Role of metallothionein in human health.
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Animals↗
Biomedical subjects
A S Prasad
Publications and source records attributed to A S Prasad.
Discovery of human zinc deficiency and studies in an experimental human model.
The importance of zinc for human health was first documented in 1963. During the past 25 y, deficiency of zinc in humans due to nutritional factors and several disease states has now been recognized. The high phytate content of cereal proteins is known to decrease the availability of zinc, thus the prevalence of zinc deficiency is likely to be high in a population consuming large quantities of cereal proteins. Alcoholism, malabsorption, sickle cell anemia, chronic renal disease, and chronically debilitating diseases are now known to be predisposing factors for zinc deficiency. A spectrum of clinical manifestations ranging from mild to severe degree have now been recognized in human zinc-deficiency states. Zinc is required for many biological functions including DNA synthesis, cell division, and gene expression. It is required for the activity of many enzymes in biological systems. Recent studies indicate that zinc is needed for cell-mediated immunity.
Animals↗
Role of zinc in human health.
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Gene Expression Regulation↗
Activities of purine catabolism related enzymes in zinc deficiency: relationship to T-lymphocyte dysfunction and hyperammonemia.
The activities of liver, muscle, and red blood cell enzymes involved in the degradation of purine were assayed in zinc deficient (ZD), pair-fed control (PF) and ad libitum-fed control (Ad lib) rats. Diets (1.5 ppm of zinc in ZD diet and 110 ppm in control diet) were fed to rats for 6 weeks after which they were sacrificed and tissues isolated for several assays. Results indicated a significant increase in the concentration of plasma NH3 (P less than .0005) and uric acid (P less than .05), and a decrease in the concentration of blood urea nitrogen (BUN) (P less than .025) in ZD rats compared to both control groups. The activities of liver and red blood cell (RBC) nucleoside phosphorylase (NPase) were lower (P less than .025) in ZD rats. Activity of 5'adenosine monophosphate deaminase (AMPDA) was higher in liver (P less than .0001) and muscle (P less than .01) in ZD groups vs. controls. Activity of hypoxanthine polyribosyl transferase (HPRT) in liver was higher (P less than .005) in ZD group compared to controls. The present findings could be viewed from two aspects: first, they provide an insight into the specific role of zinc on T-lymphocyte function which is believed to be mediated by the regulatory effect of zinc on the enzyme nucleoside phosphorylase and, second they provide a possible mechanism for hyperammonemia observed in zinc deficient human subjects and experimental animals.
Adenosine Deaminase↗
Ecto 5' nucleotidase (5'NT) as a sensitive indicator of human zinc deficiency.
Ecto 5' nucleotidase (5'NT) is an integral plasma membrane enzyme located on most mammalian cells, and it is zinc dependent. We assayed 5'NT activity in the lymphocytes of two groups of subjects. The first group of six subjects had a mild state of zinc deficiency, as measured on the basis of zinc levels in lymphocytes, granulocytes, and platelets, but were otherwise healthy. They received 50 mg zinc as acetate orally for 12 weeks. The second six subjects were normal human volunteers in whom a mild state of zinc deficiency was induced experimentally by dietary techniques (4.2 to 5.6 mg daily zinc intake). For the assay of 5'NT, intact lymphocytes were incubated with 8-14C-labeled inosine monophosphate as substrate. Product and substrate were separated by thin-layer chromatography. Zinc level in cells was measured by flameless atomic absorption technique. In the first group of subjects with zinc deficiency, the decreased activity of 5'NT was corrected and the cellular zinc levels were normalized by oral zinc supplementation (p less than 0.01). In the second group of subjects, the baseline data were compared with those in early zinc depletion (4 to 8 weeks) and late depletion periods (greater than 20 weeks). A decrease in the activity of 5'NT was observed during the early zinc depletion phase. Zinc levels in lymphocytes, granulocytes, and platelets decreased significantly only during the late zinc depletion phase (p less than 0.01). Plasma zinc level did not change even during the late zinc depletion phase. Our studies show that 5'NT activity may be a sensitive and useful indicator of mild deficiency of zinc in human subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
5'-Nucleotidase↗
Clinical and experimental. Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism. 1963.
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Anemia, Hypochromic↗
Pancreaticobiliary secretion of zinc and copper in normal persons and patients with Wilson's disease.
The objectives of this study were (1) to examine basal and cholecystokinin-stimulated pancreaticobiliary secretion of zinc in normal subjects with zinc-adequate and zinc-deficient diets, and (2) to investigate whether basal and stimulated secretion of zinc was abnormal in patients with Wilson's disease before and after zinc therapy. Gastroduodenal intubation was performed in six healthy subjects and five patients with Wilson's disease. After intravenous infusion of octapeptide of cholecystokinin (40 ng/kg/hr) the pancreaticobiliary secretion of zinc increased from a basal rate of 283.1 +/- 75.8 nmol/L/min to a peak of 716.6 +/- 175.3 nmol/L/min in normal subjects. Normal subjects with a zinc-deficient diet had both lower basal (66.8 +/- 15.8 nmol/L/min) and stimulated (559.5 +/- 31 nmol/L/min) pancreaticobiliary secretion of zinc than with a zinc-sufficient diet. In contrast to the markedly reduced pancreaticobiliary secretion of copper, patients with Wilson's disease not treated with zinc had normal basal (226.6 +/- 126 nmol/L/min) and stimulated (728.7 +/- 195.5 nmol/L/min) zinc secretion. These studies indicate that a considerable amount of zinc is being secreted in pancreaticobiliary fluid in healthy subjects and there was no impairment of zinc secretion in patients with Wilson's disease. Our data also indicate that pancreaticobiliary secretion of zinc is dependent on the zinc status of the subjects, suggesting that endogenous secretion of zinc may play a significant role in the homeostasis of zinc.
Acetates↗
Net renal tubular reabsorption of zinc in healthy man and impaired handling in sickle cell anemia.
Zinc deficiency is a significant clinical finding in sickle cell anemia (SCA) and abnormalities of zinc handling such as hyperzincuria are present. The cause of increased urinary zinc excretion in SCA is not clear. To define the renal handling of zinc in SCA and in healthy subjects, we measured zinc (total and ultrafilterable plasma zinc, urine zinc) and creatinine clearance in eight healthy and seven SCA subjects. Ultrafilterable zinc in plasma was assessed by equilibration of plasma with 65Zn followed by filtration through Amicon Cetriflo CF25 cones. While the mean filtered load of zinc was not significantly different between the two groups, the mean zinc excretion rate was approximately three-fold higher in patients (1.73 +/- 0.96 vs. 0.63 +/- 0.39 micrograms/min, P less than .05). In controls, zinc excreted was significantly less than zinc filtered (P less than .005), the fractional excretion of zinc averaging 0.49 +/- 0.31, indicating net reabsorption. This was not the case for the SCA patients. We conclude that there is impaired renal tubular handling of zinc in SCA.
Absorption↗
Zinc absorption in human small intestine.
We determined the intestinal site of zinc absorption in humans and investigated the interaction between intestinal absorption of zinc and other solutes using the triple-lumen steady-state perfusion technique. Twenty-one healthy subjects participated in the study. During intestinal perfusion of a balanced electrolyte solution containing 0.1 mM zinc acetate, zinc absorption occurred throughout the entire small intestine. However, the jejunum had the highest rate of absorption (357 +/- 14 nM.min-1.40 cm-1) compared with the duodenum (230 +/- 33 nM.min-1.40 cm-1) and ileum (84 +/- 10 nM.min-1.40 cm-1). Over a range of zinc concentrations infused into the jejunum (0.1, 0.9, and 1.8 mM) there were linear increases in the rate of zinc absorption (P less than 0.05). Intestinal absorption of zinc was significantly stimulated by the addition of glucose (20 mM). Zinc absorption increased from 459 +/- 39 to 582 +/- 45 nM.min-1.40 cm-1 (P less than 0.05). Conversely, zinc (0.9 mM) also enhanced the absorption of glucose, which was increased from 293 +/- 43 to 447 +/- 27 microM.min-1.40 cm-1 (P less than 0.05). The enhanced absorption of zinc or glucose was not accompanied by any increase in absorption of water and sodium. In contrast, increasing the concentration of zinc in the perfusate resulted in decreased absorption of sodium and water in a dose-related manner. In conclusion, our study demonstrated that zinc absorption is concentration dependent and occurs throughout the small intestine. The jejunum has the highest rate of absorption of zinc. The interactions between absorption of zinc and other solutes suggest that the transport process of zinc is carrier mediated.
Acetates↗
Nucleotides in lymphocytes of human subjects with zinc deficiency.
Cell-mediated immunity in human subjects is affected adversely as a result of zinc deficiency. The mechanism by which a deficiency of zinc may affect lymphocyte proliferation and functions, is not well understood at present. Nucleoside phosphorylase (NPase), a purine catabolic pathway enzyme, is zinc dependent, and a congenital deficiency of this enzyme is known to affect adversely cell-mediated immunity. This effect has been related to an accumulation of toxic nucleotides in lymphocytes as a result of NPase deficiency. Inasmuch as the effect of zinc deficiency on the activity of NPase and the levels of nucleotides in human lymphocytes has not been previously reported, we assayed these parameters in human subjects with zinc deficiency before and after zinc supplementation. A mild deficiency of zinc was diagnosed in those having decreased zinc in two out of three cell lineages (less than 42 micrograms in granulocytes, less than 48 micrograms in lymphocytes, and less than 1.70 microgram in platelets, per 10(10) cells). In comparison with five subjects with sufficient zinc, six subjects with zinc deficiency showed a decrease in the activity of NPase (p = 0.01), an increase in adenosine diphosphate (ADP) level (p = 0.008), a decreased adenosine triphosphate (ATP)-to-ADP ratio (p = 0.0001), and an increase in both guanosine triphosphate (GTP) (p = 0.02) and deoxyadenosine triphosphate (dGTP) (p = 0.04 in the lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine Diphosphate↗
Factors underlying abnormal zinc metabolism in uremia.
Zinc balance studies were completed in ten hemodialyzed adult uremic patients and five normal controls to determine the cause of abnormal zinc metabolism in uremia. Subjects were fed standard hospital foods providing nutrients in amounts recommended for adult stable hemodialyzed patients. The amount of zinc in the diet was kept constant at 10 mg per day. After one week of stabilization, blood, urine, used dialysate (in patients on dialysis days) and stool samples were collected daily for the next two weeks. In comparison to controls, patients had lower plasma zinc levels (mean +/- SD, 112 +/- 10 vs. 82 +/- 12 micrograms/dl, P less than 0.01), lower urinary zinc excretion (560 +/- 120 vs. 40 +/- 20 mg/24 hrs, P less than 0.001) and higher fecal zinc losses (8.1 +/- 0.7 vs. 10.2 +/- 0.6 mg/24 hrs, P less than 0.01). Dialytic zinc losses were minimal (26 +/- 4 micrograms/treatment). During the study period, patients were in a negative zinc balance while normal controls maintained a positive zinc balance on 10 mg dietary zinc intake. These results demonstrate that augmented fecal zinc excretion in the presence of hypozincemia contributes to the negative zinc balance in hemodialyzed uremic patients.
Adult↗
Immunological effects of zinc deficiency in sickle cell anemia (SCA).
Zinc deficiency occurs frequently in SCA subjects. Our studies have shown that several parameters of cellular immune functions may be altered in SCA subjects and related to a deficiency of zinc. These include anergy to certain common antigens, which was reversible following zinc supplementation, decreased activity of natural killer (NK) cells, decreased production of interleukin (IL-2), decreased T4/T8 ratio and serum thymulin. Inasmuch as we have observed similar immunological changes in human volunteers (non-SCA) in whom we restricted only zinc intake and produced a mild specific deficiency of zinc, we conclude that the above changes in SCA were due to zinc deficiency. Although it is well known that susceptibility to infections is a common problem in SCA subjects, the pattern of infections related to cell mediated immune dysfunction has not been well documented. Whether or not supplementation with zinc will alter the pattern of infection and decrease morbidity in SCA on a long-term basis remains to be determined.
Adult↗
Cell cycle distribution defect in PHA-stimulated T lymphocytes of sickle cell disease patients.
T lymphocytes from normal human controls and sickle cell disease (SCD) patients were isolated from peripheral blood and cultured for 72 hours following addition of phytohemagglutinin. The ratio for the fraction of cells in DNA synthesis (S phase) over the fraction in G2 phase (S/G2) was significantly higher in SCD patients in comparison to the controls (mean +/- SD) (4.01 +/- 0.78 vs. 2.78 +/- 0.76, P less than 0.02). Following in vivo zinc supplementation to two subjects, the S/G2 ratio was normalized. We conclude that the distribution of T lymphocytes in cell cycle is altered in SCD patients and that this effect may be zinc-dependent.
Adolescent↗
Zinc tolerance test in uremia: effect of calcitriol supplementation.
The effect of 1,25(OH)2D3 on zinc absorption was indirectly determined in hemodialysis patients using the oral zinc tolerance test. The increment in plasma zinc and the area under the curve following an oral zinc load of 25 mg were studied in seven patients, before and after 6 weeks of therapy with 1 microgram/day of 1,25(OH)2D3 [Rocaltrol(R)]. Before therapy, fasting plasma zinc, 2 hour plasma zinc, and the area under the curve (AUC) were subnormal (hemodialysis patients vs normals: 96 +/- 2 vs 105 +/- 3 micrograms/dl, p less than 0.05, 161 +/- 8 vs 222 +/- 16 micrograms/dl, p less than 0.025, and 188 +/- 25 vs 302 +/- 33 micrograms hr/dl, p less than 0.025, respectively). Following Rocaltrol, serum calcium level increased (8.9 +/- .12 to 9.8 +/- .4 mg/dl, p less than 0.05), parathyroid hormone levels decreased (20.4 +/- 8.9 to 13.6 +/- 7.2 ng/ml, p less than 0.05), but there was no significant change in fasting plasma zinc, 2 hour plasma zinc, or AUC (89 +/- 3 micrograms/dl, 149 micrograms/dl, and 176 +/- 18 micrograms hr/dl, respectively). These results suggest that short-term 1,25(OH)2D3 therapy had no significant impact on zinc absorption or plasma zinc level in uremics.
Adult↗
Zinc in growth and development and spectrum of human zinc deficiency.
Growth retardation is seen in experimental animals as a result of severe dietary restriction of several essential trace elements. However, in humans, the effect of zinc deficiency is most pronounced. Growth failure and hypogonadism in males, related to a deficiency of zinc, have been recognized in many developing countries. A mild deficiency of zinc, affecting growth and development in children and adolescents, has been reported from developed countries as well. Zinc deficiency in humans may manifest as severe, moderate, or mild. The manifestations of severe zinc deficiency include bullous pustular dermatitis, alopecia, diarrhea, emotional disorder, weight loss, intercurrent infections due to cell-mediated immune dysfunctions, hypogonadism in males, neurosensory disorders, and problems with healing of ulcers. This condition can be fatal. A moderate level of zinc deficiency has been reported in a variety of conditions. Clinical manifestations include growth retardation and male hypogonadism in adolescence, rough skin, poor appetite, mental lethargy, delayed wound healing, cell-mediated immune dysfunctions, and abnormal neurosensory changes. A mild level of zinc deficiency may manifest with decreased serum testosterone level and oligospermia in males, decreased lean body mass, hyper-ammonemia, neurosensory changes, anergy, decreased serum thymulin activity, and decreased IL-2 activity. Although the clinical aspects of severe and moderate levels of zinc deficiency are well known, the recognition of mild levels of zinc deficiency has been difficult. Currently plasmas zinc appears to be the most widely used parameter for assessment of human zinc status, and it is known to be decreased in cases of severe and moderate deficiency of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Elevated plasma copper in chronic renal failure.
Hypercupremia has been described in patients undergoing chronic dialysis. To further characterize dialysis-associated hypercupremia, we studied plasma copper (PCu) and ceruloplasmin (Cp) in patients on hemodialysis (n = 20) and peritoneal dialysis (n = 25), in uremic patients (n = 10) not yet on dialysis, and in normal age-matched control subjects (n = 20). PCu was significantly elevated in all three patients groups (mean +/- SD) (20.6 +/- 4.1, 19.8 +/- 4.6, 19.8 +/- 4.9 mumol/L, respectively) vs control subjects (16.5 +/- 2.7 mumol/L). However, Cp levels were not significantly different among the four study groups (330 +/- 60, 320 +/- 70, 370 +/- 100, and 360 +/- 90 mg/L, respectively). Calculated nonceruloplasmin copper was significantly higher in all uremic groups. The measurement of chelatable Cu confirmed the presence of significantly higher extractable Cu in hemodialysis (2.7 +/- 0.6 mumol/L) and peritoneal dialysis patients (2.4 +/- 0.5 mumol/L) than control subjects (1.5 +/- 0.3 mumol/L). Cu is elevated in uremia regardless of dialysis status and this elevation is not accounted for by an increase in plasma ceruloplasmin.
Adult↗
Serum thymulin in human zinc deficiency.
The activity of thymulin (a thymic hormone) is dependent on the presence of zinc in the molecule. We assayed serum thymulin activity in three models of mildly zinc-deficient (ZD) human subjects before and after zinc supplementation: (a) two human volunteers in whom a specific and mild zinc deficiency was induced by dietary means; (b) six mildly ZD adult sickle cell anemia (SCA) subjects; and (c) six mildly ZD adult non-SCA subjects. Their plasma zinc levels were normal and they showed no overt clinical manifestations of zinc deficiency. The diagnosis of mild zinc deficiency was based on the assay of zinc in lymphocytes, granulocytes, and platelets. Serum thymulin activity was decreased as a result of mild zinc deficiency and was corrected by in vivo and in vitro zinc supplementation, suggesting that this parameter was a sensitive indicator of zinc deficiency in humans. An increase in T101-, sIg-cells, decrease in T4+/T8+ ratio, and decreased IL 2 activity were observed in the experimental human model during the zinc depletion phase, all of which were corrected after repletion with zinc. Similar changes in lymphocyte subpopulation, correctable with zinc supplementation, were also observed in mildly ZD SCA subjects. Inasmuch as thymulin is known to induce intra- and extrathymic T cell differentiation, our studies provide a possible mechanism for the role of zinc on T cell functions.
Adolescent↗
Recurrent pneumothoraces in miliary tuberculosis.
An 18-year-old female patient with miliary tuberculosis presented with bilateral, simultaneous pneumothoraces, which were recurrent with a bronchopleural fistula. The recurrent pneumothoraces were managed with tube thoracostomy and pleurodesis. Various possible pathogenetic mechanisms of this rare complication are discussed.
Adolescent↗