Zinc (Zn, atomic weight 65.38) is a metallic, divalent transition element.


DMTI divalent cation transporter 1 (SLC11A2)

MTF-1 metal response element-binding transcription factor-1

ZnT-1 zinc transporter 1 {SIC30A1 )

ZnT-2 zinc transporter 2 (SLC30A2)

ZnT-3 zinc transporter 3 (SLC30A3)

ZnT-4 zinc transporter 4 (SLC30A4)

ZIP zinc- and iron-régula red protein

Nutritional summary

Function Zinc is essential for the activation of numerous genes and as cofaetor for many enzyme reactions.

Requirements. At least H mgd zinc are necessary to maintain adequate stores lor women consuming a mixed diet, and 11 mg for men (Food and Nutrition Board Institute of Medicine, 20021. Vegetarians and pregnant or breastfeeding women need slightly more. Sources: Oysters are exceptionally rich, other shellfish and meats also are good sources. Phytate from whole grains and some vegetables interfere with zinc absorption. Deficiency Low intake is associated with loss of appetite, scaling skin lesions, and impaired immune function.

Excessive intake: Consumption of more than 40mgd may deplete eoppcr stores, impair immune function, and lower 1101 levels.

Dietary sources

Foods contain elemental zinc, much of it bound to proteins or DNA. Meats (2-3mg.i(K)gl, and shelllish (cooked clams 2.7mg. 100g> provide most, oysters arc exceptionally rich (>70mg per serving). Plant foods are much poorer sources.

Digestion and absorption

More than 70% of a small zinc dose (less than 3 mg) is absorbed from the small intestine when there is no interference from other meal constituents (LÔnnerdal. 2000). Protein hydrotysates and some amino acids, particularly histidine and cysteine, increase fractional zinc absorption. Higher than minimal zinc doses, replete zinc status, and the presence of phytate in the same meal greatly decrease absorption efficiency. Concurrent high intakes of iron, calcium or other divalent metal cations do not appear to impact zinc absorption significantly (Sandstrom. 2001).

Significant amounts of zinc enter the intestinal lumen with secretions from the pancreas. Intraluminal digestion by proteases, DNAses and KNAses releases zinc from the food matrix. Zinc forms complexes w ith histidine. cysteine, and nucleotides that are absorbed better than zinc alone. Absorption is reduced by phytate (Lônncrdal, 20(H)).

The main mechanism for zinc uptake from the intestinal lumen is with Z1P4 (SLC39A4), a member of the ZIP family (Wang et a/., 2002). This transporter is expressed at the luminal side of enterocytes throughout the small and large intestine. A related protein, provisionally designated hORFI. may contribute to zinc uptake from the colon ( Wang et at,. 2002). Genetic variants of this gene are associated wilh the rare familial condition acrodermatitis enteropathies. The proton-coupled divalent cation transporter 1 (DMTI. SLCI1A2) appears to provide a minor uptake route. DMT I also transports iron, copper, cadmium, and other divalent metal ions that may compete with zinc (McMahon and Cousins. I<)9tf). This may be the basis for diminished zinc uptake in the presence of high amounts of calcium. Enterocyte intracellular iron concentration is the main determinant of DMT I expression and translocation to the apical membrane: low iron status upregulates DMTI expression, and more so if the subject is pregnant or has a familial hemochromatosis phenotype.

A possible alternative route for zinc uptake is v ia the hydrogen ion peptide cotrans-porter (SLC15A1. PepTI) when complcxed to small peptides (Tacnet et at., 1993). Uptake as a complex with indiv idual amino acids may explain why histidine and cysteine improve intestinal zinc absorption (L6nnerdal, 2000).

Metallothioneins are a ubiquitous family of cysteine-rich small peptides thai bind zinc and some other heavy metals with high capacity [up to 12 atoms per peptide).

DNA-Zn flNA-Zfi Ztl

DNA-Zn flNA-Zfi Ztl

(last wiiti lecas I

Intestinal lumen


melallothiortein isequeatralmnj

(last wiiti lecas I

Intestinal lumen


Brush border membrane


Capillary lumen

S a sola! era I Capillary membrane endothelium

Figur» 11.11 Intestinal zinc absorption

A dozen genetically distinct metallothionein isoforms occur in liver, additional ones in brain, tongue and stomach. Metallothionein regulates zinc transfer into porta! blood through binding and retaining it within the enteroeyte until shedding into the intestina) lumen. High intracellular zinc concentration from luminal or endogenous increases metallothionein production and this, in turn, decreases net zinc absorption (Davis end.. 1998).

Zinc is exported from enteroeytes into portal blood by zinc transporters I iZnT-l. SLC30A1) and 2 (ZnT-2, SLC30A2). ZnT-l expression is upregulated when zinc intake is high (McMahon and Cousins. 1998). Another pathway for zinc transport across the basolateral enteroeyte membrane is via the zinc-regulated transporter 1 (SLG39A11,

With increasing intraluminal concentrations net zinc movement across the tight junctions ofthe epithelial layer (paraeellular pathway) becomes more significant. Regulatory mechanisms involving DMTI or metallothionein thus are bypassed when high-dose supplements arc ingested.

Transport and cellular uptake

Blood circulation: Newly absorbed /inc in portal blond is bound to albumin (Cousins, 1986) and alpba-2-macroglobulm (Osterberg and Malmensten. 1984) as is the zinc in peripheral blood. Typical venous concentrations are between It) and 17 m.1110! 1. lower in people wiih severe zinc deficiency.

A hormone-responsive zinc Uptake transporter (SLC39A1) of the zinc- and iron-regulated protein (ZIP) family (Costello el al„ 1999) mediates the uptake into prostate cells. ZIP2 is another closely related transporter that may mediate cotransport of zinc and bicarbonate into cells (Gaither and Eide. 2000). ZnT-2 (SLC30A2) and be involved in zinc efflux or uptake into endosoraal and lysosomal v esicles in intestine, kidney, and testis, ZnT-3 (SJX30A3) is involved in zinc uptake into vesicles in neurons and in testis. ZnT-4 (SLC30A4) is another zinc exporter, which is highly expressed in mammary gland and brain. Transport of zinc across the plasma membrane of neurons is freely reversible and not ATP or ion-dependent (C'olv in. 1998).

In the mammary gland zinc is exponed into milk by ZnT-4; complexing with simultaneously secreted metallothionein greatly increases zinc bioavailability for the breastfed infant.

Zinc is presumably released again from metalloproteins, histones. and DMA when these arc broken down by intracellular (lysosomal) digestion.

Blood bram barrier: The mechanism for zinc uptake into brain capillary epithelial cells is unresolved. It is likely to involve mediation of uptake from blood by a zinc-histidinyl complex and DMTI (Takeda, 2000). Transport from blood into and out of cerebrospinal fluid via the choroid plexus is a major pathway for the maintenance of brain zinc homeostasis, but the molecular mechanisms at that site arc not any better understood than for brain capillary epithelium.

Matemo-fetal transfer: Zinc moves across the placental membrane by a slow process, that equally facilitates transfer in either direction depending on the prevailing concentration gradient (Beer et al.. 1992).


Zinc stores in replete women are about 1.5 g, and 2,5 g in men (King and Keen, 1994). Muscles ami bone contain most of the body s /inc. Turnover of zinc-containing proteins and UNA. which constitute the bulk of zinc in muscle and hone, is very slow, with a half-life of about 30(1 days (Wastney et a!,. 211(H)). This means that less than 6 mg are mobilized per day as zinc-containing structures are hroken down. In contrast, zinc associated with metal lothionein in the liver is turning over with a half-life of about two weeks and can be readily mobilized. This much smaller pool can cover for a sudden shortfall in dietary intake, therefore. However, due to the small size of this rapidly exchangeable pool (less than 170mg), zinc depletion can become functionally relevant within a week (Miller et al.. 1994).


About 1 mg day appears to be lost w iih sweat, skin, and hair. Fecal losses (unabsorbed zinc from both diet and endogenous secretions) depend on zinc intakes and status (Lee et at, 1990). and can be less than I mg/day (Stan et at. 19%). Ejaculate contains about 1 mg. and menstrual losses range from 0.1 to 0.5 mg. Losses with urine have been estimated to be 0.4 -0.6 mg/day (2- 10"» of intake).

Since \ irtually all zinc in blood is complexed to larger proteins (albumin, alpha-2-macroglobulin). relatively little gets into filtrate in the kidneys. The small amount that gets into ultraiiltrate is reabsorbed mainly from the distal renal tubule \ ia ZnT-1 (Victery etai. 1981).


While zinc flux and concentration is regulated at various points, control of melallo-thionein expression is the most important mechanism for maintaining zinc adequacy. Increased metallothionein expression in the small intestine decreases intestinal absorption. increased expression in the fix or expands stores. Metallothionein expression is induced by the metal response element-binding transcription factor-1 < MTF-I). This zinc sensor with iis six zinc-coordinated peptide loops (zinc fingers) binds to multiple metal response elements of the metallothionein promoters when the free zinc ion concentration is high (Langmade ft al.. 2000). MTF-I also induces expression of ZnT-1. This latter change might be primarily responsible for increased excretion of zinc into bile and pancreas juice.

Binding of another transcription factor, upstream stimulatory factor family (DSF), to a separate promoter sequence (antioxidant response element) is involved in the induction of metallothionein expression in response to oxygen free radical (H:Oi) stress.


Zinc is a cofactor of several hundred enzymes and is needed for the replication and function of DNA. Inadequate supplies impair food digestion and absorption, synaptic signaling, gene expression, control of oxidant stress, growth and wound healing, immune function, taste and appetite, and many other functions. I,ess than adequate zinc availability appears to interfere with organ formation during early pregnancy (Hurley. 19SI), It is ollen difficult to establish a tight link between individual /inc-dependent structures and functional status, because zinc impacts so many concurrent and sometimes competing processes. Only a limited selection will be touched on in the following.

Intestinal digestion Zinc is an essential cofactor of carbonic anhydrases, proteases, phosphatases and other enzymes involved in food digestion and absorption. The role of carbonic anhydrases for gastric acid production is described below. The car-box ypeptidases AI and A2 (EC3.4.2,1) are zinc-dependent digestive enzymes from the pancreas. Several peptidases of the intestinal brush border are zinc enzymes, including leucine arhinopeptidase (LAP. EC3.4.11,1). membrane alanine aminopepti-dase (aminopeptidasc N. EC3.4.I1.2), glutamyl aminopeptidasc (aminopeptidasc A. EC3.4.11.7). membrane dipeptrdase (EC3.4.13.19), angiotensin I-converting enzyme (EC3.4.15.1), neprilysin (EC3.4.24.II). and meprin A (EC3.4.24.1 K), Another zinc-containing brush border enzyme (pteroylpoly-gamma-glutamate carboxypepiidase. EC3.4.19.8) is needed to cleave off gam ma-glutamyl residues from dietary folate prior to absorption. Alkaline phosphatase (EC3.1.3,1, requires both zinc and magnesium) at the intestinal brush border digests complex forms of thiamin, riboflavin, and pantothenate. pH-Regulation: The conversion of carbon dioxide to its weak acid helps cells to adjust proton concentration w ith a readily available and easily removable reagent. This equilibrium reaction is catalyzed by the zinc enzyme carbonate anhydmse (EC4.2.I.I). The ten or more genetically distinct isoforms of this handy enzyme provide line tuned kinetic properties and regulatory characteristics for a w ide range of functions thai include acidification, signaling, promoting cell proliferation, bone resorption, and respiration. A long known role of the enzymes I, II. and IV is to provide protons for hydrochloric acid production in the stomach. Gastrin, histamine, and acetylcholine activate these isoenzymes, while somatostatin and several acid-suppressing drugs inhibit them. Carbonic anhydrase VI, gustin, is a special form in salivary glands, that helps to maintain taste bud growth (possibly by acting on bud stem cells) and function (I lenkin et uL, 1999). Adequate zinc intake appears to promote taste acuity. Nutrient metabolism: Zinc-containing alcohol dehydrogenases (ADM. EC 1.1,1.1) in the stomach wall and liver oxidize cthanol. A particular ADD isoenzyme is needed for the conversion of the transport and storage form retinol into the retinal form used for vision. Optimal zinc status may lower the risk of macular degeneration (Age-Related Eye Disease Study Research Group. 2001).

Several zinc-dependent folate hydrolases in lysosomes. membranes, and cytosol are essential for folate metabolism and transport in tissues.

DNA replication and transcription: Zinc lingers are DNA-binding domains of transcription factors in which the zinc ion is tetrahedrally coordinated to cysteine and,or histidine residues. These zinc-complexing structures are very ubiquitous features that give zinc a central role in expression of virtually any type of protein. Zinc is a cofactor of many enzymes participating in the synthesis of DNA and RNA during cell div ision and gene expression. Important zinc enzymes include DNA polymerase (EC2.7.7.7) and

DNA-dependent RNA polymerase (EC2.7.7.6); many others are regulated through zinc-finger proteins.

RNA editing: Zinc is a cofactor of the apolipoprotein B RNA editing complex, which deaminates specific cytidine moieties in a few mRNA species, most prominently of apolipoprotein B. but also of tumor necrosis factor-«, c-myc and other centrally important regulators of growth and differentiation (Anant and Davidson, 2000). The same complex also extensively edits the translational repressor NATI. which is involved in postnatal heart development (Pak and Pang, l 999).

Immune function: The zinc-dependent peptide hormone (hymulin comes from the thymus. Thymulin helps to maintain immune function by activating T-lvmphocytcs and enltancing the cytotoxicity of natural killer cells. Zinc may also act directly by promoting the proliferation of lymphocytes and decrease susceptibility to programmed cell death (apoptosis). Since zinc is an essential cofactor of many enzymes involved in proliferation of any rapidly dividing cell, it becomes very difficult to differentiate this from a more specific role as a direct effector. Whatever the proximate mechanism, there is no doubt that counts of both natural killer cells and 1111 lymphocytes decline with zinc deficiency. Related to suboptimal zinc are also low production of interlcukin-2. tumor necrosis factor-«, and interferon-y (Prasad. 1998). and possibly of 11-6. Fuel metabolism: The interactions of zinc with players in carbohydrate metabolism are numerous and not yet fully understood. Only a few are to be mentioned here. Zinc chelates insulin during storage and thus plays a role in control of its secretion. Glucagon rapidly lowers the intracellular concentration of the free zinc ion. Zinc itself opposes the effect ofcAMP on glycolysis.

Free radical metabolism: Zinc contributes importantly to the defense against oxidative stress. It docs so partly as a cofactor of superoxide dismutases (SOD, EC 1.15,1.1) in cy to plasma (SODl) and in the extracellular space (SOD3). Protection of sulfhydryl groups and other direct effects of zinc on redox reactions have been demonstrated (Powell. 2000).

Other functions: A link of zinc to vascular function is established through its rote as a cofacior of nitric oxide synthases (ECl.14.13.39).


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