clinical aspects of trace elements: zinc in human...

Clinical aspects of traceelements: Zinc in human

nutrition – Zinc metabolismMICHELLE M PLUHATOR MSC, ALAN BR THOMSON MD PHD FRCPC FACP FRS FACC, RICHARD N FEDORAK MD FRCPC

THIS REVIEW IS THE SECOND OF A

five-part series that examines zincin terms of its biochemistry and physi-ology, metabolism, dietary require-

ments, nutritional assessment andstates of excess and deficiency.

Although zinc has been the most in-tensely studied trace element, much re-

mains unknown about its metabolism.Little is known about its absorptionand transport across the intestinaltract. Additionally, the control mecha-nisms that allow the body to regulate itszinc content and absorption are poorlyunderstood. This review presents anoverview of what is currently knownabout the normal intestinal absorption,intracellular and extracellular metabo-lism, transport, excretion and homeo-stasis of zinc in the human body. Thealterations in zinc metabolism that oc-cur with age and changing physiologi-cal conditions are also highlighted.

INTESTINAL ABSORPTIONOF ZINC

Absorption of zinc is thought to oc-cur throughout the small intestine (1).Although the highest rate of zinc ab-sorption appears to occur in the jeju-num, the duodenum is the first segmentexposed to zinc postprandially, and itmay thus serve as the primary site forquantitative zinc absorption (1).

Investigators presume that intesti-nal absorption of zinc is aided byligands. In the intestinal lumen zinc islikely matched to a ligand with an af-finity for this element. The digestion offood leads to the introduction of aminoacids, pancreatic secretions, organicacids, phosphates and other cations ca-pable of associating with zinc into theintestinal lumen (2-4). The resultantcomplexes are then presented to thesurface of the mucosal cell.

NUTRITION

MM PLUHATOR, ABR THOMSON, RN FEDORAK. Clinical aspects of traceelements: Zinc in human nutrition – Zinc metabolism. Can J Gastroenterol1995;9(6):327-332. Although zinc has been the most intensely studied traceelement, much remains to be learned about its metabolism. Little is known aboutthe normal mechanisms of absorption and transport across the intestinal tract. Inaddition, numerous unknowns surround the intricacies of bodily zinc homeosta-sis. Part two of this five-part review presents current views on the normal intesti-nal absorption, intracellular and extracellular metabolism, transport, excretionand homeostasis of zinc in the human body. The alterations in zinc metabolismthat occur with age and changing physiological conditions are also discussed.

Key Words: Absorption, Intestinal transport, Metabolism, Trace element, Zinc

Aspects cliniques et métaboliques des éléments traces : le zincdans la nutrition humaine

RÉSUMÉ : Bien que le zinc soit l’élément trace le plus étudié, beaucoup reste àdécouvrir au sujet de son métabolisme. On en sait relativement peu sur son moded’absorption et son transport normaux dans les voies digestives. De plus, de nom-breuses inconnues entourent les relations complexes de l’homéostasie du zincdans l’organisme. Dans la deuxième partie de cette série de cinq articles, nous pas-serons en revue l’opinion actuelle sur l’absorption intestinale, le métabolisme in-tra- et extra-cellulaire, le transport, l’excrétion et l’homéostasie du zinc dansl’organisme humain. Les altérations qui affectent le métabolisme du zinc en fonc-tion de l’âge et de l’état de santé physiologique sont également abordées.

Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton,Alberta

Correspondence: Dr RN Fedorak, Division of Gastroenterology, Department of Medicine,University of Alberta, 519 Robert Newton Research Building, Edmonton, Alberta T6G 2C2.Telephone 403-492-6941, fax 403-492-3744, e-mail: [email protected]

Received for publication August 16, 1994. Accepted January 23, 1995

CAN J GASTROENTEROL VOL 9 NO 6 SEPTEMBER/OCTOBER 1995 327

As the intraluminal zinc complexesapproach the enterocytes lining the in-testinal mucosa, they contact the gly-cocalyx covering of the brush bordermembrane. Few studies have assessedthe role of the glycocalyx in zinc ab-sorption. However, two potential sce-narios have been proposed: zinc is re-leased from the luminal complexesbecause of a greater affinity for somesurface groups of the glycocalyx; or zinccomplexes attach to the glycocalyx andare transported across the mucous layerintact (5).

Events at the surface of the brushborder membrane have not been fullydefined. Using triple-lumen steadystate perfusion technology, researchershave found that, over the range of 0.1to 1.8 mM of zinc, the rate of zinc ab-sorbed is proportional to the amountinfused (1). The rate of zinc absorptionplateaus with higher concentrations,suggesting a saturable transport mecha-nism. Additionally, that study investi-gated the relationship between theintestinal absorption of zinc and that ofglucose and sodium. A ‘symport’phenomenon was found for zinc andglucose absorption (ie, zinc and glucoseinteract with a common carrier), while

an ‘antiport’ effect was exerted on so-dium absorption (ie, zinc decreases in-testinal absorption of sodium, and athigh concentrations may even cause anet excretion of sodium). Human in-testinal zinc absorption is, therefore,likely to be a carrier-mediated trans-port process.

Intracellularly, a flux of zinc frommucosa to serosa and from serosa tomucosa appears to be in progress at alltimes (6). Zinc entering the enterocyteequilibrates with the intracellular zincpool and can be bound by metal-lothionein and stored until maturecells are sloughed off, used in the me-tabolism of the absorbing cell or passedthrough the serosal border to be pickedup by the portal bloodstream (4,7)(Figure 1).

A key role for metallothionein, asulphur-rich metal-binding protein, inzinc homeostasis was first suggested byRichards and Cousins (8). The authorshypothesized that when metal-lothionein was synthesized inside theintestinal cell, it could trap zinc andmake it unavailable for transfer to thecirculating plasma. The amount ofmetallothionein present in the mucosawas found to be negatively correlated

to zinc absorption, thereby exercisinghomeostatic control of zinc metabo-lism. Other reports do not support thisconcept. Jackson et al (9) refuted theearlier hypothesis when they gave 65Znby gavage to rats and followed thedistribution of radioisotope over time.They found that both control andzinc-depleted rats retained the sameamount of 65Zn in the intestinal wall,even though more 65Zn appeared inthe carcasses of the zinc-depleted rats.When large amounts of zinc were in-jected intraperitoneally, zinc absorp-tion decreased after 6 to 24 h, possiblybecause of the synthesis of metal-lothionein. Subsequent studies byCousins (10) have shown that rela-tively large quantities of zinc areneeded to induce metallothionein pro-duction, and this event is not likely tohappen under physiological levels.

SYSTEMIC TRANSPORTOF ZINC

Approximately 50% of zinc in theplasma is freely exchangeable andloosely bound to albumin; 7% is boundto amino acids such as histidine andcysteine, and the remainder is bound tomacroglobulins and other serum pro-teins (2,11). Alpha2-macroglobulincomprises a tightly bound pool ofplasma zinc. The metabolic fate andthe physiological significance of zinccirculating with this protein are notclear. Because it is an acute-phase pro-tein that is induced during inflamma-tion, alpha2-macroglobulin’szinc-binding capacity may be related tohost immune functions (12). A smallportion of zinc, about 0.1 to 0.2% of to-tal plasma zinc, is ultrafilterable (12).Ultrafilterable zinc could act as a donorfor a high affinity, cellular zinc trans-port system, or it could represent an in-termediate state betweenprotein-bound zinc and that marked forcell uptake (12).

Plasma is the major route of zinctransportation within the body. Theplasma’s zinc content is approximately1 �g/mL, and in most tissues rangesfrom 11 to 150 �g/g (13). It is, there-fore, obvious that an active or facili-tated uptake of zinc by all tissues mustoccur, but little is known about this

Figure 1) Dietary zinc is transported across the intestinal lumen (A). Newly absorbed zinc is boundby metallothionein and stored (B), used in cell metabolism (C) or released to the plasma (D). Whendietary zinc is elevated, plasma zinc and thionein synthesis increase (dashed lines). A large quantity ofzinc entering the intestinal cell from the plasma becomes bound to metallothionein (E). Adapted fromreference 7

328 CAN J GASTROENTEROL VOL 9 NO 6 SEPTEMBER/OCTOBER 1995

PLUHATOR et al

process. Even less is known about thetransportation of zinc out of the tissuesinto the plasma. Certain tissues (eg,gastrointestinal mucosal cells) secretezinc as part of their normal physiologi-cal function. It also appears that a turn-over of zinc in other tissues results in aloss of zinc from the cells via unknownmechanisms. It is certain, however,that a constant renewal/exchange sys-tem is required to maintain sufficientlevels of cellular zinc (10).

Under conditions of catabolism, lossof zinc from the tissues may be exces-sive. For example, during periods ofmuscle catabolism, a large loss of zincfrom skeletal muscle results in in-creased urinary and fecal excretion ofzinc (13). This elevated urinary zincmay be related to the loss of peptidesand amino acids from the muscle dur-ing breakdown, which could increasethe ultrafilterable ‘pool’ of zinc inplasma. Another possible explanationis that zinc could be associated withmyoglobin and thus be lost as a result ofthe myoglobinuria that accompaniessevere muscle breakdown (13).

Approximately 30 to 40% of thezinc that enters the hepatic venous sup-ply is removed by the liver, from whichit is subsequently released back into theblood (14). Circulating zinc is incorpo-rated at differing rates into various ex-trahepatic tissues, all of which havedifferent rates of zinc turnover. Uptakeof zinc by the central nervous systemand the bones is relatively slow, andthis zinc remains firmly bound for longperiods. Zinc is incorporated in the hairand thus becomes unavailable to thetissues. The most rapid accumulationand turnover of zinc occurs in the pan-creas, liver, kidney and spleen (14).Uptake and exchange of zinc by redcells and muscle is much slower.

The kinetics of zinc absorption andelimination follow a two-componentmodel. The initial rapid phase has ahalf-life in humans of 12.5 days, andthe slower pool turns over with a half-life of approximately 300 days (14).The latter pool appears to include mostof the skeletal muscle zinc. Zinc enter-ing the plasma is cleared within hours,largely through entry into the blood

cells and tissues rather than by excre-tion from the body.

The major organ involved in zincmetabolism is the liver. The liver cyto-sol of humans and other mammals con-tains zinc-binding components ofdiffering molecular weight and lability,the amounts and proportions of whichvary with the zinc nutritional statusand age of the animal or human (14).When the liver zinc content is in-creased above normal levels (30 �g/gwet weight), the additional zinc is asso-ciated mainly with metallothionein.Short term fluctuations inmetallothionein-bound zinc levelscould be directly related to daily varia-tions in zinc intake (15).

ZINC EXCRETIONGiven normal dietary circum-

stances, the feces are the major route ofzinc excretion. A healthy human adultwhose zinc balance is in equilibrium,and who ingests 10 to 15 mg zinc/day,excretes approximately 90% of thisamount in the feces, with 2 to 10% ex-creted in the urine (16). Fecal excre-tion includes the excretion of bothunabsorbed dietary zinc and endoge-nous zinc. The level of excretion of en-dogenous zinc in the feces variesaccording to the balance between trueabsorption and metabolic needs. Thisvariation is one of the primary mecha-nisms for maintaining zinc homeostasis(14). Weigand and Kirchgessner (17)demonstrated that the endogenous fe-cal zinc excretion of rats on a zinc de-pletion diet was so low that it wasexceeded by urinary zinc losses, whichare not affected by dietary zinc intakein the rat. An increase in endogenous

fecal excretion that correlates posi-tively with dietary zinc increases hasbeen demonstrated in the human (18).The actual amount of endogenous zinclost from the human body in the fecesmay range from less than 1 mg to sev-eral milligrams daily (14) (Table 1).

Endogenous fecal losses of zinc arisewhen zinc is secreted from the bodyinto the gut and is not subsequently ab-sorbed. Matseshe et al (19) used amarker perfusion technique to measurethe intraluminal quantities of zinc inthe gastrointestinal tract of healthyadult men who consumed different testmeals. Over the 5 h following the meal,between 144 and 300% of the amountof zinc ingested was recoverablethrough aspiration done at the liga-ment of Treitz. The source of this addi-tional zinc (2.2 to 4.8 mg) was themeal-stimulated secretion of pancre-atic fluid. The researchers concludedthat an enteropancreatic circulationexisted in humans. The pancreatic out-put of zinc (which is six times greaterthan that of bile) is the largest source ofendogenous mineral re-excretion intothe intestinal lumen (6). Much of thiszinc must eventually be resorbed toavoid a negative zinc balance.

The proportion of a dose of 65Znthat subsequently appeared in pancre-atic, biliary and gastroduodenal secre-tions in human subjects was notenough to account for the total ex-creted in the feces (14). It was discov-ered that the other major pathway ofzinc excretion is provided by the intes-tinal mucosal cells. Zinc within thesemucosal cells may include unabsorbedzinc taken up from the intestinal lumenand zinc re-entering the cells from the

TABLE 1Zinc balance

Amount Percentage of intake Reference

Intake 10 to 15 mg/day

Absorption 3 to 5 mg/day 30 2

Excretion

Feces 9.0 to 14.0+ mg/day* 90 14

Urine 0.3 to 0.5 mg/day 2 to 10 14

Sweat 0.4 to 2.8 mg/day Variable 22

Semen 0.6 mg/ejaculum†

Variable 22

Menses 0.005 to 0.015 mg/day‡

Negligible 29

*Upper limit for fecal zinc excretion based upon excess dietary plus endogenous excretion;†Seminal zinc

excretion dependent upon individual level of sexual activity;‡Based upon a 30-day cycle


Zinc metabolism

plasma under conditions of net effluxfrom the serosal surface to the lumen.Intestinal metallothionein synthesis,which is sensitive to the body’s zincstatus, may enhance the value of thisroute of excretion to the overall processof homeostatic control of zinc levels(14).

The amount of zinc excreted in theurine of healthy adults is about 0.3 to0.5 mg/day (14) (Table 1). Relativelyhigh urinary zinc excretion rates occurin both term and premature infants,but by two months of age these rates aredown to 0.01 to 0.02 mg zinc/kg bodyweight/day (20). Young children aged33 to 90 months excrete a mean of0.187±0.097 mg/24 h (21). In adults,the amount of zinc excreted in theurine varies with the level of intake.In the case of adult men who consumeda severely zinc-deficient experimentaldiet (0.28 mg/day), urinary zinc wasdecreased threefold to 0.14 mg/day(22).

Urinary zinc arises largely from theultrafilterable portion of plasma zinc(23). Net reabsorption of up to 95% offiltered zinc under basal conditions oc-curs in the distal parts of the renal tu-bule (23). The amount of zinc excretedcorrelates with the rate of urine (vol-ume) production and creatinine excre-tion (24). The modest increases inurinary zinc output seen during preg-nancy may thus be due to increased tu-bular flow rates. In parenterally fedinfants, little stool is passed; thereforeurinary loss becomes the main route forzinc excretion. Eighty-seven per cent ofzinc excretion occurs in the urine ofparenterally fed infants compared with8% in healthy breast-fed infants (20).Adults supported by total parenteralnutrition likewise show increased uri-nary zinc excretion (25,26). Thischange may partially be explained bythe low fecal output of these patients.Additionally, experimental studiesdone on various total parenteral nutri-tion solutions and single amino acid in-fusions have confirmed that infusedamino acids, particularly cysteine andhistidine, are potent stimulators ofrenal zinc excretion (20). Causes ofincreased zincuria may include an in-crease in the ultrafilterable portion of

plasma zinc and the prevention of zincresorption through its being bound toamino acids secreted into the renal tu-bule (23).

Healthy adults living in a temperateNorth American climate have been re-ported to lose from 0.4 to 2.8 mg of zincdaily in sweat (22). Studies have re-ported that whole body sweat losses arerelated to dietary intake. When intakesof zinc were 8.3 mg/day, young men lostan average of 0.5 mg zinc in sweat daily;losses were reduced to 0.24 mg/day on amarginal zinc intake and increased to0.62 mg/day when subjects were re-pleted with a zinc intake of 34 mg/day(27). This reduction of sweat lossesduring times of dietary deficiency mayrepresent a mechanism for the conser-vation of zinc. Normal sweat contains1.15±0.03 �g zinc/mL, approximately75% of which is in the cell-free por-tion, with the remainder associatedwith desquamated epithelial cells (28).

Menstrual losses of zinc are negligi-ble, with average losses of between 0.1and 0.5 mg zinc occurring per period(29). This represents a loss of about0.005 to 0.015 mg/day over a typical30-day cycle, which is a minute frac-tion of the normal zinc intake.

Despite the high concentrations ofzinc found in the prostate and prostaticsecretions, very few experiments haveinvestigated seminal zinc losses in men.Baer and King (22) found that seminalzinc losses were roughly comparablewith the amounts lost daily in sweatand urine, and were responsible for20% of the total endogenous zinc lossesexperienced by their subjects. Oneseminal emission increased the loss by0.6 mg/ejaculum/day. The amount ofzinc lost via this route was quite vari-able within and among individuals. Inaddition, losses depend on the individ-ual level of sexual activity.

ZINC HOMEOSTASISThe relatively constant levels of

zinc found in the body, even though in-take varies greatly over time, suggestthat an efficient mechanism for wholebody homeostasis exists. Homeostasis ismaintained by control of gastrointesti-nal absorption and bodily excretion ofzinc. Higher absorption in cases of

lower body zinc load and increased ex-cretion during times of high zinc intakeboth contribute to zinc homeostasis.Although changes in urinary zinc out-put contribute little to the mainte-nance of whole body homeostasis givennormal dietary intakes, during times ofovert zinc depletion, a major decreasein the urinary zinc output occurs (30).

An increase in zinc absorption ratesis a well-described gastrointestinal re-sponse to a diet low in zinc, but de-creases in the rate of gastrointestinalzinc excretion are also known to occurin response to such a diet (22). In con-trast, an increase in dietary zinc intakeresults in both a reduced fractional ab-sorption of zinc and an increase in thegastrointestinal excretion of zinc (31).

When these primary homeostaticmechanisms are not sufficient to han-dle large dietary reductions or excessesof zinc, a second line of defence enters.A large excess of zinc leads to tremen-dous losses via nonphysiological routes(eg, hair) (13), while a highly zinc-deficient diet causes a selective loss ofzinc from certain body fluids and tissues(13). Animal studies have shown thatplasma zinc levels can drop rapidly afterthe introduction of a low zinc diet (32)and that liver zinc levels reflect recentdietary intakes (33). However, tissuesthat show symptoms of acute zinc defi-ciency (eg, skin, hair and gut) show lit-tle initial change in their total zinccontent. The rapid fall in plasma zinclevels that follows the introduction of adiet low in zinc may be part of a homeo-static mechanism developed to supportpreferentially zinc maintenance in tis-sues susceptible to deficiency symp-toms (13). In much the same way, thepreferential removal of surplus zincthrough incorporation into the hair islikely a method of preventing damageto other tissues.

The mucosal cell appears to play animportant role in zinc homeostasis.Mucosal uptake of zinc occurs via twoprocesses: a nonsaturable process notaffected by dietary zinc intake, and asaturable process stimulated by zinc de-pletion. Results of studies of weanlingrats provided with a range of dietaryzinc from 5.6 to 141 mg/kg showedthat, even though zinc intake rose line-


PLUHATOR et al

arly, true absorption, apparent absorp-tion and apparent retention eachplateaued at about the 40 ppm level(17). At the lowest dietary intakes, aquantitative (100%) absorption of die-tary zinc takes place, and fecal zinc isderived entirely from endogenouslosses. However, at higher levels of zincintake, a decrease in true absorptionand an increase in endogenous excre-tion into the gut combine to providestable bodily retention. Studies of insitu ligated loops of rat intestine in-fused with zinc concentrations rangingfrom 1 to 200 �g/mL have displayedsaturation kinetics suggestive of acarrier-mediated function (34). Fur-ther, at the lower end of zinc infusionlevels (1 to 50 �g/mL), mucosal bind-ing took place at specific sites; beyondthis range, binding was not specific.Thus, absorption occurs via a saturableprocess: above a certain level, the ca-pacity of this process is exceeded. Ex-cretion of zinc is the main regulator ofzinc homeostasis at higher dietary zincintake levels (35).

CHANGES IN ZINCMETABOLISM WITH AGE ANDPHYSIOLOGICAL CONDITIONS

Recommended intake levels of zincare highest for infants and for pregnantand lactating women. These higherlevels take into account the increaseddemands for zinc experienced by thegrowing fetus and infant; milk produc-tion also requires an increased zinc sup-ply. However, there is also a possibilitythat the efficiency of intestinal zinc ab-sorption is increased during these timesof rapid growth and production. Stud-ies by Davies and Williams (36) onpregnant rats found that the absorptivecapacity of the small intestine in-creased during periods of pregnancyand lactation. Zinc absorption per duo-

denal loop was found to increase afterthe 12th day of pregnancy and to con-tinue to rise during lactation. Duringthe latter part of pregnancy, zinc ab-sorption was found to increase specifi-cally (ie, in contrast to a generalincrease in nutrient absorption),probably to meet the increased needs ofthe fetus because maternal zinc reten-tion levels were unchanged. Mucosalhypertrophy was responsible for thegeneral increase in nutrient absorption,including zinc, during lactation. Swan-son et al (37), using stable isotopes,found no significant difference in thezinc absorption of pregnant and non-pregnant women. It is possible that asmall increase in zinc absorption ratesduring human pregnancy may be suffi-cient to store enough zinc to cover theneeds of the fetus, while the rat, with itsmany fetuses and short pregnancy term,may require a much faster zinc accrualrate (5).

Little information is available onthe effect of ageing on zinc metabolismin humans. It is, however, well knownthat the newborn animal absorbs zincto a higher degree than does the olderanimal (17). Studies done on rats ofdifferent ages suggested that the trans-port system displayed a higher affinityfor zinc at a young age. Total zinc up-take was shown to increase with age,and values were higher for younger ver-sus adult rats. Another study showedthat the intestinal absorption of 65Zndecreases with age in rats (38). In hu-mans, the retention of zinc with age hasbeen reported (39). The values for zincbalances reported for children andyoung adults, compared with zinc bal-ances of older persons, indicate thatzinc metabolism changes with age (40).Decreases in both plasma and tissuelevels of zinc have been reported,mainly in individuals with pathological

conditions. However, these persons areusually older individuals. As ageing andvarious disease states may both affectzinc status, it becomes important to beable to distinguish between the effectsof the two variables. Very little infor-mation exists on zinc metabolism inthe older adult population. Among theparameters of zinc metabolism thatmay possibly change with age are intes-tinal absorption of zinc, endogenousexcretion, tissue retention and zinc bal-ance, plasma levels and exchangeablezinc pool status. Should it be possible todistinguish significant changes in zincmetabolism associated with age, cor-rective measures may aid in reversingthese changes; such corrective meas-ures may also prevent the developmentof disease states in which abnormal zincstatuses are involved.

CONCLUSIONSAlthough medical researchers have

a more comprehensive understandingof the role of zinc in human nutritionand homeostasis than they do for anyother trace element, there is a consid-erable lack of knowledge about normalzinc metabolism and the metabolicsources of the pathological changesthat occur during times of zinc defi-ciency. The relatively constant controlexerted over zinc levels in the tissuesand body fluids, maintained even withdiverse dietary intakes, suggests that ef-ficient mechanisms work to controlwhole body homeostasis. Investigationof the factors responsible for theseadaptive controls will likely providelong-anticipated insights into the com-plexities of zinc metabolism, includingthe ways in which human physiologicalprocesses change as the human bodyages, and faces the challenges of preg-nancy, growth and disease.

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clinical aspects of trace elements: zinc in human...

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