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PubMed1983

How adequate is plasma zinc as an indicator of zinc status?

Determination of plasma zinc is the most widely used parameter for assessing the body status of this trace element. Plasma zinc levels are influenced by a wide variety of conditions, including infections and other factors causing stress. Low plasma zinc levels are not always indicative of zinc deficiency. Liver zinc is a much better parameter than plasma zinc for assessing subclinical deficiencies induced by dietary factors or disease. When the plasma zinc level is reduced, there is a reciprocal increase in plasma copper, and as such the copper:zinc ratio in plasma may reflect the temporary shift in plasma zinc. Whenever possible, plasma zinc level determinations should be complemented with zinc concentration determinations in a nucleated tissue, such as liver, muscle or bone. Zinc-dependent enzymes may not always reflect the status of the element in the body. In summary, then, plasma levels of zinc alone cannot be regarded as definitive evidence for assessing the body status or deficiency states of zinc.

Diet↗

PubMed1997

Manipulations of zinc in the spinal cord, by intrathecal injection of zinc chloride, disodium-calcium-EDTA, or dipicolinic acid, alter nociceptive activity in mice.

Zinc is concentrated in the dorsal horn of the spinal cord and has been proposed to alter excitability of primary afferent C-fibers, structures believed to be important in nociceptive transmission. Based on the inhibitory effect of zinc on the activity of various other neurotransmitters that play a role in nociception, we tested the hypothesis that zinc modulates pain transmission. To test this, we examined the effect of exogenous zinc, administered intrathecally (i.t.), on nociception in the mouse. We also assessed the impact of decreased concentrations of endogenously occurring zinc in the extracellular fluid brought about by an i.t. injection of either ethylenediaminetetraacetic acid disodium-calcium salt (Ca++EDTA), a calcium-saturated, membrane-impermeable chelator of divalent cations, or of dipicolinic acid, a zinc chelator. Injection of zinc produced a dose-related antinociceptive effect, optimal at 90 min in the writhing assay, but had no effect on tail-flick response latencies. In contrast, injection of either Ca++EDTA or dipicolinic acid produced a dose-related hyperalgesia in the tail-flick assay at 90 min after injection. Responses induced in the writhing assay were unaffected by Ca++EDTA. Although zinc had no effect on thermal nociception, the hyperalgesic effect of Ca++EDTA was antagonized by coadministration of Ca++EDTA with zinc. Similarly, the antinociceptive effect of zinc on writhing responses was attenuated when coadministered with Ca++EDTA. Zinc also inhibited primary afferent C-fiber activity because 10 ng of zinc i.t. inhibited the behavioral response induced by injection i.t. of 1 nmol of capsaicin. Neither zinc nor Ca++EDTA altered writhing or tail-flick latencies, respectively, when injected intracerebroventricularly. These findings support the hypothesis that endogenous zinc, localized in the dorsal horn of the spinal cord, plays a role in the regulation of pain.

Analgesics↗

PubMed2004

Zinc absorption as a function of the dose of zinc sulfate in aqueous solution.

BACKGROUND: Zinc supplements are used extensively in medicine and research and for public health purposes in the prevention and treatment of zinc deficiency. However, little is known about the efficiency of zinc utilization after different doses. OBJECTIVE: The objective was to determine the relation between dose of aqueous zinc and absorbed zinc (AZ) in healthy adults. DESIGN: Eight healthy adults (3 men and 5 women) aged 33.8 +/- 9.8 y (x +/- SD) received 3 pairs of zinc doses (2 and 5, 10 and 15, and 20 and 30 mg) in random order in 3 phases (1 pair per phase). There was a 3-wk washout between phases. Aqueous zinc sulfate labeled with 70Zn or 68Zn was orally administered in the postabsorptive state on days 1 and 6, respectively; intravenous 67Zn was administered 1 h after the first oral zinc dose. Two urine samples were collected daily from days 3 to 15; zinc isotopic ratios were determined by inductively coupled plasma mass spectrometry. Fractional absorption of zinc (FAZ) was determined by dual-isotope-tracer ratio; AZ was calculated by multiplying FAZ by dose. RESULTS: Mean (+/-SD) AZ values at doses of 2.2, 5.2, 10.4, 15.2, 20.3, and 30.1 mg ingested Zn were 1.6 +/- 0.4, 3.5 +/- 1.3, 7.4 +/- 1.0, 9.5 +/- 2.2, 11.0 +/- 4.4, and 11.2 +/- 2.1 mg, respectively. A saturable dose-response model, the Hill equation, was selected to model the relation of AZ to ingested zinc. Parameter estimation by nonlinear regression predicted a maximum zinc absorption of 13 mg for larger doses. CONCLUSIONS: Increases in aqueous zinc doses >20 mg result in relatively small and progressively diminishing increases in AZ postabsorptively in healthy adults.

Absorption↗

PubMed2005

Zinc coordination environments in proteins determine zinc functions.

Estimates of the number of zinc proteins in humans are now possible and a functional annotation of the zinc proteome can begin. The catalytic and structural roles of zinc in hundreds of enzymes and thousands of so-called "zinc finger" protein domains have provided a molecular basis for the numerous biological functions of this essential element. Additional, regulatory functions of zinc/protein interactions are being recognized. They include roles of the zinc ion in signal transduction, in controlling the architecture of protein complexes, and in redox-active zinc sites, where the binding and release of zinc is under redox control. Moreover, a considerable number of proteins participate in cellular zinc homeostasis, e.g. membrane transporters, and cellular storage, sensor, and trafficking proteins. These proteins have evolved with mechanisms to handle zinc ions rather specifically and selectively. They perform their functions with a remarkably modest set: One redox state of the zinc ion and nitrogen, oxygen, and sulfur ligands from the side chains of histidine, glutamate/aspartate, and cysteine, respectively. By permutation of the ligands in this set, the functional potential of the zinc ion has been fully explored. Different coordination environments modulate the chemical characteristics of the zinc ion, control the kinetics of its binding, and allow it to be either metabolically active or inert. Insights into all these functions are building an understanding of why zinc is so critical for such a multitude of life processes.

Gene Expression Regulation↗

PubMed1996

Solution structure of a naturally-occurring zinc-peptide complex demonstrates that the N-terminal zinc-binding module of the Lasp-1 LIM domain is an independent folding unit.

The three-dimensional solution structure of the 1:1 complex between the synthetic peptide ZF-1 and zinc was determined by 1H NMR spectroscopy. The peptide, initially isolated from pig intestines, is identical in sequence to the 30 N-terminal amino acid residues of the human protein Lasp-1 belonging to the LIM domain protein family. The final set of 20 energy-refined NMR conformers has an average rmsd relative to the mean structure of 0.55 A for the backbone atoms of residues 3-30. Calculations without zinc atom constraints unambiguously identified Cys 5, Cys 8, His 26, and Cys 29 as the zinc-coordinating residues. LIM domains consist of two sequential zinc-binding modules and the NMR structure of the ZF-1-zinc complex is the first example of a structure of an isolated module. Comparison with the known structures of the N-terminal zinc-binding modules of both the second LIM domain of chicken CRP and rat CRIP with which ZF-1 shares 50% and 43% sequence identity, respectively, supports the notion that the zinc-binding modules of the LIM domain have a conserved structural motif and identifies local regions of structural diversity. The similarities include conserved zinc-coordinating residues, a rubredoxin knuckle involving Cys 5 and Cys 8, and the coordination of the zinc ion by histidine N delta in contrast to the more usual coordination by N epsilon observed for other zinc-finger domains. The present structure determination of the ZF-1-zinc complex establishes the N-terminal half of a LIM domain as an independent folding unit. The structural similarities of N- and C-terminal zinc-binding modules of the LIM domains, despite limited sequence identity, lead to the proposal of a single zinc-binding motif in LIM domains. The coordinates are available from the Brookhaven protein data bank, entry 1ZFO.

Adaptor Proteins, Signal Transducing↗

PubMed2000

A dual role for zinc fingers in both DNA binding and zinc sensing by the Zap1 transcriptional activator.

The Zap1 transcriptional activator of Saccharomyces cerevisiae controls zinc homeostasis. Zap1 induces target gene expression in zinc-limited cells and is repressed by high zinc. One such target gene is ZAP1 itself. In this report, we examine how zinc regulates Zap1 function. First, we show that transcriptional autoregulation of Zap1 is a minor component of zinc responsiveness; most regulation of Zap1 activity occurs post-translationally. Secondly, nuclear localization of Zap1 does not change in response to zinc, suggesting that zinc regulates DNA binding and/or activation domain function. To understand how Zap1 responds to zinc, we performed a functional dissection of the protein. Zap1 contains two activation domains. DNA-binding activity is conferred by five C-terminal C(2)H(2) zinc fingers and each finger is required for high-affinity DNA binding. The zinc-responsive domain of Zap1 also maps to the C-terminal zinc fingers. Furthermore, mutations that disrupt some of these fingers cause constitutive activity of a bifunctional Gal4 DNA-binding domain-Zap1 fusion protein. These results demonstrate a novel function of Zap1 zinc fingers in zinc sensing as well as DNA binding.

Cell Nucleus↗

PubMed1985

The effect of topical zinc absorption from wounds on growth and the wound healing process in zinc-deficient rats.

An experiment with local application of zinc oxide from a zinc tape to wounds was performed on 80 male Sprague-Dawley rats. Tapes with or without zinc oxide were applied on excisional wounds of both zinc-deficient and zinc-sufficient animals. The reduction in wound area was more pronounced in zinc-tape-treated animals given both a zinc-deficient and zinc-sufficient diet. The operative trauma had a negative effect on the animals' growth rate, although the state of zinc deficiency in the operated rats could be relieved by the local application of zinc. The results of the present study indicate that topically absorbed zinc from wounds promotes both the early wound healing phase and growth in both zinc-deficient and zinc-sufficient rats.

Administration, Topical↗

PubMed2006

Zinc supplementation and serum zinc during diarrhea.

OBJECTIVE: Zinc deficiency is very common in developing countries and is more pronounced during an episode of diarrhea. Supplementation with zinc improves diarrhea and might correct zinc deficiency in both the short and longer term. METHOD: We conducted a nested study within a cluster randomized treatment trial. Fifty children with diarrhea living in the zinc treated clusters, 50 children with diarrhea living in control clusters, and 50 healthy children living in the control clusters were enrolled. We assessed serum zinc at the start of the diarrhea episode, which was 1-3 days after supplementation began in zinc treated children, and again one week after the diarrhea ended and supplementation ceased. Baseline characteristics and serum zinc concentration were assessed. RESULTS: Serum zinc was low in 44% of healthy children at the first blood draw. Compared to healthy controls, serum zinc was 3.1 mmol/L higher among children with diarrhea who were supplemented with zinc at first blood draw and 1.3 mmol/L higher 3 weeks later. CONCLUSION: Zinc supplementation enhances serum zinc concentration when given as a treatment for diarrhea and helps children maintain a more adequate zinc status during the convalescent period.

Child, Preschool↗

PubMed1990

Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in the El (epilepsy) mouse.

The effects of dietary zinc status on the development of convulsive seizures, and zinc concentrations in discrete hippocampal areas and other parts of the limbic system were studied in the El mouse model receiving zinc-adequate, zinc-deficient or zinc-loaded diets. Seizure susceptibility of the El mouse was increased by zinc deficiency, and decreased by zinc loading, while an adequate diet had no effect. Zinc loading was accompanied by a marked increase in hippocampal zinc content in the El mouse. Conversely, hippocampal zinc content declined in the El mouse fed a zinc-deficient diet. These results suggest that zinc may have a preventive effect on the development of seizures in the El mouse, and hippocampal zinc may play an important role in the pathophysiology of convulsive seizures of epilepsy.

Animals↗

PubMed1986

Pancreatic acinar cell function and morphology in rats fed zinc-deficient and marginal zinc-deficient diets.

The prevalence of marginal zinc nutriture in several populations of people in this country and the lack of reports on the effect of marginal zinc nutriture in experimental animals prompted us to look at pancreatic acinar cell function and morphology in rats fed a zinc-deficient diet ad libitum: 4 and 50 ppm zinc-supplemented diets in amounts isocaloric to a zinc-deficient diet and Rodent-Blox fed ad libitum for a period of 49 +/- 1 (SEM) days. Because of a diminished rate of energy expenditure in zinc-deficient rats, animals receiving 50 ppm zinc-supplemented diets were offered less food, resulting in decreased body weight and pancreas weight, DNA, RNA, total protein, lipase, amylase, and secretion of protein. Specific changes due to zinc deficiency included (a) further decrease in body weight and (b) increase in content, specific activity, and secretion of lipase. Both the size and volume fraction of zymogen granules were reduced in zinc deficiency. The lumina of acinar and small ducts were collapsed with paucity of secretion products. Zinc deficiency may therefore lead to a defect in discharge mechanism. A further reduction in volume fraction of zymogen granules in the 4 ppm zinc-supplemented group was associated with increased secretion of serine proteases (trypsinogen and chymotrypsinogen), which constitute approximately 46% of total secretory protein in the pancreas under normal dietary conditions. This indicated an accelerated discharge due to an unknown mechanism. Changes in the secretion of digestive enzymes in the present study simulated ethanol-induced secretory alterations that were previously observed. Because abnormal zinc nutriture and chronic alcoholism are commonly associated, it is speculated that zinc deficiency may play a role in the ethanol-induced secretory alterations.

Amylases↗

PubMed1992

Neurons of origin of zinc-containing pathways and the distribution of zinc-containing boutons in the hippocampal region of the rat.

Recent methods allow the study of neurons that contain zinc in synaptic vesicles of their boutons (Timm-stainable boutons) by the intravital precipitation (local or throughout the CNS) of the vesicular zinc with selenium compounds and its subsequent retrograde transport to the parent neurons, where the precipitate can be silver enhanced. The present study is a description of the distribution of zinc-containing neurons, their possible connections and their terminal fields within the hippocampal region of the rat. Problems inherent to the methods are addressed. Finally, based on the results and a review of literature, the possible function of zinc in the hippocampal region is considered. Neurons which contain silver-enhanced precipitates were observed in layers II, V and VI of the lateral entorhinal area and in layers V and VI of the medial entorhinal area. In the parasubiculum, labeled cells were seen in layer II/III of the parasubiculum a and in layer V. Labeled cells in the presubiculum were concentrated in layers III and V, in the hippocampal pyramidal cell layer and the dentate granule cell layer, but neurons containing precipitates were largely absent from the subiculum. Zinc-containing axonal boutons defined subpopulations within principal hippocampal neuron populations. Within layer II of the lateral entorhinal cortex and the pyramidal cell layer for regio inferior deeply situated neurons were labeled, whereas superficially placed pyramidal cells were labeled in regio superior. The neuropil staining described in the present study corresponded to that found in earlier studies. However, glial and vascular staining or unspecific background were largely absent, and the neuropil staining could unequivocally be identified light microscopically. Methodological problems are most prominently reflected in unstained mossy fibers in some animals. Based on series from animals treated with decreasing doses of sodium selenite and increased survival times, this problem can be related to small amounts of circulating reactive selenium and a competition of zinc compartments (vesicles) for the selenium. Staining will fail where the competition prevents individual compartments from reaching a threshold amount of zinc precipitate for silver amplification. A guide to evaluate histological material is provided. The distribution of zinc-containing boutons and their cells of origin indicate that zinc-containing and zinc-negative projections are not organized as parallel pathways. The mossy fibers provide an example of a pure zinc-containing pathway. Projections from regio superior to the dorsal presubiculum are likely to be zinc-negative while projections from the same area to the subiculum are zinc-containing.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2005

Modulation of aconitase, metallothionein, and oxidative stress in zinc-deficient rat intestine during zinc and iron repletion.

Potential interactions between zinc and iron during absorption and its functional consequences on intestinal oxidative damage and antioxidant status were studied using the zinc-deficient rat as a model. Zinc depletion produced mild-moderate iron deficiency in addition to zinc deficiency, which could be corrected by repletion with iron and zinc. The localization and intensity of both iron and zinc in the intestinal mucosa showed a pronounced decrease in the presence of the other metal, indicating negative interactions. Zinc-deficient intestine exposed to iron alone exhibited elevated peroxidative damage and compromised functional integrity, despite increased expression of ferritin. Inclusion of zinc significantly reduced the damage and improved the functional integrity, accompanied by decreased expression of ferritin. Decreased expression of ferritin in the presence of zinc was consistent with reduced aconitase activity, suggesting its modulation by zinc. Further, inclusion of iron along with zinc was associated with induction of ferritin and metallothionein in tune with the amount of iron and zinc localized in the intestinal mucosa, respectively. These results suggest that zinc and iron interact negatively with cytosolic aconitase, but prove beneficial in reducing the oxidative stress, apart from improving functional integrity and iron/zinc status.

Aconitate Hydratase↗

PubMedDate not supplied

Zinc coordination sphere in biochemical zinc sites.

Zinc is known to be indispensable to growth and development and transmission of the genetic message. It does this through a remarkable mosaic of zinc binding motifs that orchestrate all aspects of metabolism. There are now nearly 200 three dimensional structures for zinc proteins, representing all six classes of enzymes and covering a wide range of phyla and species. These structures provide standards of reference for the identity and nature of zinc ligands in other proteins for which only the primary structure is known. Three primary types of zinc sites are apparent from examination of these structures: structural, catalytic and cocatalytic. The most common amino acids that supply ligands to these sites are His, Glu, Asp and Cys. In catalytic sites zinc generally forms complexes with water and any three nitrogen, oxygen and sulfur donors with His being the predominant amino acid chosen. Water is always a ligand to such sites. Structural zinc sites have four protein ligands and no bound water molecule. Cys is the preferred ligand in such sites. Cocatalytic sites contain two or three metals in close proximity with two of the metals bridged by a side chain moiety of a single amino acid residue, such as Asp, Glu or His and sometimes a water molecule. Asp and His are the preferred amino acids for these sites. No Cys ligands are found in such sites. The scaffolding of the zinc sites is also important to the function and reactivity of the bound metal. The influence of zinc on quaternary protein structure has led to the identification of a fourth type of zinc binding site, protein inteface. In this case zinc sites are formed from ligands supplied from amino acid residues residing in the binding surface of two proteins. The resulting zinc site usually has the coordination properties of a catalytic or structural zinc binding site.

Animals↗

PubMed2004

Protection against zinc toxicity by metallothionein and zinc transporter 1.

Cells protect themselves from zinc toxicity by inducing proteins such as metallothionein (MT) that bind it tightly, by sequestering it in organelles, or by exporting it. In this study, the interplay between zinc binding by MT and its efflux by zinc transporter 1 (ZnT1) was examined genetically. Inactivation of the Znt1 gene in baby hamster kidney (BHK) cells that do not express their Mt genes results in a zinc-sensitive phenotype and a high level of "free" zinc. Restoration of Mt gene expression increases resistance to zinc toxicity approximately 4-fold, but only slightly reduces free zinc levels. Expression of ZnT1 provides greater protection (approximately 7-fold) and lowers free zinc substantially. Selection for zinc resistance in BHK cells that cannot synthesize either MT or ZnT1 is ineffective. However, parental BHK cells that grow in high concentrations (>500 microM) of zinc can be selected; these cells have amplified their endogenous Znt1 genes. The Znt1 gene is also amplified in zinc-resistant mouse cells that cannot induce their Mt genes. However, if Mt genes can be expressed, then they are preferentially amplified. Thus, both ZnT1 and MT genes contribute to zinc resistance in BHK cells, whereas ZnT1 plays a larger role in regulating free zinc levels.

Animals↗

PubMed2004

Zinc-stimulated endocytosis controls activity of the mouse ZIP1 and ZIP3 zinc uptake transporters.

The mouse mZip1 and mZip3 zinc transporters have been implicated in zinc acquisition by the cells of many tissues. This hypothesis raised the question of whether activity of these proteins is regulated to maintain zinc homeostasis. Neither mZIP1 nor mZIP3 mRNA levels are highly regulated by zinc status. Therefore, we investigated whether zinc controls the activity of these proteins post-translationally by altering their subcellular distribution. When expressed in transfected cells grown in zinc-replete medium, both mZip1 and mZip3 were largely present in intracellular organelles. However, these proteins were found to rapidly transit between the plasma membrane and intracellular compartments in zinc-replete cells. Zinc deficiency increased plasma membrane levels of mZip1 and mZip3 by decreasing their rates of endocytosis. Greater zinc deficiency was required to alter mZip3 distribution than was needed to affect mZip1. Increased surface levels correlated with increased zinc uptake activity. Taken together, these results suggest that post-translational control of mZip1 and mZip3 localization plays a role in zinc homeostasis. Moreover, our results indicate that zinc-responsive endocytosis is a conserved mechanism controlling activity of many mammalian zinc uptake transporters.

Animals↗

PubMed2007

A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity.

Zinc is an essential nutrient. Genetic evidence for this nutritional requirement in humans is the zinc deficiency disease, acrodermatitis enteropathica. This disorder is caused by mutations in hZIP4 (SLC39A4), a zinc importer required for zinc uptake in enterocytes and other cell types. Studies in mice have demonstrated that levels of the mZIP4 mRNA are reduced by elevated dietary zinc, resulting in a decreased abundance of the ZIP4 protein at the plasma membrane. Moreover, studies in cultured cells have demonstrated that low micromolar concentrations of zinc stimulate the endocytosis of the mZIP4 protein resulting in a reduction in cellular zinc uptake. In this study, we demonstrate an additional level of hZIP4 regulation involving ubiquitination and degradation of this transporter in elevated zinc concentrations. Mutational analysis identified a cytoplasmic histidine-rich domain that was essential for ubiquitin-dependent degradation of ZIP4 and protection against zinc toxicity. However, this motif was dispensable for zinc-induced endocytosis. These findings indicate that ubiquitin-mediated degradation of the ZIP4 protein is critical for regulating zinc homeostasis in response to the upper tier of physiological zinc concentrations, via a process that is distinct from zinc-stimulated endocytosis.

Cation Transport Proteins↗

PubMed1979

Zinc retention and losses of zinc in sweat by preadolescent girls.

Preadolescent girls, ages 7 to 9 years, were fed levels of zinc ranging from 5.61 to 14.61 mg/day during an 18-day metabolic study. All other nutrients were provided at or above Recommended Dietary Allowance levels. The sweat loss of zinc was measured using an arm-bag method and whole body zinc loss was calculated from whole body nitrogen and arm loss of nitrogen and zinc. Fecal zinc reflected dietary zinc, but urinary zinc remained relatively stable. The mean daily loss of zinc through sweat was calculated to be 1.43 mg. Zinc retentions were not significantly different (P greater than 0.05) though the retention increased generally with intake of zinc. A comparison of these data with previously reported studies indicated that the absorption of zinc was usually in the range of 20 to 30%. Based on sweat losses reported by others and found in this study and on usual absorption of zinc, it appears that diets should provide a minimum of 7 mg of zinc daily for growing children.

Child↗

PubMed1980

Alterations in zinc absorption and salivary sediment zinc after a lacto-ovo-vegetarian diet.

The effect of a lacto-ovo-vegetarian diet on plasma zinc tolerance tests and plasma and saliva zinc levels was measured in 12 nonvegetarian women. A diet meeting the Recommended Dietary Allowances for all nutrients, including zinc, was fed to the subjects for 22 days. Initial zinc status of subjects was determined by zinc analysis of their diet, hair, plasma, and saliva. Plasma response to an oral load of 50 mg Zn was determined in five subjects before and after the dietary period. Zinc levels of salivary sediment, which consisted primarily of epithelial cells, significantly decreased from initial values of 128 to final levels, of 94 microgram/g. No significant differences were found in zinc levels of plasma or whole mixed saliva. Plasma response to initial zinc tolerance tests were inversely correlated (P < 0.05) to dietary protein levels. Significantly increased plasma zinc uptake and areas under zinc tolerance curves were found after consumption of vegetarian diets compared to diets containing meats. The increased plasma response to a zinc load and decrease in salivary sediment zinc after a vegetarian diet indicate that this diet adversely affects zinc status.

Adult↗