Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Copper”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,441 records · Page 80Linked to original sources
PubMed1990

Comparison of copper status in rats when dietary fructose is replaced by either cornstarch or glucose.

The purpose of this study was to determine what levels of starch or glucose replacement for fructose in the copper-deficient diet (copper) can minimize the fructose-copper interaction. Experimental diets contained either 100% fructose as the carbohydrate source, or the fructose was partially replaced with 50% starch, 50% glucose, 75% starch, or 75% glucose. Diets were either copper adequate (7-8 ppm) or inadequate (less than 1 ppm). Male weanling rats were fed their respective diet for 5 weeks and then fasted overnight. After decapitation, blood was collected and liver and heart were removed. Plasma copper was significantly reduced and ceruloplasmin was not detected in all copper-deficient groups. Copper deficiency increased plasma cholesterol, as well as heart and liver weight in the glucose groups, but not in the starch groups. Those organ weights were heavier in glucose-copper than starch-copper rats. Erythrocyte copper-zinc-superoxide dismutase activity was greater in starch-copper rats. Erythrocyte copper-zinc-superoxide dismutase activity was greater in starch-copper than glucose-copper rats regardless of carbohydrate amount. Hepatic copper concentration of the group fed starch-copper was twice levels observed in glucose-copper. The 50% glucose rats had lower hepatic copper than the 75% glucose rats. Hepatic copper-zinc-superoxide dismutase activity showed patterns similar to hepatic copper. Cardiac copper was greater in starch-copper than glucose-copper rats. Cardiac copper-zinc-superoxide dismutase activity was equally reduced in all copper-deficient groups. The 50% starch-replaced diet was more effective in minimizing copper deficiency than the 75% glucose-replaced diet. This poorer improvement of copper deficiency by glucose than starch may partially be due to a more severe reduction of food intake in glucose than in starch diets.

Animals↗
PubMed1997

Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential. OH-inactivating ligand.

It has long been established that copper complexes of inactive substances exert antiinflammatory activity and that copper complexes of nonsteroidal antiinflammatory drugs (NSAIDs) are more active than these drugs by themselves. Based on these observations, it was proposed that copper complexes of NAIDs are their active metabolites. This hypothesis was not confirmed for salicylic acid, however, as computer-aided speciation studies have shown that no copper-salicylate complex can reach significant levels in blood plasma. In view of this result, it was of interest to test with the same technique the influence on copper metabolism of an inactive substance known to be activated by copper. Anthranilic acid was chosen for this test in the present work. First, copper(II)-anthranilate interactions have been investigated by glass electrode potentiometry under physiological conditions. Given the key role of histidine as copper(II) ligand in blood plasma, copper(II)-histidine-anthranilate ternary equilibra have also been determined. Computer simulations of copper distribution have then been run relative to the two main biofluids in respect of global metabolism, i.e., gastrointestinal (g.i.) fluid and blood plasma. Like salicylic acid, anthranilic acid is expected to favor copper g.i. absorption, but cannot either exert any significant influence on plasma copper distribution. Clearly, the fact that anthranilate becomes antiinflammatory when administered with copper cannot originate in any effect of anthranilate on copper global metabolism. Speciation investigations have then been extended to the synovial fluid. Whereas salicylate does not appear to be a better ligand of copper in this medium than in blood plasma at any pH between 7.4 and 5.5, anthranilate on the contrary can mobilize increasing fractions of copper as the pH decreases, i.e., the more inflammation, the more copper is bound to anthranilate. This is in line with the recent observation that salicylate inactivates copper-induced .OH radicals through its bulk scavenging properties whereas .OH inactivation by anthranilate under the same conditions is a direct function of the copper-anthranilate binding. Anthranilate thus seems to correspond to the recently defined notion of .OH-inactivating ligand (OIL). More generally, these results provide a beginning of rationale for the antiinflammatory properties of copper complexes with substances that are active or inactive against inflammation by themselves. The extra antiinflammatory activity induced by copper on NSAIDs appears to be independent of any Cu(II)-NSAID association in vivo. On the contrary, the binding of inactive substances with copper(II) at inflammatory sites seems to be essential to their activation by copper.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Copper poisoning in the Kruger National Park: field investigation in wild ruminants.

Chronic copper poisoning was investigated in ruminants within the Phalaborwa area of the Kruger National Park (KNP). Exposure of ruminants to environmental copper pollution resulting form copper smelting operations of a mine in the area was examined by comparing impala faecal copper concentrations in dung heaps and tissue (liver, lung and kidney) copper concentrations of organs collected from impala and buffalo culled within three risk zones (high, moderate and low) of the study area in relation to the distance from the smelter over a period of 4 years. An additional area within the KNP not exposed to the environmental copper pollution from the mine served as control. Tissue copper accumulation was also determined in tracer impala placed in the highest risk zone. The results of this study confirmed the occurrence of chronic copper poisoning in impala and indicated an inverse relationship in extent of impala faecal copper elimination and in tissue copper accumulation in impala and buffalo with distance from the copper smelter. Impala liver copper concentrations were shown to be a reliable indicator of copper accumulation for these ruminants. The presence lung copper concentrations, indicating the exposure to airborne copper were the highest in impala culled in the zone closest to the smelter. Liver copper concentrations above the diagnostic limit of 150 ppm for chronic copper poisoning in domestic sheep were consistently found in impala within the highest risk zone. Clinical pathological measurements suggested that AST activity could possibly be used as an indicator for chronic copper poisoning in impala. It is concluded that, in addition to the environmental and geo-botanical evidence previously reported, the copper smelter of a nearby copper mine is the most likely source of copper pollution responsible for chronic copper poisoning in impala and the occurrence of high copper concentrations in buffalo in the Phalaborwa area of the KNP.

Air Pollutants↗
PubMed2001

Copper transportion of WD protein in hepatocytes from Wilson disease patients in vitro.

AIM: To study the effect of copper transporting P-type ATPase in copper metabolism of hepatocyte and pathogenesis of Wilson disease (WD). METHODS: WD copper transporting properties in some organelles of the cultured hepatocytes were studied from WD patients and normal controls.These cultured hepatocytes were incubated in the media of copper 15 mg x L(-1) only, copper 15 mg x L(-1) with vincristine (agonist of P-type ATPase) 0.5mg x L(-1), or copper 15 mg x L(-1) with vanadate (antagonist of P-type ATPase) 18.39 mg x L(-1) separately. Microsome (endoplasmic reticulum and Golgi apparatus), lysosome, mitochondria, and cytosol were isolated by differential centrifugation. Copper contents in these organelles were measured with atomic absorption spectrophotometer, and the influence in copper transportion of these organelles by vanadate and vincristine were comparatively analyzed between WD patients and controls. WD copper transporting P-type ATPase was detected by SDS-PAGE in conjunction with Western blot in liver samples of WD patients and controls. RESULTS: The specific WD proteins (M(r)155,000 lanes) were expressed in human hepatocytes, including the control and WD patients. After incubation with medium containing copper for 2 h or 24 h, the microsome copper concentration in WD patients was obviously lower than that of controls, and the addition of vanadate or vincristine would change the copper transporting of microsomes obviously. When incubated with vincristine, levels of copper in microsome were significantly increased, while incubated with vanadate, the copper concentrations in microsome were obviously decreased. The results indicated that there were WD proteins, the copper transportion P-type ATPase in the microsome of hepatocytes. WD patients possessed abnormal copper transporting function of WD protein in the microsome, and the agonist might correct the defect of copper transportion by promoting the activity of copper transportion P-type ATPase. CONCLUSION: Copper transportion P-type ATPase plays an important role in hepatocytic copper metabolism. Dysfunction of hepatocytic WD protein copper transportion might be one of the most important factors for WD.

Adenosine Triphosphatases↗
PubMed1995

Uneven hepatic copper distribution in Wilson's disease.

BACKGROUND/AIMS: Determination of hepatic copper concentration is important in the diagnosis of Wilson's disease. We studied copper distribution in the cirrhotic liver of a patient who died of Wilson's disease. METHODS: A liver slice extending from the left to the right lobe was divided into 38 samples. Each sample was analyzed for copper content by Induced Coupled Plasma Atomic Emission Spectroscopy. RESULTS: The mean copper concentration in the liver was 1370 micrograms/g dt. A striking variability, up to 2-3-fold, in copper levels was observed between the samples: the copper concentration ranged from 880 to 2100 micrograms/g dt, with significant differences even between adjacent samples. Lobar differences were also observed, with a tendency of the right lobe to accumulate more copper than the left lobe. Histochemical analyses confirmed the uneven distribution of copper even at the acinar level. Copper was mainly stored in periportal hepatocytes (zone 1) and at the periphery of the regenerating nodules. Moreover, we observed some nodules with the majority of hepatocytes full of copper granules, adjacent to areas of parenchyma negative for copper stains. CONCLUSIONS: Our data show that: 1) copper is unevenly distributed in Wilson's disease in the cirrhotic stage; 2) a lobar pattern of copper distribution is evident in this case, characterized by a higher copper concentration in the right lobe; 3) the observed lobar pattern is different from that described in the newborn liver, characterized by a higher copper content in the left compartment of the liver; 4) copper content determined in a small liver sample cannot be considered as absolutely representative of the mean hepatic copper concentration. From a practical point of view, our data show that sampling variability deserves more consideration in the diagnosis and in the monitoring of Wilson's disease. The use of hepatic copper concentration in monitoring the efficacy of the copper-chelating therapy may be unreliable, particularly in the cirrhotic stage, because of the patchy distribution of copper, as demonstrated in this study.

Adult↗
PubMedDate not supplied

Effect of maternal diabetes and dietary copper on fetal development in rats.

To test whether diabetes associated alterations in copper metabolism contribute to diabetes-induced teratogenicity in rats, pregnancy outcome was compared between diabetic and nondiabetic rats fed either a copper adequate (12 micrograms/g diet) or low copper diet (1 microgram/g diet). The dietary regimen was begun two weeks prior to mating and continued throughout pregnancy. To facilitate the reduction of maternal copper stores in the low copper groups, the low copper diet was supplemented with a copper chelator, triethylenetetraamine, at 1% for one week; the chelator was removed from the diet one week prior to mating. Pregnancy was terminated on gestation day 20. Maternal and fetal tissues were assessed for copper concentrations, the activities of the cuproenzymes copper, zinc superoxide dismutase and ceruloplasmin, and the copper binding protein metallothionein. Dams fed the low copper diet had low tissue copper concentrations, and low plasma ceruloplasmin and erythrocyte superoxide dismutase activities compared to copper-adequate dams. Fetuses in the low copper groups were characterized by low liver copper concentrations. Gross structural and skeletal anomalies were only observed in the diabetic groups; maternal copper intake did not influence the frequency of these anomalies. However, fetuses in the low-copper nondiabetic group, and both diabetic groups, were characterized by low liver copper, zinc superoxide dismutase activity suggesting that fetal copper metabolism was influenced by both copper intake and diabetes.

Animals↗
PubMed2006

Intracellular copper does not catalyze the formation of oxidative DNA damage in Escherichia coli.

Because copper catalyzes the conversion of H(2)O(2) to hydroxyl radicals in vitro, it has been proposed that oxidative DNA damage may be an important component of copper toxicity. Elimination of the copper export genes, copA, cueO, and cusCFBA, rendered Escherichia coli sensitive to growth inhibition by copper and provided forcing circumstances in which this hypothesis could be tested. When the cells were grown in medium supplemented with copper, the intracellular copper content increased 20-fold. However, the copper-loaded mutants were actually less sensitive to killing by H(2)O(2) than cells grown without copper supplementation. The kinetics of cell death showed that excessive intracellular copper eliminated iron-mediated oxidative killing without contributing a copper-mediated component. Measurements of mutagenesis and quantitative PCR analysis confirmed that copper decreased the rate at which H(2)O(2) damaged DNA. Electron paramagnetic resonance (EPR) spin trapping showed that the copper-dependent H(2)O(2) resistance was not caused by inhibition of the Fenton reaction, for copper-supplemented cells exhibited substantial hydroxyl radical formation. However, copper EPR spectroscopy suggested that the majority of H(2)O(2)-oxidizable copper is located in the periplasm; therefore, most of the copper-mediated hydroxyl radical formation occurs in this compartment and away from the DNA. Indeed, while E. coli responds to H(2)O(2) stress by inducing iron sequestration proteins, H(2)O(2)-stressed cells do not induce proteins that control copper levels. These observations do not explain how copper suppresses iron-mediated damage. However, it is clear that copper does not catalyze significant oxidative DNA damage in vivo; therefore, copper toxicity must occur by a different mechanism.

Catalysis↗
PubMed2004

Copper storage diseases: Menkes, Wilsons, and cancer.

The trace element copper is vital to the healthy functioning of organisms. Copper is used in a multitude of cellular activities including respiration, angiogenesis, and immune responses. Like other metals, copper homeostasis is a tightly regulated process. Copper is transported from dietary intake through the serum and into cells via a variety of transporters. There are a variety of copper chaperones designed to insure that copper is sequestered from interaction with cellular membranes, proteins, or DNA where its properties can result in oxidative damage. However, there are disease states in which copper transporters crucial to homeostasis are impaired resulting in potentially toxic copper accumulation. Wilsons and Menkes diseases are two such cases. Wilsons disease (hepatolenticular degeneration) is an autosomal recessive disorder resulting in extreme accumulation of copper in the liver with deposits elsewhere in the body. Menkes is characterized by a systemic copper deficiency (different from the liver specificity of Wilsons disease) and is the result of an X-linked recessive mutation in a copper transporter. Uptake of copper is impaired due to inability to remove existing copper from cells primarily in the small intestine. Though the causes are dramatically different, cancer also shares a similar diagnostic in the accumulation of copper in effected tissues. Studies have shown greatly elevated levels of copper in cancer tissues, and some diagnostics and treatments from Wilsons and Menkes diseases, such as copper chelation therapy, have been used in the treatment of cancer. Given the commonality of copper accumulation in these diseases and that common therapies exist between them, it may prove beneficial to study all three diseases in light of copper homeostasis. This review will examine the chemical nature and biological roles of copper, Wilsons and Menkes disease and their therapies, and the use of copper related therapies in cancer.

Animals↗
PubMed2005

Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat--a feasibility study.

Copper is an essential trace element. However, excess copper can lead to oxidation of biomolecules and cell damage and copper levels must be carefully controlled. While copper homeostasis has been studied extensively at the cellular level, short-term body copper fluxes are poorly understood. Here, we assessed for the first time the feasibility of measuring whole body copper flux by positron emission tomography, using 64Cu. A comparative approach comparing the Long-Evans cinnamon (LEC) rat to the wild type was chosen. LEC rats are an accepted model for Wilson disease, an inherited disorder of copper excretion in humans. In LEC rats as well as in Wilson patients, the copper transporting ATPase, ATP7B, is defective. This ATPase is primarily expressed in the liver and serves in copper secretion via the bile. Dysfunction of ATP7B leads to accumulation of copper in the liver. A control and an LEC rat were transgastrically injected with 10 microg of 64Cu and the copper flux followed for three hours by whole animal PET and concomitant collection of bile, as well as the analysis of tissue following tomography. As seen by PET, the administered copper was largely trapped in the stomach and the proximal intestine, and without a significant difference between control and LEC rat. Due to an insufficient dynamic range of the PET technology, copper which was systemically absorbed and primarily transported to the liver could only be followed by sampling and by beta-counting. Biliary copper excretion ensued after 15 min in the control rat, but was absent in the LEC rat. Biliary excretion reached saturation one hour after copper administration. The trapping of orally administered copper in the gastrointestinal tract may be an important mechanism to prevent copper toxicity under conditions of a sudden, excessive copper load, which cannot be alleviated by increased biliary secretion. This trapping does however limit the utility of PET to measure whole animal copper flux.

Adenosine Triphosphatases↗
PubMed1990

Effect of albumin on net copper accumulation by fibroblasts and hepatocytes.

The liver accumulates copper rapidly and preferentially from plasma. The effects of albumin on net copper accumulation by fibroblasts and hepatocytes were compared to determine whether preferential uptake involves hepatocyte-specific sequestering of copper. Although albumin inhibits the initial rates (30 s) of copper transport by fibroblasts and hepatocytes similarly, the effects of albumin on net copper accumulation (4 h) by these cell types were strikingly different. Fibroblasts accumulate only approximately 15% as much copper when equimolar albumin is present as from albumin-free media; hepatocytes accumulate about the same amount of copper with or without extracellular albumin present. Copper efflux data show that the special capacity of hepatocytes to accumulate copper in the presence of extracellular albumin is due to greater copper retention by hepatocytes than fibroblasts. The ability of hepatocytes to accumulate copper does not seem to be due to albumin-receptor-mediated uptake, since albumin was not co-transported with copper. The data are consistent with an equilibrium model of copper accumulation in which intracellular and extracellular copper are in equilibrium with intracellular and extracellular ligands. A high-affinity, copper-binding fraction that was previously identified in cytosols from hepatocytes was low or absent in fibroblasts. This may contain a liver-specific protein(s) that helps hepatocytes sequester and retain copper from albumin or serum-containing media. Irrespective of the exact species involved, the data are consistent with rapid, preferential copper uptake by the liver being due in part to a liver-specific, intracellular copper-binding protein(s) with a high binding affinity for copper.

Animals↗
PubMed1993

Mechanisms of tolerance in the copper-loaded rat liver.

The aim of this study was to contribute to the understanding of the pathogenesis of copper-induced damage and subsequent recovery and tolerance to copper in the copper-loaded rat liver. Male Wistar rats were allocated randomly into groups of four, fed a pelleted diet containing 1500 mg/g copper, and killed at 1, 5, 6, 10, and 15 weeks. Two additional groups were treated as follows: (a) 5 weeks copper loading followed by 5 weeks with normal rodent diet (group 5-0), (b) 5 weeks copper loading followed by 5 weeks normal diet and 5 weeks of copper reloading (group 5-0-5). Control rats were fed a normal rodent diet that contained 18 mg/kg of copper. Tissues were collected for histology, histochemistry, immunocytochemistry, and copper analysis by atomic absorption spectrophotometry and X-ray microanalysis. In the rats continuously fed the high copper diet, copper concentration rose to 444 +/- 32 micrograms/g of liver (wet weight) by Week 1 and to 726 +/- 170 micrograms/g at Week 5, decreasing to 417 +/- 9 micrograms/g at Week 15. X-ray microanalysis and dot mapping microanalysis demonstrated copper within the nucleus, nucleolus, and lysosomes of these continuously loaded rats. Recovery with unloading of liver copper was demonstrated by both qualitative and quantitative methods in group 5-0 (41.32 +/- 19 micrograms/g). Recovery and tolerance were associated with a reduction in nucleolar copper. Copper tolerance was demonstrated in group 5-0-5 and in continuously copper-loaded rats by Weeks 10 and 15. Copper tolerance was reflected by a change in intracellular levels and distribution of copper and an efficient copper unloading mechanism.

Adaptation, Physiological↗
PubMed1999

Beta-carotene 15,15'-dioxygenase activity is responsive to copper and iron concentrations in rat small intestine.

OBJECTIVE: Previous in vitro studies have suggested that beta-carotene 15,15'-dioxygenase is an iron-dependent enzyme. However, in vivo, it is difficult to alter iron tissue concentration by varying dietary iron because of homeostatic control. On the other hand, an interaction between iron and copper has been shown, i.e., copper-deficiency results in an increase of iron in rat liver. Therefore, we hypothesized that intestinal iron concentration could be increased by copper-deficiency. Our objective was to examine the effects of iron as affected by dietary copper on beta-carotene 15,15'-dioxygenase activity in the small intestine. METHODS: Weanling male Sprague-Dawley rats (40 to 45g) were divided into four dietary groups: two copper-adequate groups (6.0 microg Cu/g diet) and two copper-deficient groups (0.6 microg Cu/g) combined with either normal iron (44 microg Fe/g) or high iron (87 microg Fe/g). Iron and copper concentrations were determined by atomic absorption spectrophotometry and the dioxygenase activity by reverse phase HPLC. RESULTS: Intestinal copper concentration was significantly reduced (40%) by the consumption of the copper-deficient diets, but intestinal iron was not changed by doubling dietary iron in rats fed either copper-adequate or copper-deficient diets. However, as hypothesized, the two copper-deficient groups exhibited higher intestinal iron concentration (> or =137%, p<0.001) than the copper-adequate controls. In addition, intestinal beta-carotene 15,15'-dioxygenase activity was increased by 27% and 106%, respectively, for copper-deficient rats fed either normal or high iron diets, compared to the respective copper-adequate controls (p<0.01). The dioxygenase activity was not significantly affected by dietary iron in either copper-adequate or copper-deficient groups. Finally, the enzyme activity was positively correlated (r=0.67, p<0.0001) with iron concentration and negatively correlated (r=-0.49, p<0.01) with copper concentration in small intestine. CONCLUSIONS: Intestinal beta-carotene 15,15'-dioxygenase may be an iron-dependent enzyme sensitive to copper status in vivo.

Analysis of Variance↗
PubMed1980

Effect of high-level copper feeding on the sulfur amino acid need of chicks fed corn-soybean meal and purified crystalline amino acid diets.

Supplementation of a corn-soybean meal diet with .05% methionine maximized gain and feed efficiency of three-week-old chicks fed copper at either 0 or 250 mg/kg. With copper present at 500 mg/kg, the supplemental methionine requirement was in excess of .10%. Liver copper stores of chicks fed copper at 250 mg/kg declined linearly as supplemental methionine level increased, but methionine level had no effect on liver copper when chicks were fed 500 mg/kg copper. Liver copper accumulation did not occur in chicks fed 250 mg/kg copper when supplemental sulfur was provided as a combination of .05% methionine and 1800 mg/kg sulfide. Irrespective of methionine level, sulfide addition reduced liver copper by one-half in birds fed 500 mg/kg copper. Chicks fed the purified diet were appreciably more susceptible to copper toxicity than those fed the corn-soybean meal diet. Chicks fed the purified diet without supplemental copper required .52% sulfur amino acids (SAA). Chicks fed copper at 250 and 500 mg/kg required .65 and .70 SAA, respectively, although gain and feed efficiency were still depressed when compared with the performance of the control birds. Higher levels of methionine failed to restore growth rates to those achieved with birds fed no supplemental copper. Supplementing the copper-containing diets with up to 1.6% cystine improved performance some but failed to completely overcome the growth depressing effect of copper at 500 mg/kg. Results of additional studies indicated that the purified diet containing .70% SAA and 500 mg/kg copper was nutritionally adequate and that the marked toxicity of copper when fed in the purified diet was due to the chemical nature of the diet rather than to any specific copper-induced nutritional deficiencies.

Amino Acids↗
PubMed2023

The genetic basis of adaptation to copper pollution in Drosophila melanogaster.

Introduction: Heavy metal pollutants can have long lasting negative impacts on ecosystem health and can shape the evolution of species. The persistent and ubiquitous nature of heavy metal pollution provides an opportunity to characterize the genetic mechanisms that contribute to metal resistance in natural populations. Methods: We examined variation in resistance to copper, a common heavy metal contaminant, using wild collections of the model organism Drosophila melanogaster. Flies were collected from multiple sites that varied in copper contamination risk. We characterized phenotypic variation in copper resistance within and among populations using bulked segregant analysis to identify regions of the genome that contribute to copper resistance. Results and Discussion: Copper resistance varied among wild populations with a clear correspondence between resistance level and historical exposure to copper. We identified 288 SNPs distributed across the genome associated with copper resistance. Many SNPs had population-specific effects, but some had consistent effects on copper resistance in all populations. Significant SNPs map to several novel candidate genes involved in refolding disrupted proteins, energy production, and mitochondrial function. We also identified one SNP with consistent effects on copper resistance in all populations near CG11825, a gene involved in copper homeostasis and copper resistance. We compared the genetic signatures of copper resistance in the wild-derived populations to genetic control of copper resistance in the Drosophila Synthetic Population Resource (DSPR) and the Drosophila Genetic Reference Panel (DGRP), two copper-na&#xef;ve laboratory populations. In addition to CG11825, which was identified as a candidate gene in the wild-derived populations and previously in the DSPR, there was modest overlap of copper-associated SNPs between the wild-derived populations and laboratory populations. Thirty-one SNPs associated with copper resistance in wild-derived populations fell within regions of the genome that were associated with copper resistance in the DSPR in a prior study. Collectively, our results demonstrate that the genetic control of copper resistance is highly polygenic, and that several loci can be clearly linked to genes involved in heavy metal toxicity response. The mixture of parallel and population-specific SNPs points to a complex interplay between genetic background and the selection regime that modifies the effects of genetic variation on copper resistance.

Drosophila↗
PubMedDate not supplied

Strain-related patterns of biliary excretion and hepatic distribution of copper in the rat.

Biliary copper excretion was studied in male, bile-cannulated rats of the inbred strains Fischer, Brown Norway, WAG/Rij and Lewis. After intravenous injection of 10, 30 and 50 micrograms copper per 100 gm body weight, two patterns of copper excretion were observed; their profiles varied with the copper dose and the strain of the rats used. The lowest amounts of copper were excreted by Fischer rats, the highest by WAG/Rij rats; this was related to the effect of the copper dose on both patterns. The subcellular distribution of copper in the liver was studied in Fischer and Brown Norway rats after doses of 50, 100, and 200 micrograms per 100 gm body weight. Brown Norway rats accumulated more copper in the liver, although the copper concentration was the same in both strains 1 hr after injection of all doses. Fischer rats accumulated proportionally more copper in lysosomal and nuclear mitochondrial fractions whereas Brown Norway rats accumulated proportionally more copper in the cytosol. Gel filtration of liver supernatants revealed that the amount of copper accumulating in the protein presumed to be metallothionein was 2 to 3 times higher in Brown Norway rats, whereas in the Fischer rats more copper eluted in the void volume fraction. We conclude that both biliary copper excretion and copper distribution in the liver are under genetic control. Because of its low copper excretion and reduced binding of copper to metallothionein the Fischer rat, compared to other strains, may be a suitable model for studying the involvement of the liver in copper intoxication.

Animals↗
PubMed1985

Abnormalities in tests of copper metabolism in primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic, cholestatic syndrome characterized by fibrosing inflammation of the bile ducts that may lead to cirrhosis and death from liver failure. Previous reports have suggested abnormal hepatic copper metabolism in this disease. Therefore, in 70 patients, we prospectively determined the levels of hepatic copper, serum copper, and serum ceruloplasmin, and the rate of urinary copper excretion to assess the diagnostic and prognostic usefulness of these tests. Virtually all patients had at least one abnormal copper test. Hepatic copper levels were elevated in 87% of patients [292 +/- 38 micrograms/g dry wt (mean +/- SE)] and 24-h urinary copper levels in 64% of patients [135 +/- 15 micrograms/24 h (mean +/- SE)] to values comparable to those seen in Wilson's disease or primary biliary cirrhosis. In advanced histologic stages of primary sclerosing cholangitis, progressively higher mean levels of hepatic and urinary copper were found. In the liver, mean copper content (in micrograms per gram dry weight) in disease stages I and II was 147 +/- 36 (mean +/- SE); in stage III (fibrosis), 302 +/- 68; and in stage IV (cirrhosis), 379 +/- 69. In the urine, mean copper excretion (in micrograms per 24 h) in stages I and II was 72 +/- 14 (mean +/- SE); in stage III, 100 +/- 14; and in stage IV, 207 +/- 30. Higher hepatic and urinary copper levels at initial evaluation were associated with decreased survival during a median follow-up period of 2.6 yr: patients with hepatic copper greater than 250 micrograms/g dry wt and urinary copper excretion greater than 200 micrograms/24 h at initial evaluation had an 18-mo survival of less than 60%. We conclude that abnormal copper metabolism is a universal feature of primary sclerosing cholangitis, that hepatic copper accumulates and urinary copper excretion increases as the disease progresses, and that the hepatic copper concentration and the 24-h urinary copper determination are useful prognostic indicators in this disease.

Ceruloplasmin↗
PubMed2005

Copper regulation and homeostasis of Daphnia magna and Pseudokirchneriella subcapitata: influence of acclimation.

This study aimed to evaluate (1) the capacity of the green alga Pseudokirchneriella subcapitata and the waterflea Daphnia magna to regulate copper when exposed to environmentally realistic copper concentrations and (2) the influence of multi-generation acclimation to these copper concentrations on copper bioaccumulation and homeostasis. Based on bioconcentration factors, active copper regulation was observed in algae up to 5 microg Cu L(-1) and in daphnids up to 35 mug Cu L(-1). Constant body copper concentrations (13+/-4 microg Cu g DW(-1)) were observed in algae exposed to 1 through 5 microg Cu L(-1) and in daphnids exposed to 1 through 12 microg Cu L(-1). At higher exposure concentrations, there was an increase in internal body copper concentration, while no increase was observed in bioconcentration factors, suggesting the presence of a storage mechanism. At copper concentrations of 100 microg Cu L(-1) (P. subcapitata) and 150 microg Cu L(-1) (D. magna), the significant increases observed in body copper concentrations and in bioconcentration factors may be related to a failure of this regulation mechanism. For both organisms, internal body copper concentrations lower than 13 microg Cu g DW(-1) may result in copper deficiency. For P. subcapitata acclimated to 0.5 and 100 microg Cu L(-1), body copper concentrations ranged (mean+/-standard deviation) between 5+/-2 microg Cu g DW(-1) and 1300+/-197 microg Cu g DW(-1), respectively. For D. magna, this value ranged between 9+/-2 microg Cu g DW(-1) and 175+/-17 microg Cu g DW(-1) for daphnids acclimated to 0.5 and 150 microg Cu L(-1). Multi-generation acclimation to copper concentrations >or =12 microg Cu L(-1) resulted in a decrease (up to 40%) in body copper concentrations for both organisms compared to the body copper concentration of the first generation. It can be concluded that there is an indication that P. subcapitata and D. magna can regulate their whole body copper concentration to maintain copper homeostasis within their optimal copper range and acclimation enhances these mechanisms.

Adaptation, Physiological↗
PubMed1999

The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures.

The amyloid precursor protein (APP) of Alzheimer's disease can reduce copper (II) to copper (I) in a cell-free system potentially leading to increased oxidative stress in neurons. We used neuronal cultures derived from APP knock-out (APP(-/-)) and wild-type (WT) mice to examine the role of APP in copper neurotoxicity. WT cortical, cerebellar, and hippocampal neurons were significantly more susceptible than their respective APP(-/-) neurons to toxicity induced by physiological concentrations of copper but not by zinc or iron. There was no difference in copper toxicity between APLP2(-/-) and WT neurons, demonstrating specificity for APP-associated copper toxicity. Copper uptake was the same in WT and APP(-/-) neurons, suggesting APP may interact with copper to induce a localized increase in oxidative stress through copper (I) production. This was supported by significantly higher levels of copper-induced lipid peroxidation in WT neurons. Treatment of neuronal cultures with a peptide corresponding to the human APP copper-binding domain (APP142-166) potentiated copper but not iron or zinc toxicity. Incubation of APP142-166 with low-density lipoprotein (LDL) and copper resulted in significantly increased lipid peroxidation compared to copper and LDL alone. Substitution of the copper coordinating histidine residues with asparagines (APP142-166(H147N, H149N, H151N)) abrogated the toxic effects. A peptide corresponding to the zinc-binding domain (APP181-208) failed to induce copper or zinc toxicity in neuronal cultures. These data support a role for the APP copper-binding domain in APP-mediated copper (I) generation and toxicity in primary neurons, a process that has important implications for Alzheimer's disease and other neurodegenerative disorders.

Amino Acid Sequence↗