis in its diagnosis. Lancet 1: 1161-1164.

12. ↑ Lohmann, K. and Schuster, P. (1937). Untersuchungen über die Cocarboxylase. Biochem. Z. 294, 188-214.

13. ↑ Breslow R (1958). "[Expression error: Missing operand for > On the mechanism of thiamine action.IV.1 Evidence from studies on model systems]". J Am Chem Soc 80 : 3719–3726.doi:10.1021/ja01547a064.

14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Tanphaichitr V. Thiamin. In: Shils ME, Olsen JA, Shike M et al., editors. ModernNutrition in Health and Disease . 9th ed. Baltimore: Lippincott Williams & Wilkins; 1999

15. ↑ Luczak M, Zeszyty Probi PostepoLc Vauh Roln 1968;80,497; Chem Abstr 1969;71,2267g

16. ↑ Syunyakova ZM, Karpova IN, Vop Pitan 1966;25(2),52; Chem Abstr 1966;65,1297b

17. ↑ Webb ME, Marquet A, Mendel RR, Rebeille F & Smith AG (2007) Elucidating biosynthetic pathways forvitamins and cofactors. Nat Prod Rep 24, 988-1008.

18. ↑ Begley TP, Chatterjee A, Hanes JW, Hazra A & Ealick SE (2008) Cofactor biosynthesis—still yieldingfascinating new biological chemistry. Curr Opin Chem Biol 12, 118-125.

19. ↑ Switching the light on plant riboswitches. Samuel Bocobza and Asaph Aharoni Trends in Plant ScienceVolume 13, Issue 10, October 2008, Pages 526-533 doi:10.1016/j.tplants.2008.07.004

20. ↑ Thiamine's Mood-Mending Qualities, Richard N. Podel, Nutrition Science News, January 1999.

21. ↑ McGuire, M. and K.A. Beerman. Nutritional Sciences: From Fundamentals to Foods. 2007. California:Thomas Wadsworth.

22. ↑ Hayes KC, Hegsted DM. Toxicity of the Vitamins. In: National Research Council (U.S.). Food ProtectionCommittee. Toxicants Occurring Naturally in Foods. 2nd ed. Washington DCL: National Academy Press;1973.

23. ↑ Bettendorff L., Mastrogiacomo F., Kish S. J., and Grisar T. (1996). "[Expression error: Missing operandfor > Thiamine, thiamine phosphates and their metabolizing enzymes in human brain]". J. Neurochem. 66 :250–258.

24. ↑ Butterworth RF. Thiamin. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. ModernNutrition in Health and Disease, 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006

25. ↑ Makarchikov AF, Lakaye B, Gulyai IE, Czerniecki J, Coumans B, Wins P, Grisar T and Bettendorff L(2003). "[Expression error: Missing operand for > Thiamine triphosphate and thiamine triphosphataseactivities: from bacteria to mammals]". Cell. Mol. Life Sci 60 : 1477–1488. doi:10.1007/s00018-003-3098-4.

26. ↑ Lakaye B, Wirtzfeld B, Wins P, Grisar T and Bettendorff L (2004). "[Expression error: Missing operandfor > Thiamine triphosphate, a new signal required for optimal growth of Escherichia coli during amino acidstarvation]". J. Biol. Chem. 279: 17142–17147. doi:10.1074/jbc.M313569200. PMID 14769791.

27. ↑ 27.0 27.1 27.2 Frédérich M., Delvaux D., Gigliobianco T., Gangolf M., Dive G., Mazzucchelli G., Elias B.,De Pauw E., Angenot L., Wins P. and Bettendorff L. (2009). [Expression error: Missing operand for >Thiaminylated adenine nucleotides — chemical synthesis, structural characterization and natural occurrenceFEBS J.]. 276. pp. 3256-3268. doi:10.1111/j.1742-4658.2009.07040.x.

28. ↑ "Thiamin", Jane Higdon, Micronutrient Information Center, Linus Pauling Institute

29. ↑ 29.0 29.1 29.2 29.3 29.4 Butterworth RF. Thiamin. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ,editors. Modern Nutrition in Health and Disease, 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006.

30. ↑ Thornalley PJ (2005). "[Expression error: Missing operand for > The potential role of thiamine (vitaminB(1)) in diabetic complications]". Curr Diabetes Rev 1 (3): 287–98. doi:10.2174/157339905774574383.PMID 18220605.

31. ↑ Diabetes problems 'vitamin link', BBC News, Tuesday, 7 August 2007

32. ↑ Maurice V, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome and Related Neurologic DisordersDue to Alcoholism and Malnutrition. 2nd ed. Philadelphia: FA Davis, 1989.

33. ↑ Martin, PR, Singleton, CK, Hiller-Sturmhofel, S (2003). "[Expression error: Missing operand for > Therole of thiamine deficiency in alcoholic brain disease]". Alcohol Research and Health 27 : 134–142.

34. ↑ 34.0 34.1 Kril JJ (1996). "[Expression error: Missing operand for > Neuropathology of thiaminedeficiency disorders]". Metab Brain Dis 11 (1): 9–17. doi:10.1007/BF02080928.

35. ↑ Butterworth RF, Gaudreau C, Vincelette J et al. (1991). "[Expression error: Missing operand for >Thiamine deficiency and wernicke's encephalopathy in AIDS]". Metab Brain Dis 6: 207–12.doi:10.1007/BF00996920.

36. ↑ Harper C. (1979). "[Expression error: Missing operand for > Wernicke’s encephalopathy, a morecommon disease than realised (a neuropathological study of 51 cases)]". J Neurol Neurosurg Psychol 42 :226–231. doi:10.1136/jnnp.42.3.226. PMID 438830.

37. ↑ Butterworth RF (1993). "[Expression error: Missing operand for > Pathophysiologic mechanismsresponsible for the reversible (thiamine-responsive) and irreversible (thiamine non-responsive) neurologicalsymptoms of Wernicke's encephalopathy]". Drug Alcohol Rev 12 : 315–22.doi:10.1080/09595239300185371.

38. ↑ Rindi G, Imarisio L, Patrini C (1986). "[Expression error: Missing operand for > Effects of acute andchronic ethanol administration on regional thiamin pyrophosphokinase activity of the rat brain]". BiochemPharmacol 35 : 3903–8. doi:10.1016/0006-2952(86)90002-X.

39. ↑ McCollum EV A History of Nutrition. Cambridge, MA: Riverside Press, Houghton Mifflin; 1957.

40. ↑ Merck Veterinary Manual, ed 1967, pp 1440-1441.

41. ↑ R.E. Austic and M.L. Scott, Nutritional deficiency diseases, in Diseases of poultry , ed. by M.S. Hofstad,Iowa State University Press, Ames, Iowa, USA ISBN 0-8138-0430-2, p. 50.

42. ↑ The disease is described more carefully here: merckvetmanual.com

43. ↑ National Research Council. 1996. Nutrient Requirements of Beef Cattle , Seventh Revised Ed.Washington, D.C.: National Academy Press.

44. ↑ Polioencephalomalacia: Introduction, Merck Veterinary Manual

45. ↑ 45.0 45.1 Balk L, Hägerroth PA, Akerman G, Hanson M, Tjärnlund U, Hansson T, Hallgrimsson GT, ZebührY, Broman D, Mörner T, Sundberg H. (2009). Wild birds of declining European species are dying from athiamine deficiency syndrome. Proc Natl Acad Sci U S A. 106:12001–12006. PMID 19597145doi:10.1073/pnas.0902903106

46. ↑ Bettendorff L, Peeters M., Jouan C., Wins P., and Schoffeniels E. (1991) Determination of thiamin and itsphosphate esters in cultured neurons and astrocytes using an ion-pair reversed-phase high-performanceliquid chromatographic method. Anal. Biochem. 198: 52-59.

47. ↑ Losa R, Sierra MI, Fernández A, Blanco D, Buesa JM. (2005) Determination of thiamine and itsphosphorylated forms in human plasma, erythrocytes and urine by HPLC and fluorescence detection: apreliminary study on cancer patients.J Pharm Biomed Anal. 37:1025-1029.

48. ↑ Lu J, Frank EL. (2008) Rapid HPLC measurement of thiamine and its phosphate esters in whole blood.Clin Chem. 2008 May;54(5):901-906.

49. ↑ Shabangi M, Sutton JA. Separation of thiamin and its phosphate esters by capillary zone electrophoresisand its application to the analysis of water-soluble vitamins. Journal of Pharmaceutical and BiomedicalAnalysis 2005; 38:1:66-71.

50. ↑ [Expression error: Missing operand for > Thiamine Responsive Megaloblastic Anemia with severediabetes mellitus and sensorineural deafness (TRMA)]. PMID 249270.

51. ↑ Kopriva, V; Bilkovic, R; Licko, T (Dec 1977). "[Expression error: Missing operand for > Tumours of thesmall intestine (author's transl)]". Ceskoslovenska gastroenterologie a vyziva 31 (8): 549–53. ISSN 0009-0565. PMID 603941.

52. ↑ Beissel, J (Dec 1977). "[Expression error: Missing operand for > The role of right catheterization invalvular prosthesis surveillance (author's transl)]". Annales de cardiologie et d'angeiologie 26 (6): 587–9.ISSN 0003-3928. PMID 606152.

53. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 249270

54. ↑ Butterworth RF. Pyruvate dehydrogenase deficiency disorders. In: McCandless DW, ed. Cerebral EnergyMetabolism and Metabolic Encephalopathy. Plenum Publishing Corp.; 1985.

55. ↑ Blass JP. Inborn errors of pyruvate metabolism. In: Stanbury JB, Wyngaarden JB, Frederckson DS et al.,eds. Metabolic Basis of Inherited Disease . 5th ed. New York: McGraw-Hill, 1983.

56. ↑ Djoenaidi W, Notermans SL, Gabreëls-Festen AA, Lilisantoso AH, Sudanawidjaja A (1995). "[Expression

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error: Missing operand for > Experimentally induced beriberi polyneuropathy in chickens]". ElectromyogrClin Neurophysiol 35 (1): 53–60.

57. ↑ Bruce WR, Furrer R, Shangari N, O’Brien PJ, Medline A, Wang Y (2003). "[Expression error: Missingoperand for > Marginal dietary thiamin deficiency induces the formation of colonic aberrant crypt foci(ACF) in rats]". Cancer Lett 202: 125–129. doi:10.1016/j.canlet.2003.08.005.

58. ↑ Langlais PJ (1995). "[Expression error: Missing operand for > Pathogenesis of diencephalic lesions inan experimental model of Wernicke's encephalopathy]". Metab Brain Dis 10 (1): 31–44.doi:10.1007/BF01991781.

59. ↑ Frederikse PH, Zigler SJ Jr, Farnsworth PN, Carper DA (2000). "[Expression error: Missing operandfor > Prion protein expression in mammalian lenses]". Curr Eye Res 20 (2): 137–43. doi:10.1076/0271-3683(200002)20:2;1-D;FT137.

60. ↑ Kale S, Ulas G, Song J, Brudvig GW, Furey W & Jordan F (2008) Efficient coupling of catalysis anddynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex.Proc NatlAcad Sci U S A. 105, 1158-1163

61. ↑ Kluger R & Tittmann K (2008) Thiamin diphosphate catalysis: enzymic and nonenzymic covalentintermediates. Chem Rev 108, 1797-1833

62. ↑ Makarchikov AF, Lakaye B, Gulyai IE, Czerniecki J, Coumans B, Wins P, Grisar T & Bettendorff L (2003)Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals. Cell Mol Life Sci60, 1477-1488.

63. ↑ Bettendorff L. and Wins P. (2009). "[Expression error: Missing operand for > Thiamin diphosphate inbiological chemistry : new aspects of thiamin metabolism, especially triphosphate derivatives acting otherthan as cofactors]". FEBS J. 276: 2917-2925. doi:10.1111/j.1742-4658.2009.07017.x.

External links"Branched-Chain Amino Acid Metabolism" at ncbi.nlm.nih.govThiamin deficiency in poultryType of vitamin B1 could treat common cause of blindness

Vitamins (A11)

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Vitamin Aview original wikipedia article

Vitamin A is avitamin which isneeded by theretina of the eye inthe form of aspecific metabolite,the light-absorbingmolecule retinal.This molecule isabsolutelynecessary for both scotopic and color vision. Vitamin A also functions in a very differentrole, as an irreversibly oxidized form retinoic acid, which is an important hormone-likegrowth factor for epithelial and other cells.

In foods of animal origin, the major form of vitamin A is an ester, primarily retinylpalmitate, which is converted to an alcohol (retinol) in the small intestine. The retinolform functions as a storage form of the vitamin, and can be converted to and from itsvisually active aldehyde form, retinal. The associated acid (retinoic acid), a metabolitewhich can be irreversibly synthesized from vitamin A, has only partial vitamin A activity,and does not function in the retina or some essential parts of the reproductive system.

All forms of vitamin A have a beta-ionone ring to which an isoprenoid chain is attached,

called a retinyl group. This structure is essential for vitamin activity.[1] The orangepigment of carrots - beta-carotene - can be represented as two connected retinylgroups, which are used in the body to contribute to vitamin A levels. Alpha-caroteneand gamma-carotene also have a single retinyl group which give them some vitaminactivity. None of the other carotenes have vitamin activity. The carotenoidbeta-cryptoxanthin possesses an ionone group and has vitamin activity in humans.

Vitamin A can be found in two principal forms in foods:

retinol, the form of vitamin A absorbed when eating animal food sources, is ayellow, fat-soluble substance. Since the pure alcohol form is unstable, the vitaminis found in tissues in a form of retinyl ester. It is also commercially produced andadministred as esters such as retinyl acetate or palmitate.

The carotenes alpha-carotene, beta-carotene, gamma-carotene; and thexanthophyll beta-cryptoxanthin (all of which contain beta-ionone rings), but noother carotenoids, function as vitamin A in herbivores and omnivore animals,which possess the enzyme required to convert these compounds to retinal.Carnivores in general are poor converters of ionine-containg carotenoids, andpure carnivores such as cats and ferets lack beta-carotene 15,15'-monooxygenase and cannot convert any carotenoids to retinal (resulting in noneof the carotenoids being forms of vitamin A for these species).

HistoryThe discovery of vitamin A may have stemmed from research dating back to 1906,indicating that factors other than carbohydrates, proteins, and fats were necessary to

keep cattle healthy.[2] By 1917 one of these substances was independently discoveredby Elmer McCollum at the University of Wisconsin–Madison, and Lafayette Mendel andThomas Burr Osborne at Yale University. Since "water-soluble factor B" (Vitamin B) hadrecently been discovered, the researchers chose the name "fat-soluble factor A"

(vitamin A).[2] Vitamin A was first synthesized in 1947 by two Dutch chemists, DavidAdriaan van Dorp and Jozef Ferdinand Arens.

Equivalencies of retinoids and carotenoids (IU)As some carotenoids can be converted into vitamin A, attempts have been made to

The structure of retinol, the most common dietary form of vitamin A

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Vitamin A

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Vitamin AHistory

Equivalencies of retinoids and carotenoid(IU)

Recommended daily intake

Sources

Metabolic functions

Vision

Gene transcription

Dermatology

Retinal/retinol versus retinoic acid

Deficiency

Toxicity

Vitamin A and derivatives in medical use

See also

References

Further reading

External links

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determine how much of them in the diet is equivalent to a particular amount of retinol,so that comparisons can be made of the benefit of different foods. Unfortunately thesituation is confusing because the accepted equivalences have changed. For manyyears, a system of equivalencies was used in which an international unit (IU) was equal

to 0.3 μg of retinol, 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids.[3]

Later, a unit called retinol equivalent (RE) was introduced. 1 RE corresponded to 1 μgretinol, 2 μg β-carotene dissolved in oil (it is only partly dissolved in most supplementpills, due to very poor solubility in any medium), 6 μg β-carotene in normal food(because it is not absorbed as well as when in oils), and 12 μg of either α-carotene, γ-carotene, or β-cryptoxanthin in food (these molecules only provide 50% of the retinol asβ-carotene, due to only half the molecule being convertible to usable vitamin).

Newer research has shown that the absorption of provitamin-A carotenoids is only halfas much as previously thought, so in 2001 the US Institute of Medicine recommended anew unit, the retinol activity equivalent (RAE). 1 μg RAE corresponds to 1 μg retinol, 2μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of the three other

dietary provitamin-A carotenoids.[4]

Substance and its chemicalenvironment

Micrograms of retinol equivalent per microgramof the substance

retinol 1beta-carotene, dissolved in oil 1/2beta-carotene, common dietary 1/12alpha-carotene, common dietary 1/24gamma-carotene, commondietary

1/24

beta-cryptoxanthin, commondietary

1/24

Because the production of retinol from provitamins by the human body is regulated bythe amount of retinol available to the body, the conversions apply strictly only forvitamin A deficient humans. The absorption of provitamins also depends greatly on theamount of lipids ingested with the provitamin; lipids increase the uptake of the

provitamin.[5]

The conclusion that can be drawn from the newer research is that fruits and vegetablesare not as useful for obtaining vitamin A as was thought; in other words, the IU's thatthese foods were reported to contain were worth much less than the same number ofIU's of fat-dissolved oils and (to some extent) supplements. This is important forvegetarians. (Night blindness is prevalent in countries where little meat or vitamin A-fortified foods are available.)

A sample vegan diet for one day that provides sufficient vitamin A has been published

by the Food and Nutrition Board (page 120[4]). On the other hand, reference values forretinol or its equivalents, provided by the National Academy of Sciences, havedecreased. The RDA (for men) of 1968 was 5000 IU (1500 μg retinol). In 1974, theRDA was set to 1000 RE (1000 μg retinol), whereas now the Dietary Reference Intakeis 900 RAE (900 μg or 3000 IU retinol). This is equivalent to 1800 μg of β-carotenesupplement (3000 IU) or 10800 μg of β-carotene in food (18000 IU).

Recommended daily intakeVitamin A

Dietary Reference Intake[6]:

Life Stage GroupRDA/AI*μg/day

ULμg/day

Infants0–6 months7–12 months

400*500*

600600

Children1–3 years4–8 years

300400

600900

Males9–13 years14–18 years19 - >70 years

600900900

170028003000

Females

9–13 years14–18 years19 - >70 years

600700700

170028003000

Pregnancy<19 years19 - >50 years

750770

28003000

Lactation<19 years19 - >50 years

12001300

28003000

RDA = Recommended Dietary AllowancesAI* = Adequate IntakesUL = Upper Limit

(Note that the limit refers to synthetic and natural retinoid forms of vitamin A. Carotene

forms from dietary sources are not toxic.[7][8])

According to the Institute of Medicine of the National Academies, "RDAs are set to meetthe needs of almost all (97 to 98 percent) individuals in a group. For healthy breastfedinfants, the AI is the mean intake. The AI for other life stage and gender groups isbelieved to cover the needs of all individuals in the group, but lack of data preventbeing able to specify with confidence the percentage of individuals covered by this

intake."[9]

SourcesVitamin A is found naturally in many foods:

liver (beef, pork, chicken, turkey, fish) (6500μg 722%)carrot (835 μg 93%)broccoli leaf (800 μg 89%) - According toUSDA database broccoli florets have much

less.[10]

sweet potato (709 μg 79%)kale (681 μg 76%)butter (684 μg 76%)spinach (469 μg 52%)pumpkin (400 μg 41%)collard greens (333 μg 37%)cantaloupe melon (169 μg 19%)egg (140 μg 16%)apricot (96 μg 11%)papaya (55 μg 6%)mango (38 μg 4%)pea (38 μg 4%)broccoli (31 μg 3%)

Note: data taken from USDA database bracketed values are retinol equivalences andpercentage of the adult male RDA per 100g.

Conversion of carotene to retinol varies from person to person and bioavailability of

carotene in food varies.[11][12]

Metabolic functionsVitamin A plays a role in a variety of functions throughout the body, such as:

VisionGene transcriptionImmune functionEmbryonic development and reproductionBone metabolismHaematopoiesisSkin healthAntioxidant Activity

Egg.

VisionThe role of vitamin A in the vision cycle is specifically related to the retinal form. Withinthe eye, 11-cis-retinal is bound to rhodopsin (rods) and iodopsin (cones) at conservedlysine residues. As light enters the eye the 11-cis-retinal is isomerized to the all-"trans"form. The all-"trans" retinal dissociates from the opsin in a series of steps calledbleaching. This isomerization induces a nervous signal along the optic nerve to thevisual center of the brain. Upon completion of this cycle, the all-"trans"-retinal can berecycled and converted back to the 11-"cis"-retinal form via a series of enzymaticreactions. Additionally, some of the all-"trans" retinal may be converted to all-"trans"retinol form and then transported with an interphotoreceptor retinol-binding protein(IRBP) to the pigment epithelial cells. Further esterification into all-"trans" retinyl estersallow this final form to be stored within the pigment epithelial cells to be reused when

needed.[13] The final conversion of 11-cis-retinal will rebind to opsin to reform rhodopsinin the retina. Rhodopsin is needed to see black and white as well as see at night. It isfor this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin and

lead to night blindness.[14]

Gene transcriptionVitamin A, in the retinoic acid form, plays an important role in gene transcription. Onceretinol has been taken up by a cell, it can be oxidized to retinal (by retinoldehydrogenases) and then retinal can be oxidized to retinoic acid (by retinal oxidase).The conversion of retinal to retinoic acid is an irreversible step, meaning that theproduction of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear

receptors.[13] Retinoic acid can bind to two different nuclear receptors to initiate (orinhibit) gene transcription: the retinoic acid receptors (RARs) or the retinoid "X"receptors (RXRs). RAR and RXR must dimerize before they can bind to the DNA. RARwill form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer(RAR-RAR). RXR, on the other hand, readily forms a homodimer (RXR-RXR) and willform heterodimers with many other nuclear receptors as well, including the thyroidhormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome

proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR).[15]

The RAR-RXR heterodimer recognizes retinoid acid response elements (RAREs) on theDNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements(RXREs) on the DNA. The other RXR heterodimers will bind to various other response

elements on the DNA.[13] Once the retinoic acid binds to the receptors and dimerizationhas occurred, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptorcomplex, which may help to loosen the chromatin structure from the histones or may

interact with the transcriptional machinery.[15] The receptors can then bind to theresponse elements on the DNA and upregulate (or downregulate) the expression oftarget genes, such as cellular retinol-binding protein (CRBP) as well as the genes that

encode for the receptors themselves.[13]

DermatologyVitamin A appears to function in maintaining normal skin health. The mechanismsbehind retinoid's therapeutic agents in the treatment of dermatological diseases arebeing researched. For the treatment of acne, the most effective drug is 13-cis retinoicacid (isotretinoin). Although its mechanism of action remains unknown, it dramaticallyreduces the size and secretion of the sebaceous glands. Isotretinoin reduces bacterialnumbers in both the ducts and skin surface. This is thought to be a result of thereduction in sebum, a nutrient source for the bacteria. Isotretinoin reduces inflammation

via inhibition of chemotatic responses of monocytes and neutrophils.[13] Isotretinoin alsohas been shown to initiate remodeling of the sebaceous glands; triggering changes in

gene expression that selectively induces apoptosis.[16] Isotretinoin is a teratogen and itsuse is confined to medical supervision.

Retinal/retinol versus retinoic acidVitamin A deprived rats can be kept in good general health with supplementation ofretinoic acid. This reverses the growth-stunting effects of vitamin A deficiency, as wellas xerophthalmia. However, such rats show infertility (in both male and females) andcontinued degeneration of the retina, showing that these functions require retinal or

retinol, which are intraconvertable but which cannot be recovered from the oxidized

retinoic acid.[17]

DeficiencyMain article: Vitamin A deficiencyVitamin A deficiency is estimated to affect millions of children around the world.Approximately 250,000-500,000 children in developing countries become blind eachyear owing to vitamin A deficiency, with the highest prevalence in Southeast Asia and

Africa.[18] According to the World Health Organization (WHO), vitamin A deficiency isunder control in the United States, but in developing countries vitamin A deficiency is asignificant concern. With the high prevalence of vitamin A deficiency, the WHO hasimplemented several initiatives for supplementation of vitamin A in developing countries.Some of these strategies include intake of vitamin A through a combination of breastfeeding, dietary intake, food fortification, and supplementation. Through the efforts ofWHO and its partners, an estimated 1.25 million deaths since 1998 in 40 countries due

to vitamin A deficiency have been averted.[19]

Vitamin A deficiency can occur as either a primary or secondary deficiency. A primaryvitamin A deficiency occurs among children and adults who do not consume anadequate intake of yellow and green vegetables, fruits and liver. Early weaning can alsoincrease the risk of vitamin A deficiency. Secondary vitamin A deficiency is associatedwith chronic malabsorption of lipids, impaired bile production and release, low fat diets,and chronic exposure to oxidants, such as cigarette smoke. Vitamin A is a fat solublevitamin and depends on micellar solubilization for dispersion into the small intestine,which results in poor utilization of vitamin A from low-fat diets. Zinc deficiency can alsoimpair absorption, transport, and metabolism of vitamin A because it is essential for thesynthesis of the vitamin A transport proteins and the oxidation of retinol to retinal. Inmalnourished populations, common low intakes of vitamin A and zinc increase the risk

of vitamin A deficiency and lead to several physiological events.[13] A study in BurkinaFaso showed major reduction of malaria morbidity with combined vitamin A and zinc

supplementation in young children.[20]

Since the unique function of retinyl group is the light absorption in retinylidene protein,one of the earliest and specific manifestations of vitamin A deficiency is impaired vision,particularly in reduced light - night blindness. Persistent deficiency gives rise to a seriesof changes, the most devastating of which occur in the eyes. Some other ocularchanges are referred to as xerophthalmia. First there is dryness of the conjunctiva(xerosis) as the normal lacrimal and mucus secreting epithelium is replaced by akeratinized epithelium. This is followed by the build-up of keratin debris in small opaqueplaques (Bitot's spots) and, eventually, erosion of the roughened corneal surface with

softening and destruction of the cornea (keratomalacia) and total blindness.[21] Otherchanges include impaired immunity, hypokeratosis (white lumps at hair follicles),keratosis pilaris and squamous metaplasia of the epithelium lining the upper respiratorypassages and urinary bladder to a keratinized epithelium. With relations to dentistry, adeficiency in Vitamin A leads to enamel hypoplasia.

Adequate supply of Vitamin A is especially important for pregnant and breastfeedingwomen, since deficiencies cannot be compensated by postnatal

supplementation.[22][23].

ToxicityMain article: Hypervitaminosis ASince vitamin A is fat-soluble, disposing of any excesses taken in through diet is muchharder than with water-soluble vitamins B and C, thus vitamin A toxicity may result. Thiscan lead to nausea, jaundice, irritability, anorexia (not to be confused with anorexianervosa, the eating disorder), vomiting, blurry vision, headaches, hairloss, muscle andabdominal pain and weakness, drowsiness and altered mental status.

Acute toxicity generally occurs at doses of 25,000 IU/kg of body weight, with chronic

toxicity occurring at 4,000 IU/kg of body weight daily for 6–15 months.[24] However, livertoxicities can occur at levels as low as 15,000 IU per day to 1.4 million IU per day, withan average daily toxic dose of 120,000 IU per day. In people with renal failure 4000 IUcan cause substantial damage. Additionally, excessive alcohol intake can increase

toxicity. Children can reach toxic levels at 1500IU/kg of body weight.[25]

In chronic cases, hair loss, dry skin, drying of the mucous membranes, fever, insomnia,

fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of

the symptoms associated with less serious toxicity.[26]

It has been estimated that 75% of people may be ingesting more than the RDA forvitamin A on a regular basis in developed nations. Intake of twice the RDA of preformedvitamin A chronically may be associated with osteoporosis and hip fractures. This maybe due to the fact that an excess of vitamin A can block the expression of certainproteins that are dependent on vitamin K. This could hypothetically reduce the efficacyof vitamin D, which has a proven role in the prevention of osteoporosis and also

depends on vitamin K for proper utilization[27].

High vitamin A intake has been associated with spontaneous bone fractures in animals.Cell culture studies have linked increased bone resorption and decreased boneformation with high vitamin A intakes. This interaction may occur because vitamins Aand D may compete for the same receptor and then interact with parathyroid hormone

which regulates calcium.[25] Indeed, a study by Forsmo et al. shows a correlation

between low bone mineral density and too high intake of vitamin A.[28]

Toxic effects of vitamin A have been shown to significantly affect developing fetuses.Therapeutic doses used for acne treatment have been shown to disrupt cephalic neuralcell activity. The fetus is particularly sensitive to vitamin A toxicity during the period of

organogenesis.[13]

These toxicities only occur with preformed (retinoid) vitamin A (such as from liver). Thecarotenoid forms (such as beta-carotene as found in carrots), give no such symptoms,but excessive dietary intake of beta-carotene can lead to carotenodermia, which causes

orange-yellow discoloration of the skin.[29][30][31]

Researchers have succeeded in creating water-soluble forms of vitamin A, which they

believed could reduce the potential for toxicity.[32] However, a 2003 study found that

water-soluble vitamin A was approximately 10 times as toxic as fat-soluble vitamin.[33]

A 2006 study found that children given water-soluble vitamin A and D, which aretypically fat-soluble, suffer from asthma twice as much as a control group supplemented

with the fat-soluble vitamins.[34]

Chronically high doses of Vitamin A can produce the syndrome of "pseudotumor

cerebri".[35] This syndrome includes headache, blurring of vision and confusion. It is

associated with increased intracerebral pressure.[36]

Vitamin A and derivatives in medical useRetinyl palmitate has been used in skin cremes, where it is broken down to retinoicacid, which has potent biological activity, as described above.

The retinoids, a class of chemical compounds that are related chemically to retinoicacid, are used in medicine to modulate gene functions in place of this counpound. In

general, like retinoic acid itself, these compounds do not have full vitamin A activity.[37]

See alsoBeta caroteneRetinoidsHypervitaminosis A

References1. ↑ Carolyn Berdanier. 1997. Advanced Nutrition Micronutrients. pp 22-39

2. ↑ 2.0 2.1 Wolf, George (2001-04-19). "Discovery of Vitamin A". Encyclopedia of Life Sciences.doi:10.1038/npg.els.0003419.http://www.mrw.interscience.wiley.com/emrw/9780470015902/els/article/a0003419/current/html. Retrieved2007-07-21.

3. ↑ Composition of Foods Raw, Processed, Prepared USDA National Nutrient Database for StandardReference, Release 20 USDA, Feb. 2008

4. ↑ 4.0 4.1 Chapter 4, Vitamin A of Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron,Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, hickel, Silicon, Vanadium, and Zinc, Food andNutrition Board of the Institute of Medicine, 2001

5. ↑ NW Solomons, M Orozco. Alleviation of Vitamin A deficiency with palm fruit and its products. Asia Pac JClin Nutr, 2003

6. ↑ Dietary Reference Intakes: Vitamins

7. ↑ "Sources of vitamin A". http://www.vitamins-supplements.org/vitamin-A-sources.php. Retrieved 2007-08-27.

8. ↑ "Linus Pauling Institute at Oregon State University: Vitamin A Safety".http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA#safety. Retrieved 2007-09-02.

9. ↑ Food and Nutrition Board. Institute of Medicine. National Academies. (2001) "Dietary Reference Intakes"

10. ↑ The RAE value in the USDA data for broccoli leaves is similar to the IU value for broccoli florets, whichimplies that the leaves have about 20 times as much beta-carotene.

11. ↑ Borel P, Drai J, Faure H, et al. (2005). "[Expression error: Missing operand for > [Recent knowledgeabout intestinal absorption and cleavage of carotenoids]]" (in French). Ann. Biol. Clin. (Paris) 63 (2): 165–77. PMID 15771974.

12. ↑ Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA (2005). "[Expression error: Missing operandfor > Spinach or carrots can supply significant amounts of vitamin A as assessed by feeding withintrinsically deuterated vegetables]". Am. J. Clin. Nutr. 82 (4): 821–8. PMID 16210712.

13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Combs, Gerald F. (2008). The Vitamins: Fundamental Aspects in Nutritionand Health (3rd ed.). Burlington: Elsevier Academic Press. ISBN 9780121834937.

14. ↑ McGuire, Michelle; Beerman, Kathy A. (2007). Nutritional sciences: from fundamentals to food. Belmont,CA: Thomson/Wadsworth. ISBN 0534537170.

15. ↑ 15.0 15.1 Stipanuk, Martha H. (2006). Biochemical, Physiological and Molecular Aspects of HumanNutrition (2nd ed.). Philadelphia: Saunders. ISBN 978116002093.

16. ↑ Nelson, A. M.; et al. (2008). "[Expression error: Missing operand for > Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells]".Journal of Clinical Investigation 118 (4): 1468–1478. doi:10.1172/JCI33869.

17. ↑ http://la.rsmjournals.com/cgi/content/abstract/5/2/239 Lab Anim 1971;5:239-250. The production ofexperimental vitamin A deficiency in rats and mice. T. Moore and P. D. Holmes.doi:10.1258/002367771781006492.

18. ↑ "Office of Dietary Supplements. Vitamin A". National Institute of Health. http://www.dietary-supplements.info.nih.gov/factsheets/vitamina.asp. Retrieved 2008-04-08.

19. ↑ "Micronutrient Deficiencies-Vitamin A". World Health Organization.http://www.who.int/nutrition/topics/vad/en/index.html. Retrieved 2008-04-09.

20. ↑ Zeba AN, Sorgho H, Rouamba N, et al. (2008). "Major reduction of malaria morbidity with combinedvitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial".Nutr J 7: 7. doi:10.1186/1475-2891-7-7. PMID 18237394. http://www.nutritionj.com/content/7/1/7.

21. ↑ Roncone DP (2006). "[Expression error: Missing operand for > Xerophthalmia secondary to alcohol-induced malnutrition]". Optometry (St. Louis, Mo.) 77 (3): 124–33. doi:10.1016/j.optm.2006.01.005. PMID16513513.

22. ↑ Strobel M, Tinz J, Biesalski HK (2007). "[Expression error: Missing operand for > The importance ofbeta-carotene as a source of vitamin A with special regard to pregnant and breastfeeding women]". Eur JNutr 46 Suppl 1: I1–20. doi:10.1007/s00394-007-1001-z. PMID 17665093.

23. ↑ Schulz C, Engel U, Kreienberg R, Biesalski HK (2007). "[Expression error: Missing operand for >Vitamin A and beta-carotene supply of women with gemini or short birth intervals: a pilot study]". Eur J Nutr46 (1): 12–20. doi:10.1007/s00394-006-0624-9. PMID 17103079.

24. ↑ Rosenbloom, Mark. "Toxicity, Vitamin". eMedicine. http://www.emedicine.com/emerg/topic638.htm.

25. ↑ 25.0 25.1 Penniston, Kristina L.; Tanumihardjo, Sherry A. (February 1, 2006). "The acute and chronic toxiceffects of vitamin A". Am. J. Clin. Nutr. 83 (2): 191–201. PMID 16469975.http://www.ajcn.org/cgi/content/abstract/83/2/191.

26. ↑ Eledrisi, Mohsen S.. "Vitamin A Toxicity". eMedicine. http://www.emedicine.com/med/topic2382.htm.

27. ↑ Masterjohn, C (December 4, 2006). "Vitamin D toxicity redefined: vitamin K and the molecularmechanism.". http://www.ncbi.nlm.nih.gov/pubmed/17145139.

28. ↑ Forsmo, Siri; Fjeldbo,Sigurd Kjørstad; Langhammer, Arnulf (2008). "[Expression error: Missing operandfor > Childhood Cod Liver Oil Consumption and Bone Mineral Density in a Population-based Cohort ofPeri- and Postmenopausal Women: The Nord-Trøndelag Health Study]". Am. J. Epidemiol. 167 (4): 406–411. doi:10.1093/aje/kwm320. PMID 18033763.

29. ↑ Sale TA, Stratman E (2004). "[Expression error: Missing operand for > Carotenemia associated withgreen bean ingestion]". Pediatr Dermatol 21 (6): 657–9. doi:10.1111/j.0736-8046.2004.21609.x. PMID15575851.

30. ↑ Nishimura Y, Ishii N, Sugita Y, Nakajima H (1998). "[Expression error: Missing operand for > A caseof carotenodermia caused by a diet of the dried seaweed called Nori]". J. Dermatol. 25 (10): 685–7. PMID9830271.

31. ↑ Takita Y, Ichimiya M, Hamamoto Y, Muto M (2006). "[Expression error: Missing operand for > A caseof carotenemia associated with ingestion of nutrient supplements]". J. Dermatol. 33 (2): 132–4.doi:10.1111/j.1346-8138.2006.00028.x. PMID 16556283.

32. ↑ Science News. Water-soluble vitamin A shows promise.

33. ↑ Myhre AM, Carlsen MH, Bøhn SK, Wold HL, Laake P, Blomhoff R (December 2003). "Water-miscible,emulsified, and solid forms of retinol supplements are more toxic than oil -based preparations". Am. J. Clin.Nutr. 78 (6): 1152–9. PMID 14668278. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=14668278.

34. ↑ Kull I, Bergström A, Melén E, et al. (December 2006). "Early-life supplementation of vitamins A and D, inwater-soluble form or in peanut oil, and allergic diseases during childhood". J. Allergy Clin. Immunol. 118(6): 1299–304. doi:10.1016/j.jaci.2006.08.022. PMID 17157660. http://www.jacionline.org/article/S0091-6749(06)01775-1/abstract.

35. ↑ Brazis PW (March 2004). "[Expression error: Missing operand for > Pseudotumor cerebri]". Currentneurology and neuroscience reports 4 (2): 111–6. doi:10.1007/s11910-004-0024-6. PMID 14984682.

36. ↑ AJ Giannini, RL Gilliland. The Neurologic, Neurogenic and Neuropsychiatric Disorders Handbook. NewHyde Park, NY. Medical Examination Publishing Co., 1982,pp. 182-183.

37. ↑ American Cancer Society: Retinoid Therapy

Further readingLitwack, Gerald (2007). Vitamin A. Vitamins and Hormones. 75. San Diego, CA:Elsevier Academic Press. ISBN 9780127098753.

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