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PubMed2002

Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: insight into the insulin-mimetic action of zinc.

Zinc is an important trace element found in most body tissues as bivalent cations and has essential roles in human health. The insulin-like effect of zinc cations raises the possibility that they inhibit glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase linked with insulin resistance and type 2 diabetes. Here we show that physiological concentrations of zinc ions directly inhibit GSK-3beta in vitro in an uncompetitive manner. Treatment of HEK-293 cells with zinc enhanced glycogen synthase activity and increased the intracellular levels of beta-catenin, providing evidence for inhibition of endogenous GSK-3beta by zinc. Moreover, zinc ions enhanced glucose uptake 3-fold in isolated mouse adipocytes, an increase similar to activation with saturated concentrations of insulin. We propose that the in vivo insulin-mimetic actions of zinc are mediated via direct inhibition of endogenous GSK-3beta.

Adipocytes↗

PubMed1986

Influence of dietary zinc deficiency and parenteral zinc on rat liver fructose 1,6-bisphosphatase activity.

Fructose 1,6-bisphosphatase activity in liver of rats fed a zinc deficient diet was decreased to 60% of that in zinc adequate controls. Activity in the zinc deprived rats was not restored to control values by in vitro addition of EDTA. When a physiological dose of zinc was tube fed to the depleted rats, activity increased approximately 150% within 0.5 hr of the dose, and by 1 hr plateaued to a level seen in zinc adequate controls. A significant transient decrease in activity occurred following an intraperitoneal zinc load. This is reversible by in vitro addition of EDTA. These results suggest that rat liver fructose 1,6-bisphosphatase activity is highly sensitive to zinc in vivo as has been demonstrated in vitro.

Animals↗

PubMed2001

Adrenalectomy causes loss of zinc ions in zinc-enriched (ZEN) terminals and decreases seizure-induced neuronal death.

Chelatable zinc ions from synaptic vesicles have been suggested to be involved in neuronal death caused by stroke, epilepsy and head trauma. Elevated glucocorticoid concentration exacerbates such neuron loss, while low levels protect. We have tested the notion that the neuroprotective effect of prior glucocorticoid reduction is mediated by a reduction of zinc ions contained in zinc-enriched (ZEN) synaptic vesicles. The level of vesicular zinc ions was evaluated by toluene sulfonamide quinoline (TSQ) fluorometry and zinc autometallography (ZnS(AMG)) 10 and 30 days, respectively, after adrenalectomy. The hippocampus showed significant vesicular zinc ion depletion following adrenalectomy. After the kainate injection, adrenalectomized rats showed proconvulsive seizure behavior, i.e. shortened latency to seizure onset time and increased seizure score. Additionally they showed decreased hippocampal CA3 neuronal death as compared to control animals. The present data suggest that zinc ions released from damaged ZEN terminals are involved in seizure-induced neuronal death.

Adrenalectomy↗

PubMed1997

Treatment of Wilson's disease with zinc: XIV. Studies of the effect of zinc on lymphocyte function.

Although administration of zinc to human subjects has been reported to interfere with lymphocyte function, this single report has never been confirmed or refuted. We have developed zinc as a lifelong therapy for patients with Wilson's disease. Interference with lymphocyte function occurring as a side effect of zinc therapy could produce serious problems in our patients. We evaluated lymphocyte mitogenic response and natural killer cell activity in patients with Wilson's disease treated for 5 years or longer with zinc, in comparison with normal controls, and found no differences. In a second study, we evaluated these same parameters in patients with Wilson's disease before and after 1 year of zinc therapy, and again found no significant differences. We have seen no indications of immune suppression or increased susceptibility to infections in our patients, who have now been treated with zinc for up to 15 years. We conclude that any side effects from compromised lymphocyte function caused by administration of zinc are not of concern to patients with Wilson's disease.

Copper↗

PubMed1999

Urinary excretion of essential metals following intravenous calcium disodium edetate: an estimate of free zinc and zinc status in man.

Ethylenediaminetetraacetic acid (EDTA) is a powerful metal chelating agent used in the treatment of lead poisoning. EDTA also binds strongly to other metals. Thus, following intravenous infusion of CaNa2EDTA in healthy subjects the urinary excretion of calcium, copper, iron, magnesium and zinc were assessed. CaNa2EDTA significantly increased the urinary excretion of all metals except magnesium with greatest increases for iron (x 3.8 above baseline) and zinc (x 22). In addition, an in vitro dialysis study with a simplified serum showed that zinc (4.1 X 10(-3) mumol/h) was taken up more rapidly than iron (2.9 X 10(-3) mumol/h) by EDTA. The degree of binding of iron and zinc by EDTA depends on two factors: namely, the affinity of EDTA for Zn2+ and Fe3+, and the levels of unbound hydrated Zn2+ and Fe3+ ('free' ions). Despite differences in the rate of chelation of Zn2+ and Fe3+ by EDTA we show that the measurements of (a) circulating free iron, from routine clinical measurements of transferrin bound iron, and (b) the ratio of zinc:iron excreted in urine could provide an estimate of circulating free zinc, and thereby of zinc status, in man. In addition, EDTA treatment should be evaluated for patients with iron overload.

Adult↗

PubMed2003

Zinc transporter 3 and zinc ions in the rodent superior cervical ganglion neurons.

Previous studies have revealed that zinc-enriched (ZEN) terminals are present in all parts of the CNS though with great differences in intensity. The densest populations of both ZEN terminals and ZEN somata are found in telencephalic structures, but also structures like the spinal cord demonstrate impressive ZEN systems spreading terminals several segments around the respective ZEN somata. The present study evaluates whether sympathetic neurons in the superior cervical ganglia (SCG) are ZEN neurons, i.e. contain vesicles that have zinc transporter 3 (ZnT3) proteins in their membranes and contain zinc ions. ZnT3 immunoreactivity (IR) was found in the somata and processes in the postganglionic neurons of mouse SCG. Only a small fraction of neurons (less than 5%), expressed varying degrees of ZnT3. Colchicine treatment, however, increased the number of ZnT3-positive neurons three-fold, suggesting an accumulation of ZnT3 protein in the somata. A small proportion of the postganglionic axons revealed dotted accumulations of ZnT3 IR along their courses. Double labeling showed that all ZnT3-positive neurons and axons were also tyrosine hydroxylase-positive with strong immunofluorescence, while no colocalization was found between ZnT3 and the vesicular acetylcholine transporter (VAChT) or neuropeptide Y IR. VAChT-positive preganglionic neurons were found to terminate on ZnT3 neuronal somata. 6-Methoxy 8-para toluene sulfonamide quinoline fluorescence and zinc selenium autometallography (ZnSe(AMG)) revealed that a subgroup of SCG cells contained free or loosely bound zinc ions. It is therefore concluded that ZnT3 and zinc ions are present in a subpopulation of TH-positive, NPY-negative neurons in the rodent SCG, supporting the notion that vesicular zinc ions may play a special role in the peripheral sympathetic adrenergic system.

Animals↗

PubMed2004

Differentially expressed genes execute zinc-induced apoptosis in precancerous esophageal epithelium of zinc-deficient rats.

Zinc deficiency (ZD) in rats increases esophageal cell proliferation and the incidence of N-nitrosomethylbenzylamine-induced esophageal tumors. Conversely, zinc replenishment (ZR) rapidly induces apoptosis in esophageal epithelia and reverses cancer development. We investigated gene expression changes in ZR versus ZD esophageal epithelia to identify differentially expressed genes associated with the antitumor effect of ZR. Weanling rats were fed a ZD diet for 6 weeks to establish esophageal cell proliferation or a zinc-sufficient (ZS) diet. Then, 10 ZD rats were treated with zinc gluconate intragastrically and switched to ZS diet; the remaining 10 ZD and ZS animals were treated with saline. All animals were killed 26-28 h later. Using cDNA microarrays, real-time polymerase chain reaction amplification and RNA hybridization techniques, we identified novel differentially expressed genes, including a RNA-binding protein with two RNA recognition motifs and a zinc knuckle (ZD7), and a DNA/RNA helicase with a DEAD box (ZD10) with two splice variants, ZD10a and ZD10b. In situ hybridization detected increased mRNA expression of ZD7, ZD10a and ZD10b in ZR esophageal epithelia, which displayed markedly increased occurrence of apoptotic cells, relative to ZD epithelia. Overexpression of ZD7 in human esophageal cancer cells resulted in induction of apoptosis and activation of caspase-3 and -7, activities that were inhibited by caspase-specific inhibitors. In addition, ZD7 mRNA levels and zinc-induced apoptosis in rat squamous carcinoma cells were reduced by specific small interfering ribonucleic acids. Thus, ZR rapidly induces ZD7 and ZD10 expression, which in turn stimulates apoptosis. These results provide the beginnings of a molecular pathway for zinc-induced apoptosis under conditions that reverse esophageal tumor initiation.

Animals↗

PubMed1976

Degradation of hepatic zinc-thionein after parenteral zinc administration.

A low-molecular-weight protein, zinc-thionein, a metallothionein, was implicated as having a regulatory function in zinc metabolism. The half-life (t 1/2) of hepatic zinc-thionein was determined by pulse-labelling with either L-[35S] cystine and/or 65Zn. In two experiments with L-[35S]cystine, the t 1/2 of zinc-thionein was 18h and 19h. Most of the soluble 35S-labelled hepatic proteins had a t 1/2 of 4 days. The t 1/2 of zinc-thionein calculated by using 65Zn was 20h. The close similarity between the calculated and measured t 1/2 values for zinc-thionein suggests that release of Zn2+ from zinc-thionein probably occurs simultaneously with degradation of the protein moiety.

Animals↗

PubMed1996

The yeast ZRT1 gene encodes the zinc transporter protein of a high-affinity uptake system induced by zinc limitation.

The yeast Saccharomyces cerevisiae has two separate systems for zinc uptake. One system has high affinity for substrate and is induced in zinc-deficient cells. The second system has lower affinity and is not highly regulated by zinc status. The ZRT1 gene encodes the transporter for the high-affinity system, called Zrt1p. The predicted amino acid sequence of Zrt1p is similar to that of Irt1p, a probable Fe(II) transporter from Arabidopsis thaliana. Like Irt1p, Zrt1p contains eight potential transmembrane domains and a possible metal-binding domain. Consistent with the proposed role of ZRT1 in zinc uptake, overexpressing this gene increased high-affinity uptake activity, whereas disrupting it eliminated that activity and resulted in poor growth of the mutant in zinc-limited media. Furthermore, ZRT1 mRNA levels and uptake activity were closely correlated, as was zinc-limited induction of a ZRT1-lacZ fusion. These results suggest that ZRT1 is regulated at the transcriptional level by the intracellular concentration of zinc. ZRT1 is an additional member of a growing family of metal transport proteins.

Base Sequence↗

PubMed1998

Identification of a family of zinc transporter genes from Arabidopsis that respond to zinc deficiency.

Millions of people worldwide suffer from nutritional imbalances of essential metals like zinc. These same metals, along with pollutants like cadmium and lead, contaminate soils at many sites around the world. In addition to posing a threat to human health, these metals can poison plants, livestock, and wildlife. Deciphering how metals are absorbed, transported, and incorporated as protein cofactors may help solve both of these problems. For example, edible plants could be engineered to serve as better dietary sources of metal nutrients, and other plant species could be tailored to remove metal ions from contaminated soils. We report here the cloning of the first zinc transporter genes from plants, the ZIP1, ZIP2, and ZIP3 genes of Arabidopsis thaliana. Expression in yeast of these closely related genes confers zinc uptake activities. In the plant, ZIP1 and ZIP3 are expressed in roots in response to zinc deficiency, suggesting that they transport zinc from the soil into the plant. Although expression of ZIP2 has not been detected, a fourth related Arabidopsis gene identified by genome sequencing, ZIP4, is induced in both shoots and roots of zinc-limited plants. Thus, ZIP4 may transport zinc intracellularly or between plant tissues. These ZIP proteins define a family of metal ion transporters that are found in plants, protozoa, fungi, invertebrates, and vertebrates, making it now possible to address questions of metal ion accumulation and homeostasis in diverse organisms.

Amino Acid Sequence↗

PubMed2001

Evidence for a novel role of copper-zinc superoxide dismutase in zinc metabolism.

The LYS7 gene in Saccharomyces cerevisiae encodes a protein (yCCS) that delivers copper to the active site of copper-zinc superoxide dismutase (CuZn-SOD, a product of the SOD1 gene). In yeast lacking Lys7 (lys7Delta), the SOD1 polypeptide is present but inactive. Mutants lacking the SOD1 polypeptide (sod1Delta) and lys7Delta yeast show very similar phenotypes, namely poor growth in air and aerobic auxotrophies for lysine and methionine. Here, we demonstrate certain phenotypic differences between these strains: 1) lys7Delta cells are slightly less sensitive to paraquat than sod1Delta cells, 2) EPR-detectable or "free" iron is dramatically elevated in sod1Delta mutants but not in lys7Delta yeast, and 3) although sod1Delta mutants show increased sensitivity to extracellular zinc, the lys7Delta strain is as resistant as wild type. To restore the SOD catalytic activity but not the zinc-binding capability of the SOD1 polypeptide, we overexpressed Mn-SOD from Bacillus stearothermophilus in the cytoplasm of sod1Delta yeast. Paraquat resistance was restored to wild-type levels, but zinc was not. Conversely, expression of a mutant CuZn-SOD that binds zinc but has no SOD activity (H46C) restored zinc resistance but not paraquat resistance. Taken together, these results strongly suggest that CuZn-SOD, in addition to its antioxidant properties, plays a role in zinc homeostasis.

Antioxidants↗

PubMed1990

Accumulation of zinc in egg yolk, ovarian follicles and organs after forced resting by high dietary zinc.

1. Eighteen Warren SSL hens of 71 weeks of age were forced-moulted by ad libitum feeding of a high-zinc diet (10,000 ppm zinc for 2 days followed by 5,000 ppm zinc-supplement diet for 4 days). From the start of the treatment, eggs were collected and 3 hens were slaughtered on days 0, 2, 3, 4, 5 and 6 of the study. 2. Zinc analyses were carried out on the different components of the eggs and on liver, pancreas, kidney, different yolky follicles of the ovary and various segments of the oviduct. 3. Seven-, six- and threefold increases in zinc concentration were found in pancreas, liver and kidney, respectively. 4. The shell gland and isthmus, but not the magnum, also showed slight but significant increases in Zn content. 5. Zinc accumulation was also high and almost identical in ovarian follicles F1 to F4 but slightly less in F5 and F6 follicles. 6. In the egg, a significant increase in zinc concentration was only observed in the yolk.

Animals↗

PubMed1978

[Interaction among the trace elements zinc, copper and iron after depletion and repletion of dairy cows with zinc].

Imbalances in the supply with trace elements may be caused by the excessive administration of one or several elements or the insufficient administration in relation to other trace elements. This article deals with the interactions between the trace elements zinc and copper resp. zinc and iron under the conditions of the insufficient supply with Zn (6 mg per kg dry matter of the fodder) and the supply according to the demand with other trace elements (14 mg copper resp. 83 mg iron per dry matter of the fodder). For this purpose we investigated the copper, iron and zinc content of the milk and the serum of cows that were first depleted of zinc through a semi-synthetic zinc deficiency diet and then repleted with extra allowances of zinc. The closest connections exist between the copper and zinc content of the milk. Thus extreme Zn-deficiency feeding conditions the decreased Zn-content on the one hand and increased Cu-content on the other. In contrast to this, the cows' Zn-excretion in the milk increases after Zn-repletion whereas the Cu-content decreases. This shows a distinctly negative correlation. A loose connection could only be detected for the Cu- and Zn-content of the serum. Though the Zn-content changed considerably in dependence on the Zn-supply, the Cu-content remained largely uninfluenced. The Fe-content of both milk and serum shows no interaction with the nutritive Zn-supply. Only after 19 test weeks of extreme Zn-deficiency could a slight increase of the Fe-concentration be indicated.

Animals↗

PubMed1986

Zinc requirements and zinc intakes of breast-fed infants.

Longitudinal changes in dietary zinc requirements for infants at different levels of net absorption were estimated using a factorial approach. Apart from variations in net absorption, the zinc needed for new lean body mass is the major determinant of requirements. As growth velocity declines progressively, estimated zinc requirements for growth and for replacement of urine and sweat losses decrease from a high for male infants of 780 micrograms/day at 1 mo to 480 micrograms/day in the 5th mo and then remain quite constant through the 1st yr. Calculated percentage absorption of zinc from human milk necessary to meet estimated requirements increases with duration of lactation. For infants of mothers whose zinc intake approximated 25 mg/day the calculated percentage absorption remained within plausible limits. It is suggested that the progressive decrease in milk zinc concentrations provides a mechanism for conserving maternal zinc while meeting infant needs.

Absorption↗

PubMed1989

Dietary calcium, phytate, and zinc intakes and the calcium, phytate, and zinc molar ratios of the diets of a selected group of East African children.

Dietary zinc, calcium, and phytate intakes of 66 rural Malawian children aged 4-6 y were determined during three seasons on the basis of weighed food records and analyzed food composition data. Height and weight measurements were also recorded and hair samples were collected for zinc analysis. Seasonal daily zinc, calcium, and phytate intakes of females ranged from 6.2 +/- 1.7 to 6.8 +/- 2.1 mg (mean +/- SD), from 335 +/- 170 to 401 +/- 257 mg, and from 1621 +/- 660 to 1729 +/- 592 mg, respectively and, for males, 7.0 +/- 1.7 to 8.0 +/- 2.3 mg, 342 +/- 164 to 473 +/- 310 mg, and 1857 +/- 530 to 2161 +/- 684 mg, respectively. Cereals provided greater than 42% of dietary zinc. Seasonal mean molar ratios of phytate to Zn and Ca x phytate to Zn [per 1000 kcal (4.2 MJ)] and the median Ca to phytate molar ratio ranged from 24 to 27, 151 to 188 mmol/1000 kcal (4.2 MJ), and 3.1 to 3.4, respectively. Over 78% of the children consumed diets with phytate-to-Zn and Ca x phytate.Zn-1 . 1000 kcal-1 molar ratios above values suggested to jeopardize zinc status. Correlations between hair zinc, phytate-to-Zn, and Ca x phytate.Zn-1 . 1000 kcal-1 molar ratios suggest that high phytic acid intakes may compromise zinc status in these children.

Body Height↗

PubMed1991

Intestinal metallothionein gene expression and zinc absorption in rats are zinc-responsive but refractory to dexamethasone and interleukin 1 alpha.

The effects of dexamethasone and interleukin 1 alpha on intestinal metallothionein gene expression and zinc absorption were studied. Rats given parenteral zinc served as positive controls. A single intraperitoneal or intravenous dose of dexamethasone, interleukin 1 alpha or zinc markedly increased liver metallothionein synthesis 3-9 h after injection. Intestinal metallothionein mRNA and metallothionein protein were not affected by dexamethasone or interleukin 1 alpha, but were markedly increased by parenteral zinc. Absorption of 65Zn from isolated duodenal segments was inversely related to intestinal metallothionein concentration in rats given zinc, but was not affected by dexamethasone or interleukin 1 alpha. Plasma zinc concentrations decreased in rats given dexamethasone or interleukin 1 alpha and increased in those given zinc, but they were not related to 65Zn absorption. Similarly, multiple intraperitoneal administration of either dexamethasone or interleukin 1 alpha, or oral administration of dexamethasone, for 7 d markedly increased liver metallothionein synthesis but did not affect intestinal metallothionein concentration or 65Zn absorption. These results suggest that intestinal metallothionein gene expression and 65Zn absorption are refractory to glucocorticoid hormone and interleukin 1 alpha.

Animals↗

PubMed1997

Zinc ion availability--the determinant of efficacy in zinc lozenge treatment of common colds.

This is a re-analysis of reports from 1984 to 1992 of double-blind, placebo-controlled, clinical trials of zinc lozenges in the treatment of common colds. This re-analysis was performed to test the hypothesis that major variations in daily zinc ion availability (ZIA) between chemically different lozenge formulations caused differing results in these clinical trials. Solution chemistry computations determined the bioavailability of Zn2+ ions at physiological pH from the lozenges used in these clinical trails. ZIA was derived from Fick's laws of diffusion in a bio-electric field. Lozenges that released Zn2+ ions at physiological pH (positive ZIAs) shortened colds. Lozenges that released negatively charged zinc species at physiological pH (negative ZIAs) lengthened colds. Lozenges having a zero ZIA had no effect on common colds. Lozenges with ZIA = 100 shortened colds by 7 days while ZIA = -55 lozenges lengthened colds by 4.4 days. A linear dose-response relationship exists between ZIAs of zinc lozenges and changes in duration of common colds. It is concluded that: prospective efficacy of zinc lozenges can be predicted based upon readily determined ZIA factors and ZIAs; chemically different zinc lozenge formulations having greatly different ZIAs resulted in greatly differing results in clinical trials; mast cell granule-derived Zn2+ ions are the foundation of the primary immune system; and high ZIA zinc acetate lozenges are beneficial for common colds.

Biological Availability↗

PubMed2006

Marginal zinc deficiency exacerbates bone lead accumulation and high dietary zinc attenuates lead accumulation at the expense of bone density in growing rats.

Environmental lead exposure is associated with reduced bone growth and quality, which may predispose to osteoporosis. Zinc supplementation may reduce lead accumulation; however, effects on bone development have not been addressed. Our objective was to investigate the effects of marginal zinc (MZ) and supplemental zinc (SZ) intakes on bone lead deposition and skeletal development in lead-exposed rats. In a factorial design, weanling Sprague-Dawley rats were assigned to MZ (8 mg/kg diet); zinc-adequate control (CT; 30 mg/kg); zinc-adequate, diet-restricted (DR; 30 mg/kg); or SZ (300 mg/kg) groups, with and without lead acetate-containing drinking water (200 mg Pb/l) for 3 weeks. Excised femurs were analyzed for bone mineral density (BMD) by dual-energy x-ray absorptiometry, morphometry, and mineral content. MZ had higher femur lead and lower femur zinc concentrations and impaired skeletal growth and mineralization than CT. DR inhibited growth but did not result in higher femur lead concentrations than CT. SZ had higher femur zinc and lower femur lead concentrations than the other treatments. DR and SZ had impaired BMD versus CT and MZ. Lead also retarded skeletal growth and impaired BMD, but an interaction between lead and MZ was only found for femoral knee width, which was lower in MZ exposed to lead. In summary, while MZ deficiency exacerbated bone lead concentration, it generally did not intensify lead toxicity. SZ was protective against bone lead but was detrimental to BMD, suggesting that the optimal level of SZ to reduce lead absorption, while supporting growth and bone development, requires further investigation.

Animals↗