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PubMed2004

Effects of prolonged copper exposure in the marine gulf toadfish (Opsanus beta) II: copper accumulation, drinking rate and Na+/K+ -ATPase activity in osmoregulatory tissues.

Gulf toadfish were exposed to sublethal levels of copper (12.8 or 55.2 microM) for 30 days. Drinking in control fish averaged 1 ml kg(-1)h(-1) but exposure to 55.2 microM copper resulted in a complex biophasic pattern with initial (3 h and 1 day) inhibition of drinking rate, followed by an elevation of drinking rate from day 3 onwards. Drinking led to copper accumulation in the intestinal fluids at levels three to five times higher than the ambient copper concentrations, which in turn resulted in intestinal copper accumulation. The gill exhibited more rapid accumulation of copper than the intestine and contributed to early copper uptake leading to accumulation in internal organs. Muscle, spleen and plasma exhibited little if any disturbance of copper homeostasis while renal copper accumulation was evident at both ambient copper concentrations. The liver exhibited the highest copper concentrations and the greatest copper accumulation of all examined internal organs during exposure to 55.2 microM. Elevated biliary copper excretion was evident from measurements of gall bladder bile copper concentrations and appeared to protect partially against internal accumulation in fish exposed to 12.8 microM copper. No inhibition of Na+/K+ -ATPase activity in either gills or intestine was seen despite copper accumulation in these organs. Calculations of inorganic copper speciation suggest that Cu(CO3)(2)2- complexes which dominate in seawater and intestinal fluids are of limited availability for uptake while the low levels of ionic Cu2+, CuOH+ and CuCO3 may be the forms taken up by the gill and the intestinal epithelium.

Analysis of Variance↗

PubMed1998

Copper absorption, excretion, and retention by young men consuming low dietary copper determined by using the stable isotope 65Cu.

A study was conducted in young men to evaluate the effect of a low-copper diet on copper absorption, excretion, and retention. Eleven young men were confined to a metabolic research unit for 90 d. The study was divided into three periods, with dietary copper as the only variable. Dietary copper intake was 0.66 mg/d for 24 d, 0.38 mg/d for 42 d, and 2.49 mg/d for 24 d. The stable isotope 65Cu was fed to five of the subjects once during the first and last dietary period and twice, early and late, in the second period to determine copper absorption. 65Cu was infused into an arm vein of the other six subjects once during each dietary period to estimate excretion of endogenous copper. Total copper and 65Cu were determined by isotope dilution with thermal-ionization mass spectrometry. Fractional absorption was significantly higher during the low-copper period than in either period with higher dietary copper and excretion of the infused isotope was significantly lower in the low-copper period. Subjects were in negative balance early in the first two periods but achieved balance by the end of those periods. They retained copper during the highest dietary copper period (third period). The results suggest that endogenous copper excretion is a major point of regulation of the body's copper stores. Regulation of absorption and of endogenous excretion in response to dietary copper intake helps to protect against deficiency and toxicity. However, this regulation was not sufficient to maintain copper status at the lowest intake of dietary copper, 0.38 mg/d.

Administration, Oral↗

PubMed1985

Trace element supplementation of sheep: evaluation of various copper supplements and a soluble glass bullet containing copper, cobalt and selenium.

The effect of 5 different copper supplements on copper status of Merino sheep at pasture was examined. Transient increases in plasma copper concentrations occurred following treatment with copper calcium EDTA, copper sulphate, and glass bullets impregnated with copper, cobalt and selenium, but these increases were not considered to be a reliable indication of changes in liver copper reserves. Sheep receiving the glass bullet or 2.5 g oxidised copper wire particles orally or 50 mg copper as copper calcium EDTA parenterally had liver copper concentrations significantly greater than those of untreated sheep for periods up to 51 weeks. Oral doses of 30 mg copper as copper oxychloride, or 300 mg copper as copper sulphate did not alter the liver copper reserves at any stage. The bodyweight and greasy fleece weights were not significantly altered by any of the copper supplements. Plasma vitamin B12 concentrations in sheep given the glass bullet were increased for about 5 months. Thereafter increased plasma vitamin B12 concentrations were observed in all sheep. Blood selenium concentrations were also high during the experiment thereby preventing the evaluation of the glass bullet as a source of selenium.

Animal Nutritional Physiological Phenomena↗

PubMed1999

Chronic poisoning by copper in tap water: I. Copper intoxications with predominantly gastointestinal symptoms.

Copper can induce acute and chronic intoxications in humans. Copper in tap water has caused a series of severe systemic diseases in Germany in recent years (copper induced liver cirrhosis). Besides cirrhosis, another type of disease with predominantly gastrointestinal symptoms has occurred which likewise appeared to be induced by copper in tap water. - In a retrospective investigation we looked for additional indications and proof that chronic copper poisoning has been the cause of the observed gastrointestinal diseases. All patients suffering from this type of disease had copper plumbing in their houses. - The patients (children and adults) suffered from nausea, vomiting, colic, and diarrhoea. In the group of infants, one refused formula milk (prepared with tap water) and the others suffered from persistent restlessness, unexplainable screaming (especially at night) and/or long lasting diaper rash. - We accept the diagnosis of chronic copper intoxication as the cause of the gastrointestinal symptoms when at least one of the following criteria were fulfilled: 1. first manifestation, remission and relapse of the disease depend on intake and a non-intake of water containing copper, respectively. 2. hypercupric state of the patients (i.e. pathological high concentrations of the non-ceruloplasmin-bound copper in serum and/or elevated copper levels in urine) 3. signs of systemic copper intoxication in the same patient 4. signs of systemic copper intoxication or hypercupric states in members of the patient s family or in his neighbourhood (non-relatives) - We found that the disease can even be caused by copper concentrations below the allowed concentration given by the German Guidelines for Drinking Water (Trinkwasserverordnung). - The data prove that copper in drinking water can cause gastrointestinal diseases and not only the better known systemic diseases (i.e. copper induced liver cirrhosis). Copper poisoning must be considered as a possible cause of chronic gastrointestinal diseases in those countries in which copper plumbing is common.

Adolescent↗

PubMed2004

[Use of copper oxide wire particles (Copinox) for the prevention of congenital copper deficiency in a herd of German Improved Fawn breed of goat].

In a herd of German Improved Fawn breed of goat in the year 2000 neonatal kid losses due to congenital copper deficiencies were observed. To clarify the problems and to prevent losses in the next breeding season serum copper levels of 10 dams and four control Boer goats were investigated at four time points during one year. Additionally ten kids of the following year were sampled and the serum copper levels were studied. Immediatly after parturition and 8 weeks later the dams showed low serum copper levels (10.4 +/- 11.1 micromol/l, 5.7 +/- 2.9 micromol/l resp.). At the end of the pasture season an increase of serum copper could be measured (19.3 +/- 16.0 micromol/l). To prevent enzootic ataxia due to congenital copper deficiency, the dams were treated with copper oxide wire particles in the next late gestation. At this time point serum copper concentrations started to decrease (18.5 +/- 8.4 micromol/l). The re-examination 3 month later demonstrated an increase of the serum mean copper concentrations up to 23.4 micromol/l in the dams and to 16.2 micromol/l in the kids. The serum copper levels were significantly higher compared to the levels the year before. Big variation of the serum copper levels in the control Boer goats occurred during the year, but no clinical symptoms of copper deficiency could be observed. The copper levels in the grass and soil samples were 6.8 mg/kg and 0.2 mg/kg dry substance, respectively. A secondary copper deficiency based on cadmium could be excluded through the low levels of soil samples. The contents of sulphur and molybdenum were not determined. The results indicate that the German Improved Fawn breed of goats suffered from a primary copper deficiency due to the inefficient mineral supplementation. The administration of Copinox in the last third of the gestation leads to a continious raising of the copper concentrations in the serum and is suited to prevent ataxia due to congential copper deficiency in neonatal kids.

Animals↗

PubMed1982

Copper and liver injury--experimental studies on the dogs with biliary obstruction and copper loading.

Cytotoxic effect of excessive copper in the liver of the dogs with longstanding obstructive jaundice were investigated. Common bile duct was ligated in adult mongrel dogs for a period of 21 to 93 days. Copper (0.5 mg/kg weight, every other day) was administered intravenously. Copper content and morphologic changes of the liver was compared with those of the common bile duct ligated dogs without copper administration and of the normal control. Liver copper content was quantitated by atomic absorption spectrophotometry and morphologic investigation was carried out ultrastructurally and histochemically (dimethylaminobenzylidine rhodanine stain for copper and orcein stain for copper associated protein). The copper content of the liver was 57 +/- 8.75 microgram/g wet weight (mean +/- S.E.) in the normal control, 80.84 +/- 15.76 in the common bile duct ligated dogs and 463.46 +/- 76.42 in the common bile duct ligated dogs with copper administration. There was a significant increase (p less than 0.01) of the liver copper content in the common bile duct ligated dogs with copper administration but not in the common bile duct ligated dogs without it. Histologically, the liver showed changes of longstanding cholestasis and of early biliary cirrhosis in the dogs over three months after ligation. Ultrastructurally, both groups showed dilatation of bile canaliculi with decreased and swollen microvilli protruding into their lumina, expanded pericanalicular ectoplasm with increased microfibrils and various forms of intracanalicular and intracytoplasmic bile assuming myelin-figure, crystalloid and dense-amorphous appearances. Also present were increased and dilated smooth-surfaced endoplasmic reticulum, mitochondria showing curled cristae with electron dense ground substance and decreased microvillous projections of hepatocyte cell membranes into Disse's space. Only significant morphologic difference between two groups was the presence of copper-protein complex demonstrated by rhodanine and orcein stains as intracytoplasmic coarse granules in the common bile duct ligated dogs with copper administration. These copper-protein complex granules correspond to partially membrane-bound dense bodies seen ultrastructurally, which probably represent autophagic vacuoles or lysosomal residual bodies. Above result suggests that excessive copper accumulated in the liver as lysosomal bodies in longstanding extrahepatic biliary obstruction with copper loading does not produce significant liver cell injury despite eight fold increase of the liver copper content.

Animals↗

PubMed1986

Comparisons of copper deficiency states in the murine mutants blotchy and brindled. Changes in copper-dependent enzyme activity in 13-day-old mice.

The activity of two copper-dependent enzymes, cytochrome c oxidase and copper, zinc-superoxide dismutase, was determined in six tissues of age-matched (13-day-old) copper-deficient mutant and normal mice. In the two mutants 'brindled' and 'blotchy', brain, heart and skeletal muscle had significant enzyme deficiencies. Cytochrome c oxidase was more severely affected than was superoxide dismutase. In these three tissues the degree of deficiency could be correlated with decreased copper concentration; however, enzyme activity was normal in liver, kidney and lung, despite abnormal copper concentrations in these tissues. In nutritionally copper-deficient mice, all six tissues showed decreased enzyme activity, which was most marked in brain, heart and skeletal muscle, the tissues which showed enzyme deficiencies in the mutants. Analysis in vitro of cytochrome c oxidase (temperature coefficient = 2) at a single temperature was found to underestimate the deficiency of this enzyme in hypothermic copper-deficient animals. Cytochrome c oxidase deficiency may therefore be sufficiently severe in vivo to account for the clinical manifestations of copper deficiency. An injection of copper (50 micrograms of Cu+) at 7 days increased cytochrome c oxidase activity by 13 days in all deficient tissues of brindled mice, and in brain and heart from blotchy mice. However, skeletal-muscle cytochrome c oxidase in blotchy mutants did not respond to copper injection. Cytochrome c oxidase activity increased to normal in all tissues of nutritionally copper-deficient mice after copper injection, except in the liver. Hepatic enzyme activity remained severely deficient despite a liver copper concentration three times that found in copper-replete controls. Superoxide dismutase activity did not increase with treatment in either mutant, but its activity was higher than control levels in nutritionally deficient mice after injection. This difference is probably due to sequestration of copper in mutant tissue such as kidney, but a defect in the copper transport pathway to superoxide dismutase cannot be excluded.

Animals↗

PubMed2001

Copper-induced proteolysis of the CopZ copper chaperone of Enterococcus hirae.

The cop operon is a key element of copper homeostasis in Enterococcus hirae. It encodes two copper ATPases, CopA and CopB, the CopY repressor, and the CopZ metallochaperone. It was previously shown that the transcription of the operon is induced by copper. The concomitant increase in the levels of Cop proteins, particularly the CopB copper export ATPase, allows uncompromised growth of E. hirae in up to 5 mm ambient copper. We here show by Western blotting that the steady-state level of CopZ was increased only up to 0.5 mm copper. At higher copper concentrations, the level of CopZ was decreased and became undetectable at 5 mm media copper. When CopZ was overexpressed from a plasmid, the cells exhibited increased sensitivity to copper and oxidative stress, suggesting that high CopZ expression could become toxic to cells. In wild-type cells, the level of mRNA transcripts from the cop operon remained high in up to 5 mm copper, suggesting that CopZ was proteolyzed. Cell extracts were found to contain a copper-activated proteolytic activity that degraded CopZ in vitro. In this assay, Cu-CopZ was more susceptible to degradation than apo-CopZ. The growth of E. hirae in copper increased the copper-inducible proteolytic activity in extracts. Zymographic studies showed the presence of a copper-dependent protease in crude cell lysates. Thus, copper-stimulated proteolysis plays an important role in the regulation of copper homeostasis in E. hirae.

Bacterial Proteins↗

PubMed1997

Copper status of young men consuming a low-copper diet.

A study was conducted in 11 young men to evaluate the effect of a low-copper diet on indexes of copper status and to define an amount of dietary copper at which adequate copper status could not be maintained. The young men were confined to a metabolic research unit for 90 d. The study was divided into three periods, with dietary copper as the only variable. Dietary copper was 0.66 mg/d for 24 d, 0.38 mg/d for 42 d, and 2.49 mg/d for 24 d. Plasma copper, ceruloplasmin activity, ceruloplasmin concentration, and erythrocyte superoxide dismutase (SOD) were measured at selected time points during each dietary copper period. Urine was collected throughout the study. Plasma copper, ceruloplasmin concentration and activity, and urinary copper declined significantly during the lowest dietary copper period. Plasma copper, ceruloplasmin concentration, and urinary copper increased in response to repletion. The average erythrocyte SOD concentration was lower during the depletion period than in the periods before or after depletion, but it did not decline significantly over time in the depletion period. The results suggest that these indexes are sensitive to copper depletion; that 0.38 mg Cu/d is not sufficient to maintain copper status in normal, healthy young men; and that the minimum dietary copper requirement is between 0.4 and 0.8 mg/d.

Adult↗

PubMed1994

Molecular cloning, chromosomal mapping, and sequence analysis of copper resistance genes from Xanthomonas campestris pv. juglandis: homology with small blue copper proteins and multicopper oxidase.

Copper-resistant strains of Xanthomonas campestris pv. juglandis occur in walnut orchards throughout northern California. The copper resistance genes from a copper-resistant strain C5 of X. campestris pv. juglandis were cloned and located on a 4.9-kb ClaI fragment, which hybridized only to DNA of copper-resistant strains of X. campestris pv. juglandis, and was part of an approximately 20-kb region which was conserved among such strains of X. campestris pv. juglandis. Hybridization analysis indicated that the copper resistance genes were located on the chromosome. Plasmids conferring copper resistance were not detected in copper-resistant strains, nor did mating with copper-sensitive strains result in copper-resistant transconjugants. Copper resistance genes from X. campestris pv. juglandis shared nucleotide sequence similarity with copper resistance genes from Pseudomonas syringae pv. tomato, P. syringae, and X. campestris pv. vesicatoria. DNA sequence analysis of the 4.9-kb fragment from strain C5 revealed that the sequence had an overall G+C content of 58.7%, and four open reading frames (ORF1 to ORF4), oriented in the same direction. All four ORFs were required for full expression of copper resistance, on the basis of Tn3-spice insertional inactivation and deletion analysis. The predicted amino acid sequences of ORF1 to ORF4 showed 65, 45, 47, and 40% identity with CopA, CopB, CopC, and CopD, respectively, from P. syringae pv. tomato. The most conserved regions are ORF1 and CopA and the C-terminal region (166 amino acids from the C terminus) of ORF2 and CopB. The hydrophobicity profiles of each pair of predicted polypeptides are similar except for the N terminus of ORF2 and CopB. Four histidine-rich polypeptide regions in ORF1 and CopA strongly resembled the copper-binding motifs of small blue copper proteins and multicopper oxidases, such as fungal laccases, plant ascorbate oxidase, and human ceruloplasmin. Putative copper ligands of the ORF1 polypeptide product are proposed, indicating that the polypeptide of ORF1 might bind four copper ions: one type 1, one type 2, and two type 3.

Amino Acid Sequence↗

PubMed1992

Three stages of copper accumulation in hepatocellular lysosomes: X-ray microanalysis of copper-loaded golden hamsters.

Male golden hamsters were loaded with copper by supplying them for up to 12 weeks with drinking water containing 0.5% cupric acetate. The copper feeding increased hepatic copper to widely varying levels. Energy dispersive X-ray microanalysis could always identify a copper-sulphur complex in the hepatocyte lysosomes of copper-loaded hamsters and the X-ray intensity of copper was found to be a reliable parameter to measure in-situ copper accumulation. Combining this parameter with the copper binding ratio expressed by delta Cu/delta S enabled us to discern two stages of sub-histochemical copper accumulation. The first stage was marked by low levels of both lysosomal copper and binding ratio, which suggested that this initial copper transfer was mediated by unsaturated cuproproteins. The second stage was characterized by median amounts of lysosomal copper and a binding ratio of more than 0.50. At the third stage, histochemically detectable copper appeared in animals whose lysosomal copper was extraordinarily high in later experimental periods. With the copper binding ratio being in the same range of 0.50-0.83, it seemed that saturated cuproproteins were the main mediator of copper transport in the later two stages.

Animals↗

PubMed1993

Biliary copper excretion in acutely and chronically copper-loaded rats.

Biliary copper excretion was examined in rats with acute, continuous and chronic copper loads. Copper was excreted into bile, and the concentration peaked 40 min after a venous injection of copper sulfate (127 ng/gm body weight). The excretion was significantly inhibited by colchicine. Therefore some copper may be transported in hepatocytes by a vesicular pathway and excreted into bile. Biliary copper output increased over time and reached a plateau 180 min after a continuous venous infusion of copper sulfate (318 ng/gm body weight/hr) had started, when the concentration of copper in bile was much higher than that in plasma; the bile/plasma ratio of copper concentrations was 4.32 +/- 0.46. These data support the idea that copper transport involves a specific uptake and transport system. In chronically copper-loaded rats, hepatic copper content was significantly increased compared with controls, and reaction products for copper were observed in hepatocyte granules by light microscopic examination with p-dimethylaminobenzylidene rhodanine stain. The number of lysosomes in hepatocytes increased and the shape changed. In chronically copper-loaded rats the number of tubular lysosomes was very high. However, other organelles appeared to be normal. In these rats biliary excretion of not only copper but also acid phosphatase, a lysosomal enzyme, was significantly greater than the control. Therefore hepatocyte lysosomes may play an important role in biliary copper excretion. Furthermore, when biliary lysosomal excretion increases, the tubular lysosomes actively participate in this excretion.

Acid Phosphatase↗

PubMed2000

The Fe(II) permease Fet4p functions as a low affinity copper transporter and supports normal copper trafficking in Saccharomyces cerevisiae.

The plasma-membrane of Saccharomyces cerevisiae contains high affinity permeases for Cu(I) and Fe(II). A low affinity Fe(II) permease has also been identified, designated Fet4p. A corresponding low affinity copper permease has not been characterized, although yeast cells that lack high affinity copper uptake do accumulate this metal ion. We demonstrate in the present study that Fet4p can function as a low affinity copper permease. Copper is a non-competitive inhibitor of (55)Fe uptake through Fet4p (K(i)=22 microM). Fet4p-dependent (67)Cu uptake was kinetically characterized, with K(m) and V(max) values of 35 microM and 8 pmol of copper/min per 10(6) cells respectively. A fet4-containing strain exhibited no saturable, low affinity copper uptake indicating that this uptake was attributable to Fet4p. Mutant forms of Fet4p that exhibited decreased efficiency in (55/59)Fe uptake were similarly compromised in (67)Cu uptake, indicating that similar amino acid residues in Fet4p contribute to both uptake processes. The copper taken into the cell by Fet4p was metabolized similarly to the copper taken into the cell by the high affinity permease, Ctr1p. This was shown by the Fet4p-dependence of copper activation of Fet3p, the copper oxidase that supports high affinity iron uptake in yeast. Also, copper-transported by Fet4p down-regulated the copper sensitive transcription factor, Mac1p. Whether supplied by Ctr1p or by Fet4p, an intracellular copper concentration of approx. 10 microM caused a 50% reduction in the transcriptional activity of Mac1p. The data suggest that the initial trafficking of newly arrived copper in the yeast cell is independent of the copper uptake pathway involved, and that this copper may be targeted first to a presumably small 'holding' pool prior to its partitioning within the cell.

Biological Transport↗

PubMed2003

Mutation analysis of copper transporter genes in patients with ethylmalonic encephalopathy, mitochondriopathies and copper deficiency phenotypes.

The trace metal copper is an essential cofactor for a number of biological processes, including mitochondrial oxidative phosphorylation, free-radical eradication, neurotransmitter synthesis and maturation, and iron metabolism. Consequently, copper transport at the cell surface and the delivery of copper to intracellular proteins are critical events in normal cellular homeostasis. Four genes have been reported to influence the cellular uptake and the delivery of copper to specific cell compartments and proteins. These include hCTR1, which regulates cellular copper uptake; HAH1, which mediates the transfer of copper to the Menkes and Wilson disease transporters; CCS, which is related to the transfer of copper to superoxide dismutase; and hCOX17, which directs trafficking of copper to mitochondrial cytochrome-c oxidase. At present, no genetic disorders have been associated with defects in these four copper transporter genes. In this study, we test the possibility that defective copper uptake or intracellular translocation represents the basic defect in three categories of candidate phenotypes among 22 patients: ethylmalonic encephalopathy; mitochondriopathies of unknown aetiology; and neurodevelopmental abnormalities with clinical and chemical evidence of copper deficiency. Mutation analyses of the copper uptake protein, hCTR1, and the three copper chaperones were performed by direct sequencing of the whole coding regions. No causative mutations were identified for the four copper transporter genes in 22 patients. A heterozygous polymorphism (847G>A) for CCS was detected in 7 patients. For the distinct disease entity ethylmalonic encephalopathy, we additionally show normal mRNA levels for each of the four genes. The negative results notwithstanding, we encourage ongoing study of additional patients with candidate phenotypes. Further, our results are consistent with the notion that other unknown copper-related transporters could be involved in diseases.

Blotting, Northern↗

PubMed2006

ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion.

BACKGROUND & AIMS: The Wilson protein (ATP7B) regulates levels of systemic copper by excreting excess copper into bile. It is not clear whether ATP7B translocates excess intrahepatic copper directly across the canalicular membrane or sequesters this copper into exocytic vesicles, which subsequently fuse with canalicular membrane to expel their contents into bile. The aim of this study was to clarify the mechanism underlying ATP7B-mediated copper detoxification by investigating endogenous ATP7B localization in the HepG2 hepatoma cell line and its ability to mediate vesicular sequestration of excess intracellular copper. METHODS: Immunofluorescence microscopy was used to investigate the effect of copper concentration on the localization of endogenous ATP7B in HepG2 cells. Copper accumulation studies to determine whether ATP7B can mediate vesicular sequestration of excess intracellular copper were performed using Chinese hamster ovary cells that exogenously expressed wild-type and mutant ATP7B proteins. RESULTS: In HepG2 cells, elevated copper levels stimulated trafficking of ATP7B to pericanalicular vesicles and not to the canalicular membrane as previously reported. Mutation of an endocytic retrieval signal in ATP7B caused the protein to constitutively localize to vesicles and not to the plasma membrane, suggesting that a vesicular compartment(s) is the final trafficking destination for ATP7B. Expression of wild-type and mutant ATP7B caused Chinese hamster ovary cells to accumulate copper in vesicles, which subsequently undergo exocytosis, releasing copper across the plasma membrane. CONCLUSIONS: This report provides compelling evidence that the primary mechanism of biliary copper excretion involves ATP7B-mediated vesicular sequestration of copper rather than direct copper translocation across the canalicular membrane.

Adenosine Triphosphatases↗

PubMed1998

Effect of copper supplementation on the copper status of pasture-fed young Thoroughbreds.

The effect of copper supplementation of pasture fed mares and foals on the copper status of the foals, in terms of plasma, soft tissue and bone copper concentrations and caeruloplasmin activity, was investigated. Twenty-one Thoroughbred foals from either control mares (n = 9), or copper-supplemented mares (n = 12) were divided randomly into control (pasture only, n = 10) or supplemented (pasture and oral copper sulphate, n = 11) groups. The pasture diet was grazed by all animals, and contained 4.4-8.6 mg Cu/kg dry matter (DM). The copper supplement for the mares contained copper sulphate equivalent to 0.5 mg Cu/kg liveweight (LW)/day. This daily dose was converted to allow administration as a thrice weekly dose (i.e. multiplied by 7/3) which was given for 13-25 weeks prior to foaling. The supplemented foals, also dosed 3 times a week, received 0.2 mg Cu/kg LW/day at age 21 days, which was increased to 0.5 mg Cu/kg LW/day at 49 days and was continued at this level until euthanasia at 150 days. Foal plasma copper concentration and caeruloplasmin activity increased from birth to 21 days post partum and then plateaued at a concentration similar to the mare, but the rise in these indices was not affected by copper supplementation of the mare or foal. Copper supplementation of the foal increased foal liver copper concentration at 150 days (P<0.03). Copper intake of diets containing approximately 8-28 mg Cu/kg DM is well reflected by liver copper concentration, but is poorly reflected by bone, other soft tissue copper concentrations and circulating copper status indices.

Administration, Oral↗

PubMed1999

Copper chaperones: function, structure and copper-binding properties.

Copper is an absolute requirement for living systems and the intracellular trafficking of this metal to copper-dependent proteins is fundamental to normal cellular metabolism. The copper chaperones perform the dual functions of trafficking and the prevention of cytoplasmic exposure to copper ions in transit. Only a small number of copper chaperones have been identified at this time but their conservation across plant, bacterial and animal species suggests that the majority of living systems utilise these proteins for copper routing. The available data suggest that each copper-dependent protein in the cell is served by a specific copper chaperone. Although copper chaperones cannot be substituted for one another in a given cell type, copper chaperones that deliver to the same protein in different cell types appear to be functionally equivalent. The majority of the copper chaperones identified thus far have an "open-faced beta-sandwich" global fold with a conserved MXCXXC metal-binding motif. Specificity for a given copper-dependent protein appears to be mediated by the residues surrounding the copper-binding motif. Copper binds to such proteins as Cu(I) in a trigonal complex with three sulfur ligands. Only the copper chaperone specific for cytochrome-c-oxidase, Cox17, deviates from this design.

Amino Acid Sequence↗

PubMed2006

Chronological changes in tissue copper, zinc and iron in the toxic milk mouse and effects of copper loading.

The toxic milk (tx) mouse is a rodent model for Wilson disease, an inherited disorder of copper overload. Here we assessed the effect of copper accumulation in the tx mouse on zinc and iron metabolism. Copper, zinc and iron concentrations were determined in the liver, kidney, spleen and brain of control and copper-loaded animals by atomic absorption spectroscopy. Copper concentration increased dramatically in the liver, and was also significantly higher in the spleen, kidney and brain of control tx mice in the first few months of life compared with normal DL mice. Hepatic zinc was increased with age in the tx mouse, but zinc concentrations in the other organs were normal. Liver and kidney iron concentrations were significantly lower at birth in tx mice, but increased quickly to be comparable with control mice by 2 months of age. Iron concentration in the spleen was significantly higher in tx mice, but was lower in 5 day old tx pups. Copper-loading studies showed that normal DL mice ingesting 300 mg/l copper in their diet for 3 months maintained normal liver, kidney and brain copper, zinc and iron levels. Copper-loading of tx mice did not increase the already high liver copper concentrations, but spleen and brain copper concentrations were increased. Despite a significant elevation of copper in the brain of the copper-loaded tx mice no behavioural changes were observed. The livers of copper-loaded tx mice had a lower zinc concentration than control tx mice, whilst the kidney had double the concentration of iron suggesting that there was increased erythrocyte hemolysis in the copper-loaded mutants.

Animals↗