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PubMed1994

Localization of copper to afferent terminals in rat locus ceruleus, in contrast to mitochondrial copper in cerebellum.

We examined copper localization in the locus ceruleus and cerebellum of rat brain by Timm's sulfide-silver staining, as modified by Danscher. Dense silver particles revealing copper localization were observed in sections of the locus ceruleus and cerebellum after pre-treatment with trichloroacetic acid. In the locus ceruleus, copper appeared to be distributed to neuropil rather than glial or neuronal cell bodies, and at the ultrastructural level copper was mainly localized on synaptic membranes of afferent terminals in contact with somatic spines or dendrites of locus ceruleus neurons, whereas copper was distributed to mitochondria in the granular layers of cerebellum and fine, sparse silver particles were observed throughout ependymal cells and epithelial cells of blood vessels. The specific localization of copper to afferent terminals in the locus ceruleus was confirmed by X-ray microanalysis, which showed a significant level of copper, but not zinc, in synaptic membranes. These results suggest a distinct role of copper depending on its regional distribution. Copper or copper protein may be involved in neurotransmission in the locus ceruleus but in mitochondrial activity in the cerebellum.

Animals↗

PubMed2001

High arsenic intake raises kidney copper and lowers plasma copper concentrations in rats.

The effect of high arsenic intake on copper metabolism was investigated. Male rats aged 6 wk had free access to purified diets containing either 0 or 100 mg As/kg diet and demineralized water for a period of 2 wk. Arsenic was added to the diet in the form of NaAsO2. The high-arsenic diet decreased feed and water intake and body weight gain, but significantly increased liver weight. Kidney weight was not affected. Arsenic feeding drastically elevated kidney copper concentration, but significantly reduced copper concentration in plasma. Both true absorption and biliary excretion of copper were decreased significantly in rats fed the high-arsenic diet. True copper absorption was lowered essentially through the lower copper intake in the rats fed arsenic. It is speculated that arsenic feeding primarily leads to copper accumulation in the kidney, followed by a decrease in feed intake and thus in true, absolute copper absorption, a decrease in plasma copper concentration, and a decrease in biliary copper excretion.

Animals↗

PubMed1999

Determination of the extent of excessive copper concentrations in the tap-water of households with copper pipes and an assessment of possible health hazards for infants.

During the past 20 years there has been much discussion about copper in connection with a form of Early Childhood Liver Cirrhosis (ECLC) known as Non Indian Childhood Cirrhosis (NICC). NICC is similar to Indian Childhood Cirrhosis (ICC) which occurs in India, and has already been known for many years. ICC is attributed to the excessive intake of copper derived from milk or water stored in copper and brass vessels. To determine precisely a possible connection between the amount of copper in tap-water and the risk of early childhood liver disease, an attempt was first made, through an epidemiological survey, to determine the extent of excessive concentrations of copper in the tap-water of households with copper pipes. To achieve this, water samples from 956 households were tested for copper, and the state of health of the infants in these households was documented. Infants who had been fed using water with a copper concentration of 0.8 mg/l or more received a paediatric examination with a blood check so as to rule out any possibility of liver damage. A copper level greater than 0.8 mg/l was found in only 2% of the households examined. Eight infants were examined by a paediatrician and received blood checks. (These infants had either been breast-fed up until their 12th week or had received more than 200 ml of tap water per day during their first 12 months). None of the infants examined showed any signs of liver malfunction. From the results of the study, no indication of a hazard due to copper pipes connected to public water supplies could be found.

Copper↗

PubMed2002

Effect of soil copper content and pH on copper uptake of selected vegetables grown under controlled conditions.

A one-year greenhouse experiment was conducted to study the transfer of copper from contaminated agricultural soils to edible and nonedible structures of lettuce, tomato, and onion plants. Study soils were selected from two basins of central Chile (Santiago and Cachapoal) to represent two similar total soil copper gradients with different pH values. Results showed that free ionic Cu and Cu in saturation extracts were very low in comparison to total Cu contents of study soils (<0.002% and <0.04%, respectively). The concentrations of free ionic copper and of copper in saturation extracts were correlated to total Cu levels and to soil pH. Mean copper concentrations were higher in lettuce than in tomato and onion plants and in vegetables grown on acidic soils of the Cachapoal basin. However, copper levels in edible tissues of tomato and lettuce plants were similar to copper levels described for plants grown on unpolluted soils except for onion bulbs, which had higher values. This indicates that copper translocation to edible, above-ground structures seemed to be well regulated, as their concentrations were fairly constant. The study shows that Cu concentration in study vegetables depends on various factors, including plant species and tissue; site-specific soil factors, such as pH, organic matter, dissolved organic carbon, and conductivity; and several Cu pools, such as total, extractable, and free ionic Cu. Thus, our results support the intensity/capacity concept in that Cu concentration in plants or plant tissues depends not only on the availability of free copper ions in soil solution but also on other soil copper pools that supply the element to the soil solution.

Agriculture↗

PubMed1988

Role of copper and catalytic mechanism in the copper monooxygenase, dopamine beta-hydroxylase (D beta H).

Although classically characterized as a Type II copper protein, recent work has shown that D beta H requires two coppers per subunit for optimal activity. A major challenge has been to elucidate the relationship of these copper sites to one another, specifically whether there exists a single binuclear copper site or distinct metal sites catalyzing separate functions. In this paper, copper sites have been investigated by EPR techniques and rapid mixing methods to measure the rates and stoichiometries of copper reduction by ascorbate and subsequent reoxidation by tyramine. As shown, there is little or no evidence by EPR for spin coupling between metal sites in resting enzyme. Both coppers per subunit undergo reduction and reoxidation with single exponential values of 185 s-1 and 80 s-1, respectively. Significantly, the ratio of copper reoxidation to product formation in a single turnover is close to 2:1, implicating both coppers in the catalytic mechanism and ruling out any significant spin coupling in the enzyme-product complex. In contrast to single turnover experiments, rapid kinetics in the presence of excess ascorbate reveal a very low level of E-Cu (II). This result, which appears to conflict with evidence that the dominant enzyme form in the steady state is E-P, leads us to propose a reduction of enzyme at the level of E-P rather than free enzyme. Taken together with steady state kinetic parameters using alternate reductants, the data support separate binding sites for reductants and product/substrate and hence, separate functions for each copper per subunit. A detailed catalytic mechanism for D beta H is discussed in the context of a single metal site catalyzing dopamine hydroxylation.

Binding Sites↗

PubMed1999

Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis.

The delivery of copper to specific sites within the cell is mediated by distinct intracellular carrier proteins termed copper chaperones. Previous studies in Saccharomyces cerevisiae suggested that the human copper chaperone HAH1 may play a role in copper trafficking to the secretory pathway of the cell. In this current study, HAH1 was detected in lysates from multiple human cell lines and tissues as a single-chain protein distributed throughout the cytoplasm and nucleus. Studies with a glutathione S-transferase-HAH1 fusion protein demonstrated direct protein-protein interaction between HAH1 and the Wilson disease protein, which required the cysteine copper ligands in the amino terminus of HAH1. Consistent with these in vitro observations, coimmunoprecipitation experiments revealed that HAH1 interacts with both the Wilson and Menkes proteins in vivo and that this interaction depends on available copper. When these studies were repeated utilizing three disease-associated mutations in the amino terminus of the Wilson protein, a marked diminution in HAH1 interaction was observed, suggesting that impaired copper delivery by HAH1 constitutes the molecular basis of Wilson disease in patients harboring these mutations. Taken together, these data provide a mechanism for the function of HAH1 as a copper chaperone in mammalian cells and demonstrate that this protein is essential for copper homeostasis.

Adenosine Triphosphatases↗

PubMed1996

Copper, Zinc, and Cadmium Concentrations in Peromyscus maniculatus Sampled Near an Abandoned Copper Mine

Concentrations of zinc, copper, and cadmium were determined in soil and liver, kidney, bone and stomach contents of deer mice (Peromyscus maniculatus) from two sites near an abandoned mine and one control site, on Vancouver Island, British Columbia, Canada. Soil concentrations of copper were significantly elevated at the mine and off site vs the reference site. In contrast, there was no difference in soil cadmium and zinc concentrations between the mine and reference site. Concentrations of copper, cadmium and zinc in livers of mice from the mine site were significantly elevated relative to the reference and off site locations. Cadmium kidney concentrations tended to be greater in mice from the mine versus the off site and reference site. No differences in bone cadmium, copper and zinc and, kidney copper and zinc concentrations were noted among mice from the three locations. Diet of mice from mine and off sites contained significantly greater copper concentrations than the reference population; no differences in cadmium or zinc diet concentrations in mice from the three sites were noted. Comparison of ratios of metal concentrations in diet:soil and concentrations in liver:soil suggest that for zinc and copper, soil and diet are of equal importance as a source of metal contamination to these mice. In contrast, cadmium diet:soil and cadmium liver:soil ratios were much greater than one indicative of bioconcentration of cadmium from soil to diet and from soil to liver. For assessing routes of metal exposure, in this case for deer mice inhabiting an abandoned mine site, for copper and zinc, soil will most likely be indicative of exposure conditions. In contrast, concentrations of cadmium in diet will be more representative of amounts that the animal is potentially ingesting. Of further importance is that relative to reference sites, mice inhabiting an abandoned copper mine site have significantly elevated tissue levels of copper. This is turn will provide a route of metal exposure to carnivorous birds such as owls and hawks. The toxicological significance of this exposure to birds of prey has yet to be assessed adequately.

Journal Article↗

PubMed1989

Bodyweight and serum copper concentrations of farmed red deer stags following oral copper oxide wire administration.

A diagnosis of secondary copper deficiency was established on a deer farm with a peat soil type, on the basis of confirmed enzootic ataxia in hinds, liver and serum copper concentrations and pasture and soil element analyses. Seventy-four weaner stags were selected for a trial to investigate a growth response to copper supplementation. Thirty-seven red and red x wapiti type stags were treated with 4g copper oxide wire particles at four months of age (April). A further 8g copper oxide wire was given in June. Thirty-seven untreated animals acted as controls. Bodyweights were measured on five occasions, from April 24 to November 26. Serum copper analyses were undertaken on ten deer prior to commencement of the trial, and on seven treated and eight control deer in June, July and October. Serum copper concentrations ranged from 2.0 to 19.3 micromol/l prior to the trial. In June, July and October serum copper ranged from 0.1-6.7, 0.6-5.0, and 1.3-6.3 micromol/l respectively, in control deer. In treated deer concentrations ranged from 7.2-14.7, 5.2-10.8, and 6.9-13.7 micromol/l in June, July and October respectively. The difference between mean copper concentration at each post-treatment sampling date was highly significant, (P<0.001). At the conclusion of the trial (November 26) the treated deer averaged 3.1kg heavier than controls, but this difference was not statistically significant. In view of these results and the variation in growth response trials in other species, further investigation of the effects of copper on the growth of young deer is warranted.

Journal Article↗

PubMedDate not supplied

Copper content in cervical mucus of women wearing plain and copper-bearing spring coils.

To test the hypothesis that the copper in copper-bearing intrauterine devices (IUDs) and its reaction with cervical mucus constitute the agent in preventing conception, the copper content of 300 samples of cervical mucus, 150 each from women wearing plain Spring Coil IUDs and those wearing Spring Coils containing 500 mg of copper, was determined at 3, 6 and 12 months after IUD insertion. Stoner and Dasler's modified spectrophotometric micromethod (Clin Chem 10:845, 1964) was used to quantify the copper content of the cervical mucus. Analysis showed no significant change in the copper content of the cervical mucus of women wearing plain Spring Coils compared to that of women not wearing IUDs; however, the amount of copper in the cervical mucus of women wearing copper-bearing Spring Coils was 5--6 times greater at midcycle 3, 6 and 12 months after insertion. Thus, we conclude that there is an important biologic basis for assuming that copper-bearing Spring Coils can inhibit sperm penetration through the cervical mucus and that they can initiate contraceptive activity at the cervical level.

Adult↗

PubMed1999

The copper chaperone Atox1 in canine copper toxicosis in Bedlington terriers.

Copper toxicosis, resulting in liver disease, commonly occurs in Bedlington terriers. This recessively inherited disorder, similar in many respects to Wilson disease, is of particular interest because the canine Atp7b gene, homologous to ATP7B defective in Wilson disease, is not responsible for canine copper toxicosis as has been expected. Atox1, a copper chaperone delivering copper to Atp7b, therefore became a potential candidate. We cloned canine Atox1, which shows conserved motifs of the copper-binding domain (MTCXXC) and of the lysine-rich region (KTGK), and showed 88, 80, and 41% amino acid sequence identity with the orthologous mouse, human, and yeast proteins. No gross deletions of Atox1 could be identified in the affected Bedlington terriers by Southern blot analysis of genomic DNA. The canine Atox1 gene spans about 4 kb, with a 204-bp open reading frame cDNA contained within two exons. Sequence analysis of the coding regions, including intron/exon boundaries, showed no mutations in Atox1 from genomic DNA of an affected dog. We have also identified an apparently nontranscribed canine Atox1 pseudogene, with 12 sequence changes and no intron. Mapping of Atox1 and a marker closely linked to the canine copper toxicosis locus indicated lack of synteny. Atox1 is therefore excluded as a candidate gene for canine copper toxicosis, indicating that some other unidentified gene must be responsible for this copper storage disease in dogs and also suggesting the possibility of a similar gene responsible for a copper storage disease in humans.

Amino Acid Sequence↗

PubMed1976

The Copper T 220C: a new long-acting copper intrauterine contraceptive device.

The Copper T(TCu) intrauterine contraceptive device (IUD) has been found to be an effective method of contraception but has the disadvantage of needing periodic replacement due to loss of copper through dissolution and fragmentation of the copper wire. Modification of the Copper T to overcome this disadvantage involved substitution of copper sleeves for wire on the vertical arm and the addition of copper sleeves to the horizonal arms to give an effective surface area of 220 sq. mm. of copper and an estimated life span of 20 years. A randomized comparative study was undertaken in 999 women to determine if the new model performed as well as the wire-wound Copper T 300. Net cumulative first-event rates at one year were as follows: TCu 220C-pregnancy 0.9, expulsion 3.7, removal for pain or bleeding 14.4; TCu 300-pregnancy 1.1, expulsion 3.1, removal for pain or bleeding 9.3. None of the differences in event rates were significant. If long-term follow-up confirms these findings, this new long-lasting copper intrauterine device could become the IUD of choice for all women.

Adolescent↗

PubMed2002

Copper-regulated trafficking of the Menkes disease copper ATPase is associated with formation of a phosphorylated catalytic intermediate.

The Menkes protein (MNK; ATP7A) is a copper-transporting P-type ATPase that is defective in the copper deficiency disorder, Menkes disease. MNK is localized in the trans-Golgi network and transports copper to enzymes synthesized within secretory compartments. However, in cells exposed to excessive copper, MNK traffics to the plasma membrane where it functions in copper efflux. A conserved feature of all P-type ATPases is the formation of an acyl-phosphate intermediate, which occurs as part of the catalytic cycle during cation transport. In this study we investigated the effect of mutations within conserved catalytic regions of MNK on intracellular localization and trafficking from the trans-Golgi network (TGN). Our findings suggest that mutations that block formation of the phosphorylated catalytic intermediate also prevent copper-induced relocalization of MNK from the TGN. Furthermore, mutations in the phosphatase domain, which resulted in hyperphosphorylation of MNK, caused constitutive trafficking from the TGN to the plasma membrane. A similar effect on trafficking was observed with a phosphatase mutation in the closely related copper ATPase, ATP7B, affected in Wilson disease. These findings suggest that the copper-induced trafficking of the Menkes and Wilson disease copper ATPases is associated with the phosphorylated intermediate that is formed during the catalysis of these pumps. Our findings describe a novel mechanism for regulating the subcellular location of a transport protein involving the recognition of intermediate conformations during catalysis.

Adenosine Triphosphatases↗

PubMed2003

A copper-regulated transporter required for copper acquisition, pigmentation, and specific stages of development in Drosophila melanogaster.

The trace element copper is required for normal growth and development, serving as an essential catalytic co-factor for enzymes involved in energy generation, oxidative stress protection, neuropeptide maturation, and other fundamental processes. In yeast and mammals copper acquisition occurs through the action of the Ctr1 family of high affinity copper transporters. Here we describe studies using Drosophila melanogaster to investigate the role of copper acquisition through Ctr1 in normal growth and development. Three distinct Drosophila Ctr1 genes (Ctr1A, Ctr1B, and Ctr1C) have been identified, which have unique expression patterns over the course of development. Interestingly, Ctr1B, which is expressed exclusively during the late embryonic and larval stages of development, is transcriptionally activated in response to nutritionally induced copper deprivation and down-regulated in response to copper adequacy. The generation of Ctr1B mutant flies results in decreased larval copper accumulation, marked body pigmentation defects that parallel defects in tyrosinase activity, and specific developmental arrest under conditions of both nutritional copper limitation and excess. These studies establish that copper acquisition through the Drosophila Ctr1B transporter is crucial for normal growth and in early and specific stages of metazoan development.

Amino Acid Motifs↗

PubMed1998

Functional analysis of copper homeostasis in cell culture models: a new perspective on internal copper transport.

The movement of copper ions across membrane barriers of vital organs and tissues is a priority topic in nutrition and one for which there continues to be little understanding of the mechanism. Reports of membrane-bound, copper-transporting adenosine triphosphatases (Cu-ATPases) selective for copper ions have brought new focus to the problem and prompted fresh ideas. Using a cell culture model approach, we attempted to learn whether transport into and out of cells depends on a Cu-ATPase. Measurement of transport kinetics in fibroblasts, brain glial cells, neuroblastoma cells, and placental cells showed differences in the rates of copper uptake and response to sulfhydryl reagents. BeWo cells, a human choriocarcinoma placental cell line, behaved as did Menkes fibroblasts by avidly absorbing copper but not releasing copper to the immediate environment. Further tests showed that BeWo cells did not express the transcript for the membrane-bound Cu-ATPase that has been identified with Menkes syndrome. Transcript induction, however, was achieved by growing BeWo cells on porous filters that allowed apical and basolateral surfaces to form. With transcript expression, the cells showed a capacity to release copper into the medium. BeWo cells also synthesized a form of ceruloplasmin whose structure differed from that of the plasma protein and hence may be a product of a different gene. BeWo cells may also express the gene for Wilson disease, thus linking Menkes and Wilson proteins to maternal delivery of copper. We constructed a model in which both ATPases work in concert in a vesicle-based transport mechanism. The vesicle model may help us understand the transport of copper across the placenta and all cells in general.

Adenosine Triphosphatases↗

PubMed1985

Effect of intra-epididymal injection of copper particles on fertility, spermatogenesis, and tissue copper levels in rats.

In male rats, a single injection of 10 mg metallic copper particles in oil into each caput epididymidis induced infertility, whilst leaving mating behaviour and blood testosterone levels unchanged. Fertility tended to recover 5.5 months after the copper treatment. Although the copper content of the caput epididymidis reached a level of around 100 times higher than control values, the serum copper concentration did not rise significantly. This finding and the observation that treated animals gained weight as fast as the controls suggest a low systemic toxicity of this method. The testicular copper concentration was significantly higher than that in controls and different degrees of damage, including vacuolation, karyorrhexis, pyknosis, and cytolysis, were seen mainly in pachytene spermatocytes and early spermatids. Clumps of foreign particles, apparently metallic copper, were found in the interstices of the caput epididymidis together with degenerative changes in the epithelial cells of the caput, suggesting a possible effect of copper on the epididymal epithelium. The viability of epididymal sperm decreased more markedly than the decrease in sperm density. It is therefore most likely that the major cause of infertility after copper injection into the caput epididymidis is a direct inhibitory effect of copper on the sperm, whilst damage to the seminiferous and epididymal epithelial may contribute.

Animals↗

PubMed1996

Identification of SLF1 as a new copper homeostasis gene involved in copper sulfide mineralization in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, at least 12 genes are important for cells to propagate in medium containing elevated concentrations of copper salts (J. Welch, S. Fogel, C. Buchman, and M. Karin, EMBO J. 8:255-260, 1989). Complementation studies were carried out on a copper-sensitive mutation (cup14) from this group. A new yeast gene, designated SLF1, was identified as a multicopy suppressor of the cup14 mutation. Slf1 is important for the physiological process of copper sulfide (CuS) mineralization on the surface of cells cultured in medium containing copper salts. CuS mineralization causes the cells to turn brown. Disruption of SLF1, which is located close to the telomere region of chromosome IV, leads to limited copper sensitivity, and the resulting cells lack the normal brownish coloration when grown in CuSO4-containing medium. Overproduction of Slf1 in wild-type cells confers superresistance to CuSO4 and enhances the coloration of cells cultured in the presence of CuSO4. Upon addition of KCN to Cu-grown cells, the brownish coloration was bleached instantly, and copper ions were solubilized. These data are consistent with Slf1-dependent accumulation of CuS complexes on the cell surface. Disruption of SFL1 also results in loss of the ability of yeast cells to deplete Cu but not Cd ions from the growth medium, whereas overexpression enhances Ca depletion ability and the resulting deposition of CuS particles. It is proposed that Slfl participates in a copper homeostasis pathway, distinct from the Cup1 detoxification system, that leads to sulfide generation and CuS biomineralization on the cell surface. This process may coordinate with the Cup1 pathway at different copper concentrations to prevent copper-induced toxicity.

Amino Acid Sequence↗

PubMed1990

Histochemical and immunocytochemical evaluation of copper and metallothionein in the liver and kidney of copper-loaded rats.

Histochemical methods do not always show a good correlation with analytical measurement of copper content and consequently immunoreactive staining techniques for metallothionein (MT) have recently been employed for the differential diagnosis of copper-associated diseases. This study compares histochemical with immunocytochemical methods for the assessment of copper status. Male rats were fed a high copper (1 g/kg) diet for 16 weeks and killed sequentially during this period. The livers and kidneys were analysed for copper and zinc (atomic absorption spectrophotometry), and sections were stained with rubeanic acid and rhodanine for copper and for immunoreactive MT using the DNP localization system. Immunoreactive stains for MT corresponded better with copper content than histochemical stains and were more sensitive, albeit less selective, indicators of copper accumulation. Moreover, major differences in intracellular staining were apparent between the two methods, attributed to differences in copper binding and microcompartmentalization of metal.

Animals↗

PubMed1998

Suppression of copper-induced cellular damage by copper sequestration with S100b protein.

We previously reported that S100b protein (homodimer of S100 beta subunit) can bind copper ions with a submicromolar dissociation constant (T. Nishikawa et al., J. Biol. Chem. 272, 23037-23041, 1997). In this study, a question was addressed as to whether this protein can sequester copper ions in an in vivo situation. Escherichia coli cells that had been rendered able to produce a fusion protein of rat S100 beta subunit with glutathione S-transferase displayed a marked resistance to cellular damage induced by copper alone or its combination with H2O2, compared with control cells expressing the transferase moiety only. A study by gel chromatography showed that about half of the expressed S100 beta fusion protein in the cytosol of copper-treated cells was eluted in the void volume fraction (molecular mass > 200 kDa), which contained most of the copper incorporated. The S100 beta fusion protein purified from the void volume fraction was found to contain 82% of the total copper in the fraction, while in a parallel experiment with the control cells, the glutathione S-transferase eluted in the void volume fraction contained only 18% of the total copper. Thus, it is clear that extraneously expressed S100b protein can acts as a "copper sink," thereby protecting E. coli cells from copper-induced cellular damage.

Calcium-Binding Proteins↗