Physiological Role
Tissue Distribution of Zn
Absorption and Excretion of Zn
Homeostatic Control
Interactions of Zn with Other Dietary Constituents
Dietary Sources of Zn
Zinc Deficiency

I.  Physiological Role

  1. Respiration and gastric secretion as a component of carbonic anhydrase
    H20 + CO2  H+ + CO3-
    The hydration of CO2 (CO2 + H20  H2CO3) coupled with its dissociation
    (H2CO3  H+ + CO3-) proceeds too slow to be biologically relevant without the Zn enzyme carbonic anhydrase
  2. As a constituent of several metaloenzymes, Zn is involved in carbohydrate metabolism, protein synthesis, and nucleic acid
    1. Carboxy peptidase A and B catalyzes hydrolysis of carboxyl terminal amino acids from proteins and polypeptides regardless of length of the peptide chain
      1. Aromatic or branched aliphatic side chains
      2. Basic sidechains
    2. Dehydrogenases
      1. Alcohol dehydrogenase - catalyzes oxidation of ethanol, vitamin A alcohol (vitamin A transport, utilization, rhodopsin) and certain sterols
      2. Glutamic dehydrogenase
        Glutamate + NAD    µ ketoglutarate + NH3 + NADH
      3. Lactic dehydrogenase
        Lactate + NAD   pyruvate + NADH
      4. Malic dehydrogenase (
        Malate + NAD   oxaloacetate + NADH
        (The purpose of Malic dehydrogenase is to catalyze the metabolism of malate to oxaloacetate and NAD is the hydrogen receiver. It should not be confused with Malic enzyme which is involved in hydrogenation of NADP. NADPH must be regenerated and this is done by malic enzyme
    3. Other Malate dehydrogenase (see Enzyme Nomenclature, Committee on Biochemical Nomenclature, 1972) Malate + NAD +    Pyruvate + CO2 + NADH
      1.1.140  Malate + NADP +    Pyruvate + CO2 + NADPH
      1.1.182  Malate + NADP +    Oxaloacetate + NADPH
    4. D-glyceraldehyde 3 phosphate dehydrogenase
      1. ADP ® ATP
        1. Phosphoglyceraldehyde  Phosphoglyceric acid
          1. NAD+ ® NADH
    5. Alkaline phosphatase- hydrolyzes many different esters of phosphoric acid
    6. µ - mannosidase
    7. Aldolase - catalyzes the reversible formation of fructose 1,6 bisphosphate from 3 phosphoglyceraldehyde and dihydroxy acetone phosphate
    8. Superoxide dismutase
      1. Cu, Zn superoxide dismutase is composed of two polypeptide chains with identical amino acid sequence each of which binds one Cu and one Zn at active sites
      2. The interaction between two submits cannot be broken without denaturing the enzyme
      3. Cu, Zn superoxide dismutase operates primarily in the cytoplasm and is distinct from Mn superoxide dismutase which operates primarily in  mitochondrial membranes
    9. Zn is involved in nucleic acid metabolism, protein synthesis, and plays a role in configuration of DNA and RNA
      1. DNA polymerase - At the time of each somatic cell division (mitosis), the two DNA chains separate, each serving as a template for synthesis of a complementary chain. DNA polymerase catalyzes this reaction
      2. RNA polymerase - polymerizes ribonucleotides to RNA
      3. Ribonuclease - breaks RNA down into ribonucleotides
      4. Thymidine ~nase - phosphorylates thymidine for incorporation into DNA
      5. Collagenase - hydrolyzes collagen
  3. Zn binds to histidine and cysteine residues of specific DNA binding proteins in the cell nucleus (see Berdanier, C.D. 1998. Advanced Nutrition Micronutrients. CRC Press, Boca Raton, FL)
    1. These proteins with Zn attached are called Zn fingers
    2. Vitamin A, vitamin D, and some hormones have their effects on expression of specific genes because they can bind to specific Zn fingers which in mm bind to very specific DNA regions
    3. Zn can sometimes be displaced on Zn fingers by other divalent metals
      1. When Fe substitutes for Zn, free radicals are more readily generated genomic damage
        1. When Cd substitutes for Zn, the resultant fingers are nonfunctional
  4. Zn is important for stabilization of membranes
  5. Insulin contains 2 to 4 atoms of Zn in its crystalline structure

II.  Tissue Distribution of Zn

  1. Average Zn concentration of the total body, at 20 ppm, is second only to Fe of the trace elements
  2. Zn in contrast to some other trace elements is relatively evenly distributed among tissues and organs
    1. Generally associated closely with protein and skeletal tissue
    2. Relatively little in fats and lipids
    3. Rarely occurs alone in the animal but is combined with protein or other organic compounds
  3. Zn content of most tissues appears to be under close homeostatic control and is reduced only slightly when Zn deficient ration is fed
  4. Body stores will not provide an appreciable amount of Zn for mobilization over an extended period
    1. Either capacity for storage of Zn is limited, or
    2. Effective mechanisms for mobilizing Zn are lacking

III.  Absorption and Excretion of Zn

  1. Zn is absorbed by both nonsaturable (passive diffusion) and saturable (possibly involving Zn-binding metallothionein and/or a cysteine-rich intestinal protein) processes
    1. Extracellular binding of Zn
    2. Internalization of the Zn ligand
    3. Binding of Zn to a cysteine-rich protein within the enterocyte
      1. Transfer to metallothionein or albumin
      2. Transfer from enterocyte to plasma
      3. In plasma
        1. 77% loosely bound to albumin
        2. 20% tightly bound to µ -2-macroglobulin
        3. 2-8% is ultrafilterable
      4. Ultrafillerable Zn is excreted in urine or-in feces via bile
      5. Unabsorbed Zn is excreted in feces
        1. Excretion is increased by binding agents or chelating agents which render Zn unabsorbable
        2. Examples are ligands containing sulfur, nitrogen or oxygen; phosphate groups; clay
  2. Utilization of Zn after absorption
    1. Absorbed Zn is concentrated initially in the liver
    2. Subsequently, it is distributed to the tissues
    3. Increased amino acid utilization is associated with increased tissue uptake of Zn
    4. Redistribution of Zn in the body
      1. Stress
      2. During wound healing
      3. When dietary Ca is deficient
      4. When there is increased mobilization of bone
  3. Sites of Zn absorption
    1. Small intestine is the main site of absorption (J. Nutr. 118:61-64, 1998)
    2. Absorption is greater from the duodenum than from the jejunum or ileum
    3. Absorption was not affected by ligation of the common bile duct
    4. There is also a massive secretion of Zn into the duodenum

IV.  Homeostatic Control

  1. Changes in absorption are the primary homeostatic control. Zn absorption percentage is related closely to needs of the animal
    1. When a low Zn diet is fed, percentages of dietary Zn absorbed may increase to as high as 80%
    2. With a high Zn diet, absorption is reduced, sometimes to less than 10%
    3. These changes occur within a few days
  2. Endogenous Zn enters the intestinal lumen
    1. A constituent of metalloprotein secreted by the salivary glands, intestinal mucosa, pancreas and liver
    2. Catabolism of sloughed intestinal calls
    3. Active transport across the intestinal mucosa
  3. With the possible exception of Zn metallothionein, a storage form of Zn has not been identified in soft tissue
  4. Zn in bone is usually relatively unavailable to other tissues for utilization
  5. Amounts lost in urine and sweat are too small to contribute to homeostasis

V.  Interactions of Zn with Other Dietary Constituents

  1. Copper and Zn
    1. Excess Cu may decrease Zn absorption but the effect is of minimum significance
    2. Nutritional effect of excess Zn on Cu metabolism is much stronger
      1. Zn interferes with Cu absorption and metabolism
        1. Cu may become inadequate when Zn intake is only slightly in excess
        2. Zn may compete with Cu for binding sites on an absorption enhancing protein (Physiol. Rev. 53:535-570, 1973; J. Am. Med. Assoc. 240:2188, 1978)
        3. High dietary Zn may cause synthesis of metallothionein in intestinal mucosal cell which then binds Cu and makes  it unavailable for transport to the serosal side (Am. J. Clin. Nutr. 34:1670-1675, 1981)
      2. Zn intake only 3.5 mg/d above RDA reduced Cu retention in adult males (Am. J. Clin Nutr. 41:285-292, 1985)
      3. RBC Cu inversely correlated with dietary Zn/Cu ratio and with Zn status in adolescent girls (Nutr. Res. 9:1207-1216, 1989)
      4. Supplementation with only 30 mg/d Zn lowered plasma ceruloplasmin in human subjects
      5. Zn supplements decreased RBC superoxide dismutase in adult men (Am. J. Clin. Nutr. 34:1670-1675, 1981)
      6. Increased dietary Zn associated with decreased liver Cu in rats; this effect offset when dietary Cu increased (Nutr. Rep. Intl. 40:695-706, 1989)
      7. When rats are fed high Zn levels, activities of superoxide dismutase, cytochrome C oxidase, and ceruloplasmin are all reduced
      8. Decrease in tissue Cu is less than decrease in enzyme activities (tissue Cu may stay high due to induction of metallothionein which binds Cu and makes it unavailable for incorporation into metalloenzymes
        1. Zn deficiency elevates Cu and ceruloplasmin levels; Zn therapy reverses this relationship
        2. Zn has been used to prevent accumulation of toxic levels of Cu by Wilson's disease patients
  2. Fe and Zn (J. Nutr. 116:927, 1986)
    1. Excessive Fe may aggravate borderline deficiency of Zn
    2. High dietary Zn can clear up or prevent Cu deficiency induced Fe accumulation in the liver
    3. Zn can prevent Fe induced free radical damage presumably by displacing Fe at sensitive molecular sites (Free Radical Biol. Med. 8:281-291, 1990; J. Nutr. 125:823-829, 1995, J. Exp. Med. 185:71-79, 1997)
  3. Increased dietary Zn reduces toxicity of lead
    1. Marginal Zn deficiency may increase body burden of Pb
    2. Zn reduces Pb absorption
  4. Cadmium greatly reduces Zn absorption and is also a strong antimetabolite of Zn
    1. Cd competes with Zn at active sites
    2. Cd exposure enhances the Cu, Zn, and Cd content of metallothionein
    3. Incorporation of metals other than Zn into metallothionein may require prior synthesis of Zn thioneine with subsequent displacement of Zn by other metals
  5. Phosphorus in the form of phytate reduces Zn absorption in nonruminants (J Nutr. 119:211, 1989)
    1. Phytate reduces apparent absorption of Zn in ruminants only when the rumen is bypassed (J. Nutr. 93:386, 1967)
    2. Calcium increases stability of the Zn-Phytate complex in nonruminants further reducing Zn availability
      1. Ca must be present in available form when complex is formed since feeding Ca Phytate does not affect Zn utilization
      2. Ca does not affect Zn absorption in the bovine (J. Dairy Sci. 62:1081, 1979)
  6. Clay and possibly other substances consumed by persons who practices geophagia may inhibit the availability of Zn for intestinal absorption
  7. Other organic substances inhibiting Zn absorption
    1. Component of dietary fiber in human diet
    2. Products formed during food processing
      1. Amino acid-phytate products
      2. Products of the Maillard reaction

VI.  Requirements

  1. A.          NRC recommendation for cattle is about 40 ppm Zn
  2. B.           For poultry and swine, 40-100 ppm is recommended
  3. C.           RDA for humans
    1. Infants -1 yr...........................................3-5 mg/d
    2. Children 1-10 yrs..................................l0 mg/d
    3. Adult males..........................................15 mg/d
    4. Nonlactating, nonpregnant females.....15 mg/d
    5. Pregnant females.................................20 mg/d
    6. Lactating females.................................25 mg/d

VII.  Dietary Sources of Zn

  1. Zn is widely distributed in most feeds
    1. Legume forages are generally higher than grasses in Zn
    2. High protein feeds contain substantial amounts of Zn but availability of Zn must be considered in plant protein sources
    3. In areas where soil is very low in Zn (such as western Australia) some widely used feeds may be very deficient in Zn
    4. Egg white is very low in Zn

VIII.  Zinc Deficiency

  1. Changes in agricultural practices may have increased probability of borderline Zn deficiency when no supplemental Zn is fed
  2. Causes of Zn deficiency in humans (J. Am. Col. Nutr. 4:49, 1985)
    1. The most severe manifestations of human Zn deficiency occur in infants with the genetic disease acrodermatitis enteropathica
      1. Transmitted by an autosomal recessive gene
      2. Symptoms usually begin after infants have been weaned from breast milk
      3. Symptoms-rash that usually begins around body orifices, diarrhea, failure to thrive, infections, death
      4. Condition appears to result from a defect in ligands involved in Zn absorption. (Evans says that defect is in the tryptophan metabolizing pathway proximal to synthesis of picolinic acid.
      5. Treatment
        1. Oral administration of pharmacologic doses of Zn Sulfate
        2. Physiological levels of Zn as Zn picolinate
    2. Malabsorption syndromes and inflammatory diseases of the bowel
    3. Liver disorders - alcoholic cirrhosis, hepatitis
    4. Renal dysfunction
    5. Injury, inflammation and stress
    6. Parasitic diseases
    7. Parenteral or enteral alimentation without adequate Zn
    8. Nutritional
      1. Alcoholism
      2. Protein-energy malnutrition
      3. High dietary fiber and phtate
      4. Pica
      5. Pregnancy
  3. 0.1% ZnS04-7H20 in distilled water on tongue is a test for subclinical Zn deficiency
    1. If individual is Zn deficient, he doesn't taste it
    2. If Zn is adequate, it tastes bad; the more adequate Zn is, the worse it taste
  4. Effects of Zn deficiency or protein and nucleic acid metabolism
    1. Utilization of amino acids for protein synthesis is impaired
    2. Increased protein catabolism results in increased urinary nitrogen
    3. RNA is reduced in certain tissues (RNA polymerase is a Zn enzyme)
    4. DNA synthesis is impaired almost immediately in Zn deficiency (DNA polymerase and thymidine kinase are both Zn enzymes)
    5. In addition to an enzyme role, Zn may have a role in maintaining structure of RNA, DNA, and ribosomes
  5. Effects of Zn deficiency
    1. Male reproduction
      1. Impaired spermatogenesis
      2. Testes, epididymis and prostate do not develop normally
      3. Reduced serum testosterone
    2. Females reproduction (see J. Anim. Sci. 60:1530, 1985)
      1. Rat - fetal resorption, abnormal fetal development, dystocia, prolonged labor, excessive bleeding, frequently maternal death
      2. Swine - prolonged labor, reduced litter size
      3. Hens - decreased hatchability of eggs, abnormal development of embryo, high mortality of embryo
      4. Cattle - reduced conception
      5. Sheep - reduced number of lambs per ewe.
      6. Humans - prolonged gestation, inefficient labor, atonic bleeding at delivery, possible risk to fetus
    3. Zn deficiency and keratogenesis (hyper-keratinization or thickening of epithelial tissue)
      1. Swine: parakeratosis-skin becomes rough with loss of hair and possible bleeding mostly around the mouth, eyes and legs
      2. Sheep: wool fibers lose their crimp and become thin and loose
      3. Birds: poor feathering and dermatitis
      4. Humans: acrodermatitis enteropathica
    4. Zn deficiency and wound healing
      1. Zn accumulates at the site where a wound is healing.
      2. When Zn is deficient, DNA and subsequent collagen synthesis are impaired resulting in wounds not healing or healing at a slower rate
    5. Immune system does not operate properly during Zn deficiency
      1. Atrophy of thymus
      2. Decreased lymphocytes
      3. Decreased thymic hormone production
    6. Zn deficiency in the young can permanently affect binding function
      1. Decreased brain size and learning ability
      2. Probably relates to effect of Zn on DNA and RNA synthesis
    7. Skeletal changes - collagen synthesis and turnover is reduced
    8. Abnormal prostaglandin metabolism
      1. Platelet aggregation is abnormal
      2. Prolonged bleeding time can be reversed within 4 hr by oral administration of Zn
    9. Crystalline insulin contains 0.5% Zn. Release from pancreas and physiological potency of insulin maybe reduced by Zn deficiency
    10. Zn deficiency impairs mobilization of vitamin A from liver resulting in decreased circulating vitamin A levels
  6. Manifestations of Zn deficiency in humans
    1. Anorexia
    2. Dermatitis
    3. Poor wound healing
    4. Impaired immunity
    5. Growth failure
    6. Hypogonadism
    7. 7Oligospermia (Oligo means few, scant)
    8. Impotence
    9. Hypogensia (poor sense of taste)
    10. Poor dark adaptation
    11. Neurophysiological dysfunction
  7. Manifestations of Zn deficiency in farm animals
    1. General, nonspecific
      1. Reduced feed intake, feed efficiency, and growth
    2. Clinical appearance
      1. Inflammation of mouth and nose with submucous hemorrhages
      2. Skin parakeratosis, loss of hair (mammals), decreased feather pigmentation and frizzled feathers (birds)
      3. Slow wound healing (if at all)
      4. Stiffness of joints, decreased bone mineralization, bone deformities
      5. Grinding of teeth and excessive salivation
      6. Retarded testicular development (reversible in calves but not in rats)
    3. Biochemical changes (not very effective in identifying borderline Zn deficiency
      1. Decline in plasma Zn in a few days
      2. Small decline in liver and kidney Zn
      3. Decline in hair Zn over a long period
      4. Increased in vitro uptake of 65 Zn by erythrocytes
      5. Moderate reduction in carbonic anhydrase
      6. Larger reduction in serum alkaline phosphatase
    4. A hereditary Zn deficiency occurs in a small percentage of Dutch Friesian cattle
      1. Clinical and biochemical changes almost identical to that produced with a low Zn diet
      2. Similar to acrodermatitis enteropathica in humans
      3. Defect may be due to absence of a transepithelial transport mechanism for Zn
      4. When Zn intake is high enough, diffusion may allow sufficient Zn to pass without the transport mechanism

IX.  Toxicity

  1. Low levels
    1. Adverse physiological effects not usually observed when dietary Zn concentrations are below 600 ppm
    2. Minimum Zn levels at which decreases in weight gain or body weight loss have been reported
      1. Cattle..........900 ppm
      2. Sheep.........1,500 ppm
      3. Swine.........2,000 ppm
      4. Chicks........800 ppm
      5. Turkeys......4,000 ppm
  2. High levels: > 1000 ppm Zn in diet usually causes some adverse effects
    1. Reduced weight gains
    2. Anemia
    3. Reduced bone ash
    4. Decreased tissue Fe, Cu, Mn
    5. Diminished utilization of Ca and P
    6. Diarrhea
    7. Arthritis and severe bone and cartilage
    8. 8In humans, unpleasant taste, gastrointestinal discomfort, and dizziness
    9. Death

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