Zinc (Zn) - General Discussion

- Down's Syndrome

- Cleft lip

- Cleft palate

- Brain defects (dorsal herniation, hydroencephaloceol)

- Micro- or anopthalmia (small or absent eyes)

- Micro- or agnathia

- Spina bifida

- Clubbed limbs

- Syndactyly (webbed toes and fingers)

- Diaphragmatic hernias (hiatal hernia)

- Umbilical; hernias

- Head defects

- Lung defects

- Urogenital

- Pica (geophagia, wool eating, hair eating, etc.)

- Loss of sense of smell

- Loss of sense of taste

- Infertility

- Failure of wounds and ulcers to heal

- Immune status failure

- Poor growth (short stature)

- High infant mortality

- Hypogonadism (small poorly functioning ovaries and testes)

- Remains in a prepuberty state

- Anemia

- Alopecia (hair loss)

- Acrodermatitis enteropathica (Parakeratosis in pigs and calves)

- "Frizzy" hair

- Diarrhea

- Depression

- Paranoia

- Oral and perioral dermatitis

- Weight loss (anorexia nervosa)

- Benign prostatic hypertrophy (prostate enlargement)

- Severe body odor ("smelly tennis shoe" syndrome)

- Anorexia & Bulimia

Zinc was known to be essential for bread mold 100 years ago, essential for rats 50 years ago and for humans only 20 years ago. Zinc deficiency produces a wide range of diseases including birth defects and degenerative diseases of all age groups.

There are 1.4 to 2.3 grams of Zn in the adult human. The liver, pancreas, kidney, bone and skeletal muscles have the greatest reserves of Zn, lesser amounts are found in the eye, prostate gland, semen, skin, hair, fingernails and toenails.

There are no less than 70 metalloenzymes that require Zn to function; these include carbonic anhydrase, alkaline phosphatase, lactic dehydrogenase and carboxypeptidase. Zinc helps to bind enzymes to substrates by maintaining spacial and configurational relationships. Some enzymes bind Zn so tightly that even during severe Zn depletion they can still function. Zinc participates in the metabolism of nucleic acids and the synthesis of proteins; Zinc is also an integral part of the RNA molecule itself (Zinc "metal fingers") and participates in cell division and synthesis of DNA -the DNA-dependent RNA polymerase is a zinc dependent enzyme, as is thymidine kinase.

Excesses of copper and iron and high phytate diets (vegans) will reduce availability of dietary zinc. Heavy losses of Zn occurs in sweat, therefore unsupplemented athletes are particularly at risk for Zn deficiency (i.e.- anorexia nervosa, muscle weakness, pica, etc.).

Studies on laboratory primates and other experimental animals indicate that zinc deficiency impairs reproductive performance, adversely affects voluntary food consumption, and probably restricts the utilization of dietary vitamin A or its tissue stores. The significance of these and many other observed effects of zinc deficiency, observed experimentally but not yet adequately verified in studies with human subjects, have been reviewed elsewhere.

Zinc is an essential trace mineral nutrient required for a wide array of metabolic processes. The body contains about 2.2 g of zinc, more than any trace mineral except iron. The highest concentrations occur in the skin, prostate gland, eyes, nails and hair, though it is widely distributed among tissues. Over 100 different enzymes (biological catalysts) require zinc. For example, zinc is required by DNA polymerase, an enzyme required for the synthesis of DNA (responsible for inheritance), and by RNA polymerase, an enzyme required for the synthesis of RNA. RNA guides the synthesis of proteins using the genetic information stored in DNA. Gene activators that regulate the expression of genetic information often utilize proteins containing zinc to bind to specific regions on the DNA molecule.

Possible Roles in Maintaining Health

Other roles range from protection against oxidation to digestion and blood sugar regulation. Thus zinc is classified as an antioxidant when it functions as a cofactor for superoxide dismutase, the enzyme that disarms a particularly reactive form of oxygen. In digestion, the pancreatic protease, carboxypeptidase, requires zinc for its protein degrading action. Furthermore, the hormone insulin is processed and packaged as a zinc complex. Zinc also aids the interaction of insulin with its target tissues to facilitate the uptake of blood sugar.

Zinc supports normal cell division and growth, the function of cell membranes, the immune system, bone calcification and the development and function of male reproductive organs. Many trace minerals and vitamins, including zinc, are required for normal growth and development. Zinc deficiency can cause birth defects, complicated deliveries and low birth weight, as well as impaired learning and delayed sexual development.

Immune System It is well established that zinc stimulates the immune system. Zinc activates T-lymphocytes, the soldiers and generals of the immune system. Furthermore, zinc deficiency in the womb can lead to a weakened immune system at birth and enhanced risk of infection in newborn infants. Furthermore, zinc deficiency may be partially responsible for the weakened immunity that so frequently accompanies aging. Zinc supplementation can improve white cell counts and antibody production in healthy, elderly people. There are intriguing hints that the zinc status of some AIDS patients is marginal; these patients have a severely imbalanced immune system. Zinc may help lessen symptoms of such autoimmune diseases as rheumatoid arthritis, when the body begins to attack its own tissues.

Cancer A healthy immune system helps prevent cancer, and zinc-deficient animals are more sensitive to carcinogens (cancer-causing agents). Patients with prostate cancer have significantly lower zinc levels, as do those with esophageal cancer. Whether zinc supplementation alone corrects prostate enlargement or slows prostate cancer is unproven.

Male fertility Zinc is implicated in normal prostate functions and male infertility. The male sex hormone, testosterone, may regulate zinc metabolism in the prostate, and zinc, in turn, may affect testosterone metabolism in the prostate. Zinc deficiency leads to a lowered sperm count as well as impotence, and initial studies suggest that zinc can be used therapeutically in these cases.

Vision Zinc plays a role in vision. Conversion of vitamin A to its biologically active form, retinal, requires zinc. Zinc-deficient alcoholics may suffer from night blindness, and zinc has been used in this situation. Aging frequently brings blindness. In certain cases zinc supplementation may slow the progress of vision loss due to this condition.

Tissue repair Zinc seems to promote wound healing, particularly in zinc-deficient individuals. Zinc is necessary for tissue repair and growth. Zinc ointments have been used to treat acne.

Taste Zinc deficiency leads to altered taste and smell sensitivity; diminished taste acuity may respond to zinc.

Requirements The Recommended Dietary Allowance for adults (25 to 50 years of age) has been set at 12 mg for women and 15 mg for men. Pregnancy and lactation increase a woman's requirements.

Marginal (subclinical) zinc deficiency can be a problem for many Americans. Early symptoms of a subclinical deficiency include loss of appetite, altered taste and smell, decreased appetite, as well as slow growth in children. Lethargy, white spots on fingernails, slow wound healing, impotence and delayed sexual development may follow. Chronic dieters, alcoholics, strict vegetarians, and young children with diets compromised by junk food often consume inadequate zinc and other trace nutrients. Some patients with eating disorders may be zinc deficient. Zinc may help patients recovering from injury or infection. Pregnant and lactating women require zinc and other trace minerals. Elderly people may rely on zinc-deficient foods, a situation that is compounded by their reduced ability to absorb trace minerals like zinc. Strenuous exercise increases zinc loss through sweating and increased excretion, consequently an athlete's need for zinc increases.

Factors that increase the need for zinc include kidney disease, diabetes, cystic fibrosis, inflammatory bowel disease, inherited zinc deficiency, and the use of diuretics and laxatives. A high-fiber diet and foods containing phytic acid can bind trace minerals and limit zinc uptake when large amounts are eaten. Likewise, excessive copper, iron or calcium displace zinc and limit its uptake.

Safety Zinc is relatively non-toxic, and modest zinc supplementation for insurance may be appropriate particularly when the diet is compromised or there is maldigestion or malabsorption. The ratio of zinc to copper should be about seven to one, the ratio of the RDAs. Symptoms of zinc excess include nausea, bloating, abdominal cramps, diarrhea and fever. A high zinc intake (100 to 300 mg daily) may suppress the immune system, lower HDL (high-density lipoprotein, believed to protect against heart disease) and block the absorption of copper, creating a copper deficiency. Copper deficiency in turn can increase blood cholesterol (LDL, low-density lipoprotein, the undesirable form) and lower HDL, thus increasing the risk of cardiovascular disease.

Mares-Perlman, J.A., et al., "Zinc Intake and Sources in the U.S. Adult Population 1976-1980," Journal of the American College of Nutrition, 14:4 (1995), pp. 349-57.

Odeh, M., ""The Role of Zinc in Acquired Immunodeficiency Syndrome,"" Journal of Internal Medicine, 231 (1992), pp. 463-69.

Biochemical function

Most biochemical roles of zinc reflect its involvement in. a large number of enzymes or as a stabilizer of the molecular structure of subcellular constituents and membranes. Zinc participates in the synthesis and degradation of carbohydrates, lipids, proteins and nucleic acids. It has recently been shown to play an essential role in polynucleotide transcription and translation and thus in the processes of genetic expression. Its involvement in such fundamental activities probably accounts for the essentiality of zinc for all forms of life.

PHYSIOLOGICAL FUNCTIONS

From: Minerals in Animal and Human Nutrition
by Lee R McDowell

A. Enzymes

Zinc is associated with enzymes, both as part of the molecule and as an activator. In its structural role, Zn usually stabilizes the quaternary structure of the enzymes. Substantial quantities of firmly bound Zn stabilize the structures of RNA, DNA, and ribosomes (Prask and Plocke, 1971).

In 1939 Zn was demonstrated to be a constituent of the metalloenzyme carbonic anhydrase, which contains about 0.3% Zn. Today more than 200 Zn proteins are known, and several biological roles for Zn have been clarified, including those related to cell replication and differentiation (Hambidge et al., 1986). In severe Zn deficiency, activities of plasma alkaline phosphatase; liver, retina and testicular alcohol dehydrogenase; connective tissue and fetal thymidine kinase; pancreatic carboxypeptidase A; and liver nuclear DNA-dependent RNA-polymerase may be depressed. Zinc, functioning in enzyme systems, is largely involved in nucleic acid metabolism, protein synthesis, and carbohydrate metabolism. In rapidly growing tissues, Zn deficiency greatly reduces synthesis of DNA, RNA, and protein, and hence, impairs cellular division, growth, and repair. Zinc proteins are involved in the transcription and translation of genetic material, perhaps accounting for its essentiality to all forms of life (Vallee, 1988). Im et al. (1975) found that six enzymes involved in glycolysis were decreased by 30 to 50% in the epidermis of Zn-deficient rats compared to that of controls.

B. Hormones

Zinc has many biologically significant interactions with hormones. It plays a role in the production, storage, and secretion of individual hormones as well as in the effectiveness of receptor sites and end-organ responsiveness. Among the most notable effects of Zn deficiency on hormone production and secretion are those related to testosterone, insulin and adrenal corticosteroids.

Spermatogenesis and the development of the primary and secondary sex organs in the male and all phases of the reproductive process in the female can be adversely affected by Zn deficiency. The major abnormality in the male is testicular hypofunction affecting both spermatogenesis and the production of testosterone by the Leydig cells. Less is known concerning the effects of Zn deficiency on sex hormones in nonpregnant females.

Impaired development and functioning of male reproductive organs is reported in rats, humans, calves, kids, and lambs. In lambs, testicular growth was greatly impaired, and spermatogenesis stopped within 20 to 24 weeks on a low-Zn diet (2.4 ppm) (Somers and Underwood, 1969).

Zinc is associated with insulin in the pancreas, and pancreatic concentrations are markedly reduced by dietary deficiency. Zinc-deficient rats have a reduced concentration of plasma insulin and a lower pancreatic release of immunoreactive insulin.

With inadequate Zn, Flynn et al. (1972) reported that ACTH did not stimulate corticosteroid synthesis, suggesting that ACTH is functionally dependent on Zn. A number of studies have indicated adrenal hypertrophy with Zn deficiency in rats, mice, and pigs.

C. Growth Rate

Growth retardation is universally observed in Zn deficiency, perhaps because of impairment of nucleic acid biosynthesis (O'Dell, 1981). Zinc deficiency also results in impaired amino acid utilization or protein synthesis.

Loss of appetite is one of the first signs of deficiency; with poor growth, it may be the only overt sign of a mild deficiency. Severely Zn-restricted rats eat as little as one third that of ad libitum-fed controls, with significantly less fluid (Essatara et al., 1984). Reduced feed intake may relate to the role of Zn in taste (Hambidge et al., 1986). Subsequent to the onset of deficiency and anorexia, there is loss of taste acuity (Miller et al., 1979).

Skeletal abnormalities are a prominent feature of Zn deficiency. In poultry, long bones are shortened and thickened; in calves, a bowing of the hind legs and stiffness of joints is noted. Chick bones show reduced epiphyseal cartilage width and less cell division. Bone collagen synthesis and turnover are markedly reduced, with reduced activity of tibial collagenase, a Zn metalloenzyme (Starcher et al., 1980).

D. Skin and Wound Healing

The skin, which is particularly rich in Zn, shows parakeratotic lesions, characteristic signs of deficiency. Parakeratosis is a thickening or hyperkeratinization, with failure of complete nuclear degeneration, of the epithelial cells of the skin. In more severe Zn deficiency, scaling and cracking of the paws develop with deep fissures, in addition to loss of hair and dermatitis. Zinc plays a role in skin nucleic acid and collagen synthesis (Miller et al., 1979).

Oral administration enhances the rate of wound healing in a number of species. Healing of incised wounds and thermal burns is delayed in animals with deficiency, and Zn administration normalizes the healing process (Miller et al., 1967b). Apparently only wound or burn victims with a low Zn status respond beneficially to Zn. Zinc deficiency can result in increased bleeding times, which in rats has been shown to be related to defective platelet function (Emery et al., 1990).

E. Immune Response

Zinc is essential to the integrity of the immune system. Significantly reduced thymus weight and circulating lymphocyte counts have been observed in pigs, rats, and mice. Haas et al. (1976) reported a severe depression in the antibody response of Zn-deficient mice. Deficiency causes rapid atrophy of the thymus with the predominant influence on various T-cell functions. Virtually complete loss of lymphoid tissues including thymus, tonsils, and lymph nodes has been reported in patients suffering from acrodermatitis enteropathica, a hereditary disease characterized by impaired utilization of Zn (Chesters, 1978). Diversity of effects on immunocompetence as a result of Zn deficiency is related to thymic hormone production and activity; lymphocyte function; natural killer function; antibody-dependent, cell-mediated cytotoxicity; immunological ontogeny; neutrophil function; and lymphokine production (Hambidge et al., 1986).

F. Water and Cation Balance

Early signs of Zn deficiency in most species are dehydrated appearance, elevated hematocrit, and diarrhea (O'Dell, 1981). For chickens there was no change in total water, but a marked shift of water from extra-to intracellular compartments. Extracellular water in Zn deficiency changed from 29.4 to 19.6% of body weight, and plasma volume, from 6.0 to 3.4%. Deranged electrolyte balance has been demonstrated with deficiency. A shift of sodium (Na) into tissues may explain the higher concentration of water in cells of major tissues. The deranged sodium/potassium concentrations in tissues suggest a change in membrane permeability, "leaky membranes," or a defective Na pump.

G. Relationship to Vitamin A

Zinc maintains normal concentrations of vitamin A in plasma and is necessary for the normal functioning of the general epithelium of the ovary (Smith et al., 1973; Chhabra and Arora, 1985). These workers used animals deficient in both Zn and vitamin A and demonstrated that synthesis of the retinol-binding protein (R13P), the carrier of vitamin A in the blood, is decreased in Zn deficiency, resulting in inadequate vitamin A mobilization from the liver. The precise mechanism involved is not clear. Thymidine kinase and DNA-dependent RNA polymerase depend on Zn for their activity and are vital to protein synthesis. They could, therefore, be concerned in RBP synthesis (Underwood, 1981). Activity of alcohol dehydrogenase is depressed in the liver of Zn-deficient lambs (Arora et al., 1973) and could be related to the night-blindness observed in some lambs. A postulated Zn metalloenzyme is an alcohol dehydrogenase, necessary for the interconversion of vitamin A alcohol (retinol) to vitamin A aldehyde (retinal), a process essential for normal vision.

H. Behavior and Learning Ability

Severe maternal Zn deficiency during embryogenesis in the rat has severe teratogenic consequences for the central nervous system. The learning abilities and emotional responsiveness of rats were impaired by a deficiency induced during gestation, lactation, or after weaning, even when these attributes were assessed after a period of rehabilitation with Zn (Chesters, 1978). Rhesus monkey infants from Zn-deprived dams played and explored less than the control infants (Sandstead et al., 1978).

1. Additional Functions

Chesters (1978), O'Dell (1981), and Hambidge et al. (1986) have attributed additional functions to Zn:

1. Protection of membranes. Zinc has an antioxidant effect in protecting sulfhydryl groups in membranes.

2. Prostaglandin metabolism. Metabolites of prostaglandins are affected by Zn deficiency.

3. Lipid metabolism. In Zn deficient animals, glucose incorporation into fatty acids is greatly reduced.

4. Microbial growth. Various organisms require Zn for growth, including microorganisms in the rumen.

Zinc Metabolism

Zinc is present in all the tissues and fluids of the body. The total body content has been estimated to be approximately 2 g. The zinc concentration of the lean body mass is approximately 30 mcg/g. Skeletal muscle accounts for approximately 60% of the total body content, and bone, with a zinc concentration of 100-200 mcg/g, for about 30%. Plasma zinc accounts for only about 0. 1 % of total body content; it has a rapid turnover and its level appears to be under close homeostatic control. High concentrations of zinc are found in the choroid of the eye (274 mcg zinc/g) and in prostatic fluids (300-500 mcg/ml).

There is no "store" of zinc in the conventional sense. Under conditions of bone resorption and tissue catabolism, zinc can be released and, to some extent, reutilized. Human experimental studies with low-zinc diets (2.6-3.6 mg/day) have shown that circulating plasma zinc and the activities of zinc-containing enzymes can be maintained within a normal range over several months indicating that some zinc can be made available from tissues.

Zinc is lost from the body via the kidneys, the skin and the intestine. Endogenous intestinal losses can range from 0.5 to 3 mg/day depending on zinc intake. Approximately 0.7 mg of zinc/day is lost in the urine of normal healthy subjects. Starvation and muscle catabolism increase zinc losses in urine and feces. The loss of zinc in perspiration and desquamated epidermal cells has been estimated to be 0.5 mg/day in adult men, but this also depends on zinc intake, Strenuous exercise and elevated ambient temperatures could lead to larger losses.

Prostatic fluids have a high concentration of zinc, and a semen ejaculate can contain up to 1 mg. Zinc losses in menstruation are small (0.01 mg/day). Other losses, such as that resulting from the normal daily loss of hair, are probably insignificant.

Zinc Deficiency

The principal clinical features of severe zinc deficiency in humans are growth retardation, a delay in sexual and skeletal maturation, the development of acral dermatitis diarrhea alopecia, a failure of appetite and the appearance of behavioral changes. An increased susceptibility to infections reflects the development of defects in the immune system.

The effects of marginal or mild zinc deficiency are less obvious and can readily be overlooked. A reduced growth rate and impaired resistance to infection are frequently the only manifestations of mild deficiency in humans. Several studies have now demonstrated the beneficial effects on growth velocity of supplementing the zinc intake of socially deprived children undergoing nutritional rehabilitation. Responses to zinc occurred even though gross, overt clinical evidence of deficiency was lacking. Among the many factors influencing the competence of cell-mediated immunity are the structure and biological activity of the hormone thymulin, both of which are largely zinc dependent, and it has therefore been suggested that a reduced activity of this thymic hormone, which is involved in the differentiation of T-cells' could provide an early indication of mild zinc deficiency. Other effects, which it is claimed are the result of a low zinc intake, such as impaired taste and delayed wound healing, are less consistently observed and the conditions under which such effects may appear must be defined more clearly.

Studies on laboratory primates and other experimental animals indicate that zinc deficiency impairs reproductive performance, adversely affects voluntary food consumption, and probably restricts the utilization of dietary vitamin A or its tissue stores. The significance of these and many other observed effects of zinc deficiency, observed experimentally but not yet adequately verified in studies with human subjects, have been reviewed elsewhere.

Zinc deficiency may increase arterial oxidative stress

The starting point of this study was the observation that zinc deficiency severely impairs endothelial cell function, an effect reversed by zinc supplementation. To determine how zinc affects cytokine production, the activation of a nuclear transcription factor (NF-kB) examined in endothelial cell cultures. NF-kB was chosen because this transcription factor activates genes directing the synthesis of proinflammatory cytokines and to increased oxidative stress. Cells deprived of zinc were triggered by tumor necrosis factor (TNF). TNF signals a cascade of events leading to the synthesis of proteins that regulate oxidative stress and promote free radicals. Zinc supplementation reversed the activation by TNF in these cells: zinc inhibited activation of oxidative stress transcription factors and the synthesis of Interleukin 8 and promoted a return to homeostatic balance.

Comment: Arteries are vulnerable to ongoing oxidative stress due to exposure to oxidizing agents such as drugs and free radicals, including superoxide and lipid peroxyl radicals. Blood contains an elaborate array of antioxidants, including ascorbic acid, uric acid and defensive serum proteins to limit this damage. However, antioxidant defenses are not 100% efficient. Zinc participates in these defenses by serving as a cofactor for the antioxidant enzyme, superoxide dismutase. Other aspects of zinc metabolism must be involved, since zinc deficiency causes profound oxidative damage to proteins, lipids and DNA. As one example of a nonenzymatic function, zinc is a cell membrane stabilizer. In addition, this paper shows that zinc deficiency seems to regulate cytokine-mediated activation of transcription factors, especially those triggering inflammation and oxidative stress. If zinc deficiency promotes activation of oxidative stress and inflammatory cytokines by endothelial cells, then zinc status may be important in the development of atherosclerosis. Zinc is removed by food processing and subclinical deficiencies are likely with compromised diets.

Connell P et al. Zinc attenuates tumor necrosis factor-mediated activation of transcription factors in endothelial cells. J Am College Nutr 1997; 16: 411-417.

Role of Zinc in Diabetes

The mutual connection between insulin and zinc has been clearly demonstrated. That zinc has a certain influence on the function of insulin has been rendered probable. Earlier, the hypothesis has been stated that relative zinc deficiency may play a role in the pathogenesis of maturity-onset diabetes. The possibility that the addition of zinc to insulin preparations may significantly enhance the biologic potency of insulin in vivo had also been stated. The condition of decreased glucose tolerance seen in animals fed a zinc deficient diet has not been studied in humans. Whether patients with zinc deficiency in general have concomitant glucose intolerance has not been elucidated.

It has been described that patients in the initial stage of insulin-dependent diabetes have a decreased concentration of zinc in serum. As zinc is essential for the body's defense against infections, these authors advance the possibility that a decrease in the zinc concentration in insulin, e. g., evoked by some diabetogenic agent, can lead to an increased sensitivity for isletotropic viruses in patients with hereditary disposition for insulin-dependent diabetes mellitus. Finally it can be concluded that the true role of zinc in the metabolism of insulin and in the development and medical treatment of the different types of diabetes mellitus needs further investigation.