Ananda S Prasad. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.
In 1869, J. Raulin showed for the first time that zinc is a growth factor for Aspergilus niger. Then, in 1926, it was discovered that zinc is essential for higher plants (Sommer and Lipman 1926). The importance of zinc in the growth and development of rats was demonstrated in 1934 (Todd, Elvehjem, and Hart 1934), and in 1955, H. F. Tucker and W. D. Salmon related a disease in swine called parakeratosis to a deficiency of zinc. Shortly thereafter, zinc was shown to be a growth factor for chickens (O’Dell, Newberne, and Savage 1958).
The manifestations of zinc deficiency in animals include growth failure, loss of hair, thickening and hyperkeratinization of the epidermis, and testicular atrophy. Zinc deficiency in breeding hens results in decreased hatchability and gross anomalies in embryonic skeletal development.
Although the importance of zinc for animals was established 60 years ago, it has only been during the past 30 years that zinc deficiency in humans has been recognized. In 1974, the Food and Nutrition Board of the National Research Council of the National Academy of Sciences made a landmark decision in establishing a recommended dietary allowance (RDA) for zinc.
Discovery of Zinc Deficiency in Humans
Studies in Iran
In 1958, this author joined the staff of Dr. Hobart A. Reimann, Chief of Medicine at the Nemazee Hospital of Pahlevi University in Shiraz, Iran. In the fall of that year, Dr. James A. Halsted of the Saadi Hospital of Pahlevi University invited me to discuss a patient who had severe anemia.
The patient was a 21-year-old male, who appeared to be only a 10-year-old boy. In addition to severe growth retardation and anemia, he had hypogonadism, hepatosplenomegaly, rough and dry skin, mental lethargy, and geophagia. His intake of animal protein had been negligible. He ate only wheat flour and unleavened bread and consumed nearly 0.5 kilograms (kg) of clay daily (the habit of geophagia in the villages around Shiraz is fairly common). Ten more cases that were similar arrived at the hospital for my care within a short period of time.
We documented the existence of iron-deficiency anemia in the patients, but there was no evidence of blood loss. We considered three possible mechanisms of iron deficiency: (1) The availability of iron in the high-cereal, protein-containing diet was most probably very low due to high phytate levels in the bread, which bind iron; (2) that geophagia further decreased iron absorption (as Minnich and colleagues  observed later); and (3) that an excessive loss of iron by sweating in the hot summers of Iran may have contributed significantly to negative iron balance.
After administration of ferrous sulfate (1 gram per day) orally and a nutritious hospital diet containing adequate animal protein, the anemia was corrected, hepatosplenomegaly improved, subjects grew pubic hair, and genitalia size increased (Prasad, Halsted, and Nadimi 1961). Liver function tests were unremarkable except for the serum alkaline phosphatase activity, which increased after treatment. Retrospectively, two explanations seem plausible: (1) Ordinary pharmaceutical preparations of iron might have contained appreciable quantities of zinc as a contaminant, and (2) animal protein in the diet most likely supplied available zinc, thus inducing the activity of alkaline phosphatase, a known zinc metalloenzyme.
It was difficult to account for all of the clinical features solely by tissue iron deficiency because growth retardation and testicular atrophy are not normally found in iron-deficient experimental animals. Moreover, since this syndrome was fairly prevalent in the villages near Shiraz, the rare syndrome of hypopituitarism as an explanation for growth retardation and hypogonadism was considered to be very unlikely.
We explored the possibility that zinc deficiency may have been present concomitantly with iron deficiency in these patients (Prasad et al. 1961). Because heavy metals may form insoluble complexes with phosphate, we speculated that some factors responsible for decreased availability of iron in these patients with geophagia may also have decreased the availability of zinc. B. L. O’Dell and J. E. Savage (1960) observed that the phytate (inositol hexaphosphate) present in cereal grains markedly impaired the absorption of zinc. Changes in the activity of alkaline phosphatase as observed in our patients had also been noticed after the zinc supplementation of deficient animals. Thus, it seemed that the dwarfism, testicular atrophy, retardation of skeletal maturation, and changes in serum alkaline phosphatase activity of our subjects might be explained by zinc deficiency.
I. I. Lemann (1910) had previously reported a similar clinical syndrome in patients who had hookworm infection in the United States, but this was not related to a nutritional deficiency. Similar cases from Turkey were reported by F. Reimann (1955), but without detailed descriptions. He considered a genetic defect to be a possible explanation for certain aspects of the clinical syndrome.
Studies in Egypt
In October 1960, Dr. William J. Darby invited me to meet with him at the U.S. Naval Medical Research Unit in Cairo, Egypt, where I shared with him my speculation that zinc deficiency in the Middle East was prevalent and was responsible for widespread growth retardation and male hypogonadism. The next day, Professor Darby and I went to nearby villages to assess if, indeed, growth-retarded adolescents were clinically recognizable. We were accompanied by an Egyptian male nurse who spoke both English and Arabic.
Because of the striking clinical similarities between Iranian and Egyptian dwarfs, I was able to recognize several subjects who looked like 8- or 10-year-old boys, but whose chronological ages, on questioning, appeared to be 18 to 20 years. This assured me that, indeed, growth retardation and male hypogonadism were also prevalent in Egyptian villages. Following this experience, Professor Darby approved plans to investigate zinc metabolism in growth-retarded subjects.
The clinical features of Egyptian growth-retarded subjects were remarkably similar to those of the Iranians, except that the Iranian dwarfs had more pronounced hepatosplenomegaly, a history of geophagia, and no hookworm infection. The Egyptian subjects, by contrast, had both schistosomiasis and hookworm infestations but no history of geophagia.
A detailed investigation of the Egyptian cases was carried out with associates A. Miale, Z. Farid, H. H. Sandstead, and A. Schulert. The dietary history of the Egyptian subjects was similar to that of the Iranians. The consumption of animal protein was negligible, with the diet consisting mainly of bread and beans (Vicia fava).
Zinc concentrations in plasma, hair, and red cells were decreased, and 65Zn studies showed that the plasma zinc turnover was greater, the 24 h exchangeable pool was smaller, and the excretion of 65Zn in stool and urine was less in the growth-retarded subjects in comparison to controls (Prasad, Miale, and Farid 1963). These studies established for the first time that zinc deficiency occurs in humans, without advanced cirrhosis. Liver function tests and biopsies revealed no evidence of cirrhosis in our subjects (Prasad et al. 1963b). Furthermore, in contrast to cirrhosis patients, who excreted abnormally high quantities of zinc in the urine, our patients excreted less zinc in urine than did control subjects. We also ruled out other chronic diseases that might have affected the serum zinc concentrations.
Serum iron was decreased, unsaturated iron binding capacity was increased, serum copper was slightly increased, and serum magnesium was normal in our subjects. Hair analysis for manganese, cobalt, molybdenum, and other elements revealed no difference when compared to the normal subjects. We found no evidence for deficiency of serum B12, ascorbic acid, vitamin A, carotene, or folic acid.
Iranian physicians had commonly believed that growth retardation and sexual hypofunction were the results of visceral leishmaniasis and geophagia. We, however, found no evidence of leishmaniasis in Iran. The role of geophagia was unclear, although we suspected that excess phosphate in the clay prevented absorption of both iron and zinc. The predominantly wheat diet in the Middle East, now known to contain high quantities of phytate and fiber, most probably reduced the availability of zinc.
In Egypt the cause of dwarfism was commonly considered to be schistosomiasis, and in China investigators had also implicated schistosomiasis as a causative factor for growth retardation. Yet, because the Iranian subjects exhibited dwarfism but did not have schistosomiasis or hookworm infections, the question arose as to whether schistosomiasis was the fundamental cause of dwarfism in Egypt. We initiated an investigation to find the answer (Prasad, Schulert, and Miale 1963; Prasad 1966).
It was known that schistosomiasis or hookworm infection was nonexistent in the oasis villages of Kharga, located 500 kilometers (km) southwest of Cairo, although the people of Kharga are culturally and nutritionally similar to those in the delta region. Hence, we conducted a field study in Kharga on 16 patients with hypogonadism and dwarfism. Their anemia was mild, and none had either schistosomiasis or hookworm disease. Concentrations of iron and zinc in the serum were subnormal.
Because red blood cells are rich in both iron and zinc, blood loss due to hookworm and schistosomiasis in the delta villages contributed significantly to both iron and zinc deficiencies. But in Kharga, parasitic infections were not present, and the artesian spring, the principal source of water for the Kharga villages, revealed iron and zinc concentrations of 3,170 and 18 micrograms per liter (m g/l), respectively.
In Cairo, by contrast, the iron and zinc concentrations of drinking water were 70 and 400 μg/l, respectively. Thus, although the foods consumed by the subjects in both the delta region and the oasis villages were similar, those in the latter probably derived a significant amount of iron but no zinc from their water source. Consequently, a better iron status for individuals in Kharga villages, in comparison to those in delta villages, was due to higher iron intake from water and lack of blood loss due to parasites.
Although dwarfism and hypogonadism had previously been attributed to schistosomiasis in Egypt and China, our demonstration of the existence of such patients in Iran and Kharga, where schistosomiasis was absent, showed that this parasitic infection was not necessarily responsible for these clinical features.
We were, however, unable to account for the hepatosplenomegaly on the basis of liver disease.This left three possibilities: anemia, zinc deficiency, or a combination of the two. In each case, the size of the liver and spleen decreased significantly after zinc supplementation, suggesting that zinc deficiency may have played an as-yet undefined role in hepatosplenomegaly.
In the Middle East, we examined only male subjects, as females refused to participate. But later studies from Iran by J. A. Halsted and co-workers (1972) demonstrated that zinc deficiency was probably prevalent in females manifesting growth retardation.
Our further investigations in Egypt showed that the rate of growth was greater in patients who received supplemental zinc as compared with those given iron, or those with only an adequate animal protein diet (Prasad 1966; Sandstead et al. 1967). Pubic hair appeared in all subjects within 7 to 12 weeks after zinc supplementation was initiated. Genital size became normal, and secondary sexual characteristics developed within 12 to 24 weeks in all zinc supplemented patients. No such changes were observed in a comparable length of time in the iron-supplemented group or in the group on an animal protein diet alone. Thus, our studies demonstrated that both growth retardation and gonadal hypofunction in these subjects were related to zinc deficiency. The anemia was due to iron deficiency and responded to oral iron treatment.
Chronology of Other Observations
By using the dithizone technique, R. E. Lutz (1926) assayed zinc in various tissues and concluded that the body of a 70 kg man contained 2.2 grams (g) of zinc, a figure remarkably close to that which is accepted today. R. A. McCance and E. M. Widdowson (1942) were the first to report on the absorption and excretion of zinc, and showed that the principal route of zinc excretion was in the feces, with only a small amount lost in urine.
I. Vikbladh (1950) measured serum zinc concentration by dithizone technique and reported that the level was 19.7 ± 0.24 micromoles per liter (μmol/l), a value in general agreement with those reported by using modern methods. Vikbladh (1951) also observed that the serum zinc concentration was decreased in many chronic diseases, including liver disease. B. L. Vallee and colleagues (1956) reported that the serum zinc concentration decreased in patients with cirrhosis and suggested that the hypozincemia of these subjects was conditioned by hyperzincuria.
Our studies in the early 1960s demonstrated for the first time the effects of zinc deficiency on human growth and gonadal development (Prasad, Miale, Farid et al. 1963a, 1963b; Prasad, Schulert, Miale et al. 1963; Sandstead et al. 1967), and that this deficiency may have various causes in different populations. It is now evident that nutritional, as well as conditioned, zinc deficiency may complicate many disease states in human subjects.
In 1968, R.A. MacMahon, M. L. Parker, and M. McKinnon (1968) first observed zinc deficiency in a patient who had steatorrhea. Subsequently, zinc deficiency was discovered to be common in patients with malabsorption syndromes (McClain, Adams, and Shedlofsky 1988).
V. Caggiano and co-workers (1969) were the first to report a case of zinc deficiency in the United States. The patient was Puerto Rican with dwarfism, hypogonadism, hypogammaglobulinemia, giardiasis, strongyloidiasis, and schistosomiasis. Zinc supplementation resulted in improved growth and development.
In 1972, a number of Denver children from middle-class families were reported to exhibit evidence of symptomatic nutritional zinc deficiency (Hambidge et al. 1972). They consumed a predominantly cereal protein diet low in available zinc. Growth retardation, poor appetite, and impaired taste acuity were all related to a deficiency of zinc in the children, and they were corrected with supplementation. Symptomatic zinc deficiency in United States infants was also reported later by K. M. Hambidge, C. E. Casey, and N. J. Krebs (1983). In addition, our own recent studies in the United States have shown that zinc deficiency in the well-to-do elderly may be fairly prevalent (Prasad et al. 1993). Clearly, then, a substantial portion of the U.S. population may be at risk of zinc deficiency.
Meanwhile, Halsted and colleagues (1972) published a study involving a group of 15 men who were rejected at the Iranian army induction center because of “malnutrition.” Two women were also included in their study. All were 19 or 20 years old, with clinical features similar to those reported earlier by A. S. Prasad and colleagues (Prasad et al. 1961, 1963a, 1963b). They were studied for 6 to 12 months. One group was given a well-balanced diet, containing ample animal protein plus a placebo capsule. A second group was given the same diet, plus a capsule of zinc sulfate containing 27 mg zinc. A third group received the diet for a year, with zinc supplementation during the last six months.
The zinc-supplemented subjects grew considerably faster and showed evidence of earlier onset of sexual function (as defined by nocturnal emission in males and menarche in females) than those receiving the well-balanced diet alone (Halsted et al. 1972).
A clinical picture, similar to those reported by our studies involving zinc-deficient dwarfs, has been observed in many developing countries. Therefore, it must be the case that various levels of zinc deficiency prevail in countries where diets depend too heavily on cereals.
P. M. Barnes and E. J. Moynahan (1973) studied a 2-year-old girl with severe acrodermatitis enteropathica, who was receiving diiodohydroxyquinoline and a lactose-deficient synthetic diet. The response to this therapy was not satisfactory. It was noted that the concentration of zinc in the patient’s serum was profoundly decreased, and oral zinc sulfate was administered. The skin lesions and gastrointestinal symptoms cleared completely, and the girl was discharged from the hospital. When zinc was inadvertently omitted from the child’s regimen, she suffered a relapse; however, she promptly responded to oral zinc again.
In the original report, the authors attributed the girl’s zinc deficiency to the synthetic diet, but it soon became clear that zinc was fundamental in the pathogenesis of acrodermatitis enteropathica – a rare inherited disorder – and the clinical improvement reflected improvement in zinc status. This interesting observation was quickly confirmed in other patients throughout the world. The underlying pathogenesis of zinc deficiency in these patients is most likely dietary mal-absorption of zinc, the mechanism of which remains to be determined.
R. G. Kay and C. Tasman-Jones (1975) reported the occurrence of severe zinc deficiency in subjects receiving total parenteral nutrition for prolonged periods without zinc. T. Arakawa, T. Tamura, and Y. Igarashi (1976) and A. Okada and co-workers (1976) announced similar findings in this circumstance. These observations have been documented by several investigators, and in the United States, zinc is routinely included in total parenteral fluids for subjects who are likely to receive such therapy for extended periods.
W. G. Klingberg, Prasad, and D. Oberleas (1976) were the first to report severe parakeratosis, alopecia, and retardation of growth and gonadal development in an adolescent with Wilson’s disease who received penicillamine therapy. Zinc supplementation completely reversed these clinical manifestations.
Recent literature suggests that several findings in patients with sickle cell anemia, such as growth retardation, male hypogonadism, abnormal dark adaptation, and abnormal cell-mediated immunity, are related to a deficiency of zinc (Prasad et al. 1975, 1981; Warth et al. 1981; Prasad and Cossack 1984; Prasad et al. 1988). Hyperzincuria due to renal tubular dysfunction has been noted in such subjects, and this may be a contributing factor in the pathogenesis of zinc deficiency. Hypogeusia, decreased serum testosterone level, and hyperprolactinemia due to zinc deficiency have been observed in male patients with chronic renal disease (Mahajan et al. 1979, 1980, 1982, 1985). Zinc supplementation has corrected the abnormalities that have been associated with these disparate circumstances.
During the past three decades, a spectrum of clinical deficiency of zinc in human subjects has been recognized. If the deficiency is severe, it may be life-threatening. The symptoms developed by severely zinc-deficient subjects include bullous-pustular dermatitis, diarrhea, alopecia, mental disturbances, and intercurrent infections due to cell-mediated immune disorders. These manifestations are seen in patients with acrodermatitis enteropathica, following total parenteral nutrition (without zinc), and after penicillamine therapy.
Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy, abnormal adaptation to darkness, and delayed wound healing are some of the indicators of moderate zinc deficiency in human subjects. Causes of moderate zinc deficiency that have been well documented include nutritional factors, malabsorption, sickle cell disease, chronic renal disease, and other debilitating conditions.
The beneficial effect of zinc in healing wounds of patients with zinc deficiency was first reported by W. J. Pories and W. H. Strain (1966). The symptom of abnormalities of taste was first related to a deficiency of zinc in humans by R. I. Henkin and D. F. Bradley (1969), and such abnormalities, which are reversible by zinc supplementation, have been observed in patients with chronic renal disease (Mahajan et al. 1980).
Marginal Deficiency of Zinc
Although the importance of zinc to human health has now been elucidated and its deficiency recognized in several clinical conditions, it was only recently that an experimental human model was established to permit a study of the specific effects of a mild zinc deficiency (Prasad, Rabbani, and Abbasi 1978; Abbasi et al. 1980; Rabbani et al. 1987; Prasad et al. 1988).
We did this by developing a semisynthetic soy-protein-based diet that supplies 3 to 5 milligrams of zinc per day (mg zinc/d) (Rabbani et al. 1987). All other nutrients in the diet are consistent with the RDA (1974, 1989). Male volunteers, ages 20 to 45 years, were first given a hospital diet containing animal protein for 4 to 8 weeks, which averaged 12 mg zinc/d. After that, the subjects received the experimental diet containing 3 to 5 mg zinc/d, which continued for 28 weeks. Following this period, the volunteers received a daily 27 mg zinc supplement for 12 weeks while still consuming the experimental diet. Throughout the study, all nutrients, including protein, amino acids, vitamins, and minerals (both macro- and microelements), were kept constant, except zinc, which was varied as outlined above. By this technique, we were able to induce a specific zinc deficiency in men.
Our dietary manipulation created a negative zinc balance of approximately 1 mg per day, and we calculated that in a six-month period a total of about 180 mg of negative zinc balance was achieved. A 70 kg adult male contains approximately 2,300 mg of zinc, and, therefore, a loss of 180 mg of zinc would seem to be only 8 percent of the total body zinc. But this is not necessarily the case. Approximately 28 percent of the zinc in the human body resides in bone, 62 percent in muscle, 1.8 percent in the liver, and 0.1 percent in the plasma pool. Only 10 percent of the total body zinc pool exchanges with an isotopic dose within a week’s time (Prasad et al. 1963a; Foster et al. 1979).
In an adult animal model, zinc concentrations in muscle and bone do not change as a result of mild or marginal zinc deficiency. In cases of mild or marginal zinc deficiency, one cannot expect a uniform distribution of the deficit over the entire body pool, and most likely the compartments with high turnover rates (liver and peripheral blood cells, such as lymphocytes, granulocytes, and platelets) suffer a disproportionate deficit.Thus, if one were to consider that only 200 to 400 mg zinc, which is represented by liver zinc and the mobile exchangeable pool, is the critical pool, a negative balance of 180 mg from this pool may be a considerable fraction.
Our studies in this model have indicated that a mild or marginal deficiency of zinc in humans is characterized by neurosensory changes, oligospermia, decreased serum testosterone concentration, hyper-ammonemia, decreased lean body mass, decreased serum thymulin activity, decreased IL-2 production by peripheral blood mononuclear cells, decreased NK cell activity, and alterations in T-cell subpopulations. All of these manifestations can be corrected by zinc supplementation.
When zinc deficiency was very mild (5.0 mg zinc intake during the 20- to 24-week zinc-restricted period), the plasma zinc concentration remained more or less within the normal range, whereas the zinc concentration of lymphocytes and granulocytes declined (Meftah et al. 1991). Within 8 weeks of zinc restriction, the activity of lymphocyte ecto 5′ nucleotidase (5’NT), serum thymulin activity, and IL-2 production by peripheral blood mononuclear cells decreased, and the intestinal absorption of 70Zn increased significantly, suggesting that lymphocytes, thymus, and intestinal cells are very sensitive to zinc restriction (Meftah et al. 1991; Lee et al. 1993; Prasad et al. unpublished observation).
Biochemical Advances in Zinc Metabolism
D. Keilin and J. Mann (1940) were the first to demonstrate that carbonic anhydrase was a zinc metalloenzyme. Over the next 20 years, only five additional zinc metalloenzymes were identified, but in the last 30 years the total number has greatly increased. If related enzymes for different species are included, more than 200 zinc metalloenzymes are now known to exist (Chesters 1982; Galdes and Vallee 1983).
I. Lieberman and co-workers (1963) have shown that several enzymes necessary for nucleic acid synthesis in microorganisms require zinc. It is now well known that zinc is needed for DNA polymerase 1 (in Escherichia coli), bacterial RNA polymerase (in E. coli), and reverse transcriptase (in avian myeloblastosis virus) (Wu and Wu 1983).
Until 1965, there was no evidence that zinc-dependent enzymes were adversely affected as a result of zinc deficiency. Our investigations then demonstrated that the activity of various zinc-dependent enzymes was reduced in the testes, bones, esophagus, and kidneys of zinc-deficient rats in contrast to their pair-fed controls, and that this reduction of activity correlated with the decreased zinc content of the tissues (Prasad, Oberleas,Wolf et al. 1967).
Several studies have shown that zinc deficiency in animals impairs the incorporation of labeled thymi-dine into DNA. This effect has been detected within a few days of the institution of a zinc deficient diet in experimental animals, suggesting that dietary zinc deficiency may result in an immediate impairment of DNA synthesis. Prasad and Oberleas (1974) provided evidence that this early reduction in DNA synthesis was due to an adverse effect of zinc restriction on the activity of deoxythymidine kinase. These results were confirmed by I. E. Dreosti and L. S. Hurley (1975), who showed that the activity of deoxythymidine kinase in 12-day-old fetuses taken from females exposed to a dietary zinc deficiency during pregnancy was significantly lower than in ad-libitum-fed and restricted-fed controls.
Zinc and Immunity
P. J. Fraker, S. Hass, and R. W. Luecke (1977) revealed that severely and marginally zinc-deficient young adult-A/Jax mice have abnormal T-helper cell function. In addition, it is now known that other T-lymphocyte-mediated functions are found to be adversely affected by zinc deficiency. By using the young adult mouse as a model, it was demonstrated that a moderate period of suboptimal zinc administration causes thymic atrophy, lymphopenia, and alterations in the proportions of the various subsets of lymphocytes and mononuclear phagocytes (Fraker et al. 1986). As a result, antibody-mediated responses to both T-cell-dependent and T-cell-independent antigens are significantly reduced. Cytolytic T-cell responses, NK-cell activity, and delayed-type-hypersensitivity (DTH) reactions are also depressed.
In humans, patients with acrodermatitis enteropathica (a genetic disorder of zinc absorption) exhibit atrophic thymus, lymphopenia, anergic DTH responses, and reduced NK-cell activity (Fraker et al. 1986). Impaired DTH responses, correctable with zinc supplementation, were reported in zinc-deficient sickle cell anemia patients (Ballester and Prasad 1983), as were decreased NK-cell activity, decreased IL-2 activity, decreased serum thymulin activity, and alterations in lymphocyte subpopulations (Prasad et al. 1988).
Metallothionein (MT) was discovered in 1957. M. Margoshes and Vallee (1957) identified a cadmium-binding protein in equine kidney cortex responsible for the natural accumulation of cadmium in the tissues. Metal and sulfur content are extremely high in MTs. In human cells, expression of the ISO-MT genes appears to be regulated differentially by cadmium, zinc, and glucocorticoids, and ISO-MT genes are indications for tissue-specific expression (Kagi and Schaffer 1988). A number of studies have led to the identification of various DNA segments serving as promoter sites in the 5′ region of various MT genes in induction by metal ions and hormones. In the mouse MT-1 gene, the functional metal responsive promoter is composed of a set of four closely related metal-regulatory elements, each made up of eight nucleotides and localized near the TATA box.
Zinc may be the regulator of the mRNA strands responsible for de novo synthesis of MT in intestinal cells (Cousins 1979). It has been suggested that MT programs the fluctuating levels of zinc in and out of intestinal cells and plays an important role in regulating the absorption and/or excretion of not only zinc but also cadmium and copper.
Zinc and Gene Expression
The importance of zinc in DNA-binding proteins as regulators of gene expression has been recently recognized (Brown, Sander, and Argos 1985; Miller, Mclachlan, and Klug 1985; Klug and Rhodes 1987). The first zinc-finger protein to be recognized was transcription factor-IIIA of xenopus Laevis, which contained tandem repeats of segments with 30 amino acid residues, including pairs of histidines and cysteines (Miller et al. 1985). The presence of zinc in these proteins is essential for site-specific binding to DNA and gene expression. The zinc ion apparently serves as a strut that stabilizes folding of the domain into a finger-loop, which is then capable of site-specific binding to double-stranded DNA. The zinc-finger loop proteins provide one of the fundamental mechanisms for regulating gene expression of many proteins. In humans, the steroid hormones (and related compounds, such as thyroid hormones, cholecalciferol, and retinoic acid) enter cells by facilitated diffusion and combine with respective receptors (which contain the DNA-binding domain of the zinc-finger loops) either before or after entering the nucleus. Complexing of a hormone by its specific receptor evidently initiates a conformation change that exposes the zinc-finger loops, so that they bind to high-affinity sites on DNA and regulate gene expression (Hollenberg et al. 1985; Hughes et al. 1988; Sunderman and Barber 1988).
Interaction of Zinc with Other Elements
Zinc blocks the absorption of dietary copper, and also copper in the endogenous secretions (Brewer et al. 1988). Earlier, Prasad, Brewer, Schoomaker et al. (1978) observed that when subjects with sickle cell anemia were treated with 150 mg zinc/d in divided doses in order to reduce the number of irreversible sickle cells in the peripheral blood, they showed a decrease in the concentration of serum copper and ceruloplasmin. This observation led us to consider treatment of Wilson’s disease patients with zinc. Our studies showed that zinc therapy in Wilson’s disease patients leads to a negative copper balance, most likely by induction of MT synthesis in the intestines, whereby copper is sequestered and ultimately excreted in the feces (Brewer et al. 1983, 1987). According to our experience, zinc is an effective copper removal agent, is well tolerated, and prevents accumulation of copper in the liver (Brewer et al. 1983, 1987, 1988).