folic acid · 2019-12-03 · active folic acid, which is converted to dihydrofolic acid in the...

VITAMIN B9

FOLIC ACID

Dr. Öğr.Üyesi Berrak DUMLUPINAR

Dark Green Leafy vegetablesLiverCereals


Humans are not able to synthesize folate de novo and, therefore,the daily requirements of folate are met with consumption offood rich in this vitamin..

Form in foods

Pteroil poliglutamate


1. Folate and the biologicallyactive folic acid, which isconverted to dihydrofolic acid inthe liver, are essential inmeeting the requirements ofthe function of the humanbody..

2. Folate is used to synthesize,repair and methylateDeoxyribonucleic acid (DNA);2therefore it is especially importantin pregnancy and childhood forcontinuous cell division and growth

Folate deficiency can cause many unwanted health problems,although severe deficiency is only seen months after the depletion ofthe dietary intake when the folate storage is exhausted

Macrocytic AnemiaWeakness And ConfusionMemory Deficits Shortness Of Breath

Peripheral Neuropathy Pregnancy ComplicationsDepression


Hyperhomocysteinemia and Cancer development due to impaired DNA

synthesis and repair could be the long-term complications of folate deficiencies


Does folate play a role in preventing cancer?

Folate is needed for repairing cells, making DNA,

the building blocks of protein, and forming red

and white blood cells.

Folic acid is the supplemental form of folate.

Folic acid is used in vitamin supplements, and

has been added to bread and other grain

products in order to decrease the occurrence ofneural tube defects in newborns.


Does folate play a role in preventing cancer?

Pancreatic cancerEsophageal cancerColorectal cancerBreast cancer


Spinach KaleBroccoli Lettuce ChicoryOrangesPapayaNutsBeansPeasAsparagusCitrus Fruits (Oranges, Grapefruits, Strawberries) BeansAvocadoOkraBrussels SproutsSeedsCauliflowersBeets

CornCeleryCarrotsSquash

Folic acid also is present in many multivitamin andprenatal vitamin supplements, and in standard B vitaminsupplements.


BreadCerealPasta Rice

ChickenTurkeyLambBeefpork liver.


The daily recommended allowance (RDA) offolic acid is400 mcg/day for teenagers and adults,500 mcg/day for breast-feeding women and600 mcg/day in pregnancy


The estimated body content of folate is about 10 mg to30 mg. The normal serum level of total folate is about5 to 15 ng/mL, while 16 to 21 ng/mL is the normalcerebrospinal fluid level

The normal levels of folate in erythrocytes brange from175 to 316 ng/mL. A higher percentagebof folate is storedin the liver, some in the blood and tissues. Levels below 5ng/mL of serum folate indicatebfolate deficiency andmegaloblastic anemia was seen atma level below 2 ng/mL


Food folate in the intestines after consumption are primarily hydrolyzed to monoglutamate formand absorbed via active transport across the small intestinal mucosa. Folic acid when consumed asa supplement is absorbed rapidly, primarily in the proximal portion of the small intestine viapassive diffusion. Monoglutamate is then reduced to tetrahydrofolate (THF) in the liver andconverted to either the methyl or the formyl forms before entering the bloodstream. Folate iscommonly found in the bloodstream as 5-methyl-tetrahydrofolate.

The metabolic products of folic acid normally appear in the urine 6 hours after ingestion andcomplete excretion is generally within 24 hours with a smaller residue found in the feces.



The function of folic acid metabolism

DNA synthesis and repair

Folic acid metabolism, which generates nucleic acidbuilding blocks, is important in the synthesis andrepair of DNA. Deoxyuridine monophosphate (dUMP)through addition of a methyl group by the enzymethymidylate synthase results in the de novo synthesisof deoxythymidine monophosphate (dTMP) withsubsequent phosphorylation to deoxynucleotidetriphosphate (dNTP) and thymidine triphosphate(dTTP). Thymidine triphosphate (dTTP) is one of thefour deoxyribonucleic acids essential for DNAsynthesis and repair. Folate deficiency will block theconversion of dUMP to dTMP leading to the excess ofdeoxyuridine triphosphate (dUTP)… DNADestabilization may lead to chromosome aberrationsand potentially malignant transformation

Conversion of homocysteine to methionine

A second important folate metabolic reaction isthe conversion of homocysteine to methionine bythe action of 5-methyltetrahydrofolate (5-methyl-THF). Some of thisregenerated methionine is subsequently convertedto the enzyme methionine adenosyl transferase toproduce its active form, S-adenosylmethionine(SAM). S-adenosylmethionine (SAM) participates innumerous types of methylation reactions ofmolecules such as lipids and peptides. SAM is themajor methyl contributor in the methylation ofcytosine to DNA. In folate deficiency, the reductionof methylation of cytosine in DNA might result inpro-oncogene expression and potential malignancytransformation


Cell replication and survival

Folate depletion and subsequent reduction ofDNA synthesis and DNA methylation are toxicto both normal and malignant cells becausefolate metabolism is fundamental to bothcancerous and normal cells. Folate deficiencydue to insufficient thymidine can result in DNAdamage and can also result in hypomethylationof DNA due to reduced levels of S-adenosylmethionine.. Ironically, due to theimportance of folate metabolism for cellreplication and survival, the inhibition of folicacid metabolism has been shown as asuccessful mechanism for the elimination ofmalignant cells and has therefore been trialedas antitumor therapeutics.

Aminopterin, is a folic acid analog (4-aminofolic acid) that inhibitsdihydrofolate reductase, thus,preventing the reduction of folic acidand dihydrofolic acid totetrahydrofolate (THF). Methotrexate(MTX) is another analog of folic acidthat is used to directly inhibitdihydrofolate reductase and to inhibitthymidylate synthase. Other folatestructural analogs used in cancerchemotherapy include trimetrexate,permetrexed, and raltitrexed


The malignant phenotype is not irreversible. Many agents induce or restore amore differentiated or “normal” phenotype to malignant cells. Agents thatcan induce a differentiated phenotype in malignant cells are calleddifferentiation-inducing agents

MINERALS

Differentiation-inducing agents can reverse the malignant phenotype orrestore a more normal phenotype to malignant cells, many differentiation-inducing agents possess chemopreventive properties

Of the major epithelial cancers such as breast, prostate, and colon,colon cancer appears to be most susceptible to chemoprevention


MINERALS

Animal studies, epidemiological studies, and clinical trials strongly suggest that

Ca2+ (or in combination with vitamin D) is a good chemopreventive agent for

colon cancer…

Calcium

The actions of Ca2+ at the cellular and molecular level are diverse and that Ca2+and the calcium-sensing receptor (CaSR) function as a ligand receptor system incontrolling the proliferation and differentiation of colon epithelial cells


In colon carcinoma, most of these agents have a growth inhibitory effect andalter the expression of cellular proteins, the expression and secretion ofExtraCellular Matrix (ECM) adhesion proteins and receptors for these ECMadhesion protein….

Calcium

The significance of these biological effects is the biological function ofcellular adhesion molecules and their associated signal transductionprocesses, in terms of their mechanisms controlling cell cycle progression.Therefore, the function of Ca2+ and the CaSR, the cellular adhesion and cellcycle control in regulating the differentiation process is important..


THE CELL-ADHESION MOLECULES

In multicellular organisms, cells form tissues for specialized functions. For such highdegree of organization it is indispensable for a connection to be established betweencells as well as between cells and elements of the Extra Cellular Matrix (ECM). Besidesthe connections maintaining a strict tissue structure, these interconnections also play

an important role in cell migration, cell differentiation and communicationbetween cells. Both the cell adhesion and cell-matrix connections are results ofdynamically changing interactions established by ECM components (such as collagen,glycosaminoglycans, proteoglycans, fibronectin, laminin), plasma membrane-associatedcell surface adhesion proteins, and occasionally the anchoring molecules betweencytoskeletal elements and membrane proteins.


Cell surface adhesion molecules

Traditionally cell adhesion interactions have been grouped into Ca2+dependent and Ca2+ independent classes depending on whether aconnection takes place in the presence or absence of Ca2+ .

Cell adhesion molecules based on their protein structure:1) Integrins2) Cadherins3) Cell adhesion molecules belonging to the superfamily group of

immunoglobulins4) Selectins


Integrins are responsible for the anchoring of cells to the ECM, cell to cellinteractions and also two-way signal transmission, since they take part inpathways that carry signals both to and from the cell. These propertiesmake the integrins suitable for such complex mechanisms as bloodcoagulation, inflammation, migration, tissue differentiation and cell division

Integrins

Integrins are heterodimeric surface membrane receptors that provide

calcium-dependent cell-cell and cell matrix interactions. So, cell surface

glycoproteins that provide integration between intracellular environmentand extracellular matrix

Heterodimeric structural transmembrane proteins that require bivalent

cations for their operation; usually calcium ions..


Within the superfamily of cadherins, exist one or more transmembranesections of glycoproteins, on whose extracellular domains repetitive cadherin-repeat subdomains can be found. Calcium binds to these repetitive proteinsequences. The subsequent conformational change allows bond formationbetween the cadherin molecules of neighboring cells. Cadherins are therefore

calcium dependent, „homotypic” contact-establishing adhesion

molecules. The cadherins can connect with the cytoskeleton's actin andintermediate filaments on the cytoplasmic side of the plasma membranethrough protein complexes. These protein complexes are organized around thecadherin molecules' intracellular domains. It is thus understandable, thatcadherins take part in a number of signal transduction pathways.

Cadherins


So, Cell adhesion molecules that are critical to the initiation andcontinuation of intercellular adhesion events required for theformation and stability of embryogenic tissues

When Antibodies to cadherins added to embryonic tissues, cell-celladhesion causes severe deterioration of tissue structure..


Selectins have a number of transmembrane domains, and linkthemselves to the carbohydrate groups of neighboring cell surfaces. Thecalcium-dependent binding of the protein molecule concludes with thekey role played by the lectin domain. The resulting bond is heterophilic:the selectin binds to the carbohydrate side chains of other cells' surfaceproteins or lipids; and even more specifically to the differentoligosaccharide sequences.

Selectins


CALCIUM AND THE CALCIUM-SENSING RECEPTOR

Intracellular Ca2+ has long been regarded as a “secondmessenger” in many signal transduction processes….

The characterization and cloning of the cell-surface calcium-sensing receptor(CaSR) from the human parathyroid gland, however, has shown that

extracellular Ca2+ and the CaSR constitute a first messenger system in

controlling physiologic function..

It is now known that the CaSR is a member of the superfamily of G protein–coupled receptors, which can sense minute changes in extracellular Ca2+concentration and coordinate the secretion of endocrine hormones in thecontrol and regulation of systemic Ca2+homeostasis…


CELL CYCLE CONTROL AND THE INDUCTION OF DIFFERENTIATION

Inhibition of proliferation is tightly linked to proper cellulardifferentiation while abnormal proliferation (escape from normalgrowth control) is implicated in circumventing the normaldifferentiation pathway and in driving malignant progression

Induction of differentiation of malignant cells is associated with therestoration of normal growth control and the suppression of malignantproperties. While normal cells do not grow in semisolid soft agarose(anchorage-independent growth), a hallmark of malignanttransformation is the ability to grow in soft agarose. Malignant cellstreated with differentiation-inducing agents are unable to grow in softagarose…


The ability of malignant cells to invade a matrigel matrix issignificantly reduced when treated with differentiation-inducingagents

Calcium sources

Milk And Milk DerivativesGreen Leafy VegetablesMolassesDry Beans


MINERALS

SELENIUM

CerealsMeatSeafoods

ColonRectumPancreas BreastOvaryProstateBladder Lung Skin


Relationship of Selenium Intake to Cancer

The selenocompounds in plants can have a profound effect on the healthof animals and humans. Selenomethionine (Semet) is the major

selenocompound in cereal grains and enriched yeast, whereas

Se-methylselenocysteine (SeMCYS) is the major selenocompound inselenium accumulator plants and some plants of economic importance

such as garlic and broccoli exposed to excess selenium

Usually blood or plasma levels of selenium are lower inpatients with cancer than those without this disorder..


SELENIUM

Despite these similarities, the biochemistry of selenium and sulfur differ in atleast two respects that distinguish them in biological systems. First, seleniumcompounds are metabolized to more reduced states, whereas sulfurcompounds are metabolized to more oxidized states

The chemical and physical properties of selenium are very similar to those ofsulfur. Selenium and sulfur have similar outer-valence shell electronicconfigurations and atomic sizes and their bond energies, ionization potentials,and electron affinities are virtually the same.

Second, these compounds differ in the acid strengths of their hydrides. Thehydride, H2Se, is much more acidic than is H2S.

These chemical differences between selenium and sulfur are the reasonsselenocompounds are usually 600 times more effective than their sulfuranalogs against tumors


Selenium compounds are taken into the body as selenate,

selenite, selenocystein and selenometionine. Theseselenium compounds, except for selenocysteine, which istaken with nutrients, are first converted to selonophosphataand then to selenocystin and are included in the structure ofselenoproteins


Selenium shows its effect in living organisms throughselenoprotein. the main biological form is selenocystin. andits synthesis begins by binding of the serine amino acid to thetRNA. Selenocysteine is similar to the cysteine but has aselenium atom instead of sulfur

There are only a couple of enzymes that have ascorbate as co-factor.But Vit E is not a part of any enzyme. In contrast, Se is incorporatedreadily into proteins as SeCys and SeMet. Therefore, selenoproteinsare subject to the normal protein turnover and hence repletion ofcells with Se is more important than the other two antioxidants

Selenoenzymes

Mammalian enzymes—

Glutathione peroxidases (GPX)

GPX1 Classical glutathione peroxidase (GSH-Px)

GPX2 Gastrointestinal glutathione peroxidase

(GPX-GI)

GPX3 Plasma glutathione peroxidase (Plasma GPX)

GPX4 Phospholipid hydroperoxide GPX (PHGPX)

GPX5 Androgen-regulated epididymal secretory

protein

GPX6 Odorant-metabolizing protein

Thioredoxin reductases (TrxR1-4)

Deiodonases (DI)

DI1 Iodothyronine 5’-deiodonase-1 (type 1 DI)



Sel-P Plasma selenoprotein P


SELENOCOMPOUNDS IN PLANTS AND ANIMALS

Selenocompounds present in plants may have a profound effect on the health ofanimals and humans.

Selenium is present in all eukaryotic selenoproteins as selenocysteine

The mechanisms for cancer prevention by selenium include;its effects on programmed cell death,effects on DNA repair,its role in selenoenzymes,its effects on carcinogen metabolism,its effects on the immune system,selenium as an antiangiogenic agent,its specific inhibition of tumor cell growth by certain selenium metabolites


Because GPXs act to convert peroxides to less harmful compounds and becauseperoxidative damage is associated with cancer, these peroxidases involve in thereduction of tumors

ROLE OF SELENOENZYMES

These selenoproteins have been subdivided into groups based on the location ofthe selenocysteine. The first group (including glutathione peroxidase, GPX) is themost abundant and includes proteins in which selenocysteine is located in the N-terminal portion of a relatively short functional domain..

GPXs are selenoprotein that protects the organism from oxidative damage


Since the immunity of patients with cancer is reduced and selenium hasbeen shown to boost the immune system, it is logical to conclude thatselenium could reduce tumors by this method. Several studies foundthat supranutritional levels of selenium will stimulate the cytotoxicactivities of natural killer cell and lymphokine-activated killer cells.

EFFECTS ON IMMUNITY

The enhancement by selenium of the expression of the high-affinityinterleukin-2 receptor resulted in an increased capacity to producecytotoxic lymphocytes and macrophages that can destroy tumor cells


Dietary Sources of Se• Brazil nuts, dried, unblanched, 1 oz: 840

mcg

• Tuna, canned in oil, drained, 3 1/2 oz: 78

mcg

• Noodles, enriched, boiled, 1 c: 35 mcg

• Turkey, breast, oven roasted, 3 1/2 oz:

31mcg

• Chicken, meat only, 1/2 breast: 24 mcg

• Bread, enriched, whole wheat, 2 slices: 20

mcg

• Oatmeal, 1 c cooked: 16 mcg

• Cottage cheese, lowfat 2%, 1/2 c: 11 mcg


Daily doses of 100 to 200 μg selenium inhibit geneticdamage and cancer development in humans. About 400 μgselenium per day is considered an upper safe limit. Therecommended daily allowance (RDA) for selenium is 55 μgfor both men and women, and the FAO/WHO has set 26 and34 μg selenium daily for women and men, respectively


ZINCThrough its function in nucleic acidpolymerases, zinc plays apredominant role in nucleic acidmetabolism, cell replication, tissuerepair, and growth

Pronounced zinc deficiency inanimals and humans results indepressed immune functions.Both tissue-mediated andhumoral responses are affected

Experiments in animals have shownthat zinc can either enhance orretard the growth of tumors. Zincdeficiency appears to retard thegrowth of transplanted tumors,whereas it enhances the incidenceof some chemically induced cancers


Phytosterols: Sources and Metabolism

Phytosterols (plant sterols and stanols) are like cholesterol steroid alcohols(triterpenes). They are the equivalent of cholesterol in mammalian speciesand resemble cholesterol both in structure and biological function.

They are essential structural components of the cell membrane, wherethey regulate membrane fluidity and permeability as well as membrane-associated metabolic processes.

Phytosterols present a diverse group of more than 200 differentcompounds found in various plants and marine sources


Phytosterols are known to have various bioactive properties, which mayhave an impact on human health, and as such boosted interest inphytosterols in the past decade. The most important function is theirplasma cholesterol-lowering effect via inhibition of intestinal cholesterolabsorption.

Phytosterols: Sources and Metabolism

Other claimed benefits of phytosterols are possible antioxidant activity,anti-inflammatory activity, and an anti-atherogenic effect.

Furthermore, there is accumulating evidence that phytosterols, in particularplant sterols, have beneficial effects in the development of different types ofcancers.


Phytosterols are products of the isoprenoid biosynthesis pathway and likecholesterol are synthesized from acetyl coenzyme A via squalene involvingmore than 30 enzyme-catalyzed reactions all taking place in plant cellmembranes.1 Similar to cholesterol, phytosterols serve as precursors forplant steroid hormones, so called brassinosteroids

Plant sterols occur naturally in all foods of plant origin where they arefound in the lipid-rich and fiber-rich fractions. Plant sterols exist in variousforms, such as free sterols, sterol esters esterified to fatty acids or otherorganic acids (e.g., ferulic acid for oryzanol in rice bran oil or coumaricacid), plant steryl glycosides, and acylated plant steryl glycosides


The different forms of phytosterols are assumed to exist in different parts of theplant cells. While free plant sterols are a structural part of the cell membrane,phytosterol esters are located intracellularly and represent storage products

In vegetable oil, plant sterols occur mainly as free sterols and esters of linoleicand oleic acids. The proportions of free and esterified plant sterols vary greatlybetween different vegetable oils. Glycosides as well as steryl esters of phenolicacids are commonly found in cereals and grain products.

Although cholesterol is the major sterol in mammalian cells and ergosterol inyeast and fungal cells, a complex mixture of different sterols characterizes plantcells.


FOOD SOURCES OF PHYTOSTEROLS

All plant foods contain appreciable amounts of phytosterols. In particular,vegetable oils and products made from oils such as spreads and margarineare good sources of plant sterols

Other foods that contribute to the daily intake of plant sterols are cerealgrains, cereal-based products, nuts, legumes, vegetables, and fruits

Plant stanols are also found in some foods, but at much lowerconcentrations. They are found in some cereal grains such as rye, corn, andwheat and in nonhydrogenated vegetable oils.They are also found in plantmaterial from coniferous trees such as pine and spruce.


DIETARY INTAKE OF PHYTOSTEROLS

The main food sources contributing to the daily plant sterol intake werebread, in particular fiber-rich bread and vegetable oils and fats with 36and 26% of the total plant sterol intake. For vegetarians the intake ofplant sterols is in the range of 500 mg to 1 g.

The average daily intake of plant sterols varies between 150 mg/day witha typical Western European diet to 400 mg/day for a Japanese andMexican diet


Phytosterols: Bioactivity on Cancer

Dietary phytosterols, or plant sterols, have been shown by themajority of the experimental data to be protective againstspecific cancers, including colorectal, breast, prostate, lung, andstomach carcinomas. This protective role of dietaryphytosterols appears to be independent on their effects oncholesterol absorption and is supported by the results fromlarge epidemiological studies, as well as from animal studiesand laboratory experimentation with in vitro tissue culturemodels

folic acid · 2019-12-03 · active folic acid, which is converted to dihydrofolic acid in the...

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