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PubMed1978

A comparison of the anti-inflammatory effects of copper aspirinate and other copper salts in the rat and guinea pig.

A comparison of the anti-inflammatory (AI) activity of copper compounds in models of kaolin-induced paw oedema and u.v. erythema in the rat and guinea pig is described. The results demonstrated considerable species variation, the guinea pig being more sensitive to the AI and irritant effects of copper aspirinate and the other copper compounds. The route of administration of these compounds was also an important factor in interpreting AI activity obtained. Indeed, the counter-irritation effects of the copper compounds may be largely responsible for the AI activity obtained after subcutaneous administration. The comparison between copper aspirinate and aspirin, performed in order to determine whether a copper complex of an AI drug was more active than the parent AI compound, failed to produce a clear difference in activity although copper aspirinate was more effective than aspirin in certain cases. It is concluded that this study highlights the complexities of copper therapy against inflammatory processes and furthermore indicates the importance of species, the model of inflammation and route of drug administration in interpreting data obtained with copper containing compounds.

Animals↗

PubMedDate not supplied

Zinc, copper, and zinc- or copper-dependent enzymes in human hypertension.

Imbalance of zinc and copper status has been hypothesized in human hypertension. A case-control study was carried out to elucidate the possible relationship between zinc and copper status and essential hypertension. Thirty-one subjects affected by mild stable hypertension, pharmacologically untreated, were investigated together with 31 normotensive controls individually matched for sex, age, and smoking habits. Zinc and copper in serum and urine wee measured, and serum activities of alkaline phosphatase (AP), lactic dehydrogenase (LDH), copper-zinc superoxide dismutase (Cu-Zn SOD), lysyl oxidase (LOX), and monoamine oxidase (MAO) were evaluated. No significant difference in serum and urine zinc and copper content as far as in serum activity of zinc (AP and LDH) or copper (Cu-Zn SOD, LOX, and MAO)-dependent enzymes was found between hypertensives and normotensives. Positive relationships were found in normotensives between serum and urine levels of zinc (r = 0.577; p = 0.001) and copper (r = 0.394; p = 0.028), and between serum copper and Cu-Zn SOD (r = 0.534; p = 0.002). In normotensives, diastolic blood pressure and serum zinc were positively related (r = 0.370; p = 0.041). In hypertensives, inverse correlations were observed between diastolic blood pressure and AP (r = -0.498; p = 0.004) and Cu-Zn SOD (r = 0.452; p = 0.011), and between systolic blood pressure and LOX (r = -0.385; p = 0.033). Diastolic blood pressure was related to LDH inversely in hypertensives (r = -0.357; p = 0.049) and positively in normotensives (r = 0.457; p = 0.010). In normotensives, diastolic blood pressure was inversely related with MAO (r = -0.360; p = 0.046). These findings support the hypothesis that an imbalance of zinc and copper status might be involved in human hypertension.

Alkaline Phosphatase↗

PubMed1990

Effects of copper aspirinate and aspirin on tissue copper, zinc, and iron concentrations following chronic oral treatment in the adjuvant arthritic rat.

Concentrations of copper, zinc, and iron were analyzed and compared in a number of tissues of adjuvant arthritic rats following 22 d of chronic treatment (per os) with either vehicle, aspirin or copper aspirinate, at doses of 100 mg/kg, 200 mg/kg, or 400 mg/kg. Such chronic treatment resulted in a negative balance in copper, zinc, and iron in many tissues. Among the tissues examined, liver and kidney exhibited the greatest changes in metal concentrations; brain and skeletal muscle exhibited the least. Arthritis-induced changes in the concentrations of all three metals in the liver were reversed upon treatment with aspirin. Treatment with copper aspirinate, on the other hand, resulted in an extremely high accumulation of copper in the liver. Arthritis-induced changes in copper, zinc, and iron concentrations in the pancreas and copper concentration in the plasma were generally not reversed upon treatment with either aspirin or copper aspirinate. Among the three metals examined, the degree of change observed as a result of drug treatments was greatest for iron and least for zinc. Finally, it appeared that the effects of aspirin and copper aspirinate on tissue metal concentrations were independent of the antiarthritic effects of these compounds.

Administration, Oral↗

PubMed1984

Molecular localization of copper and zinc in rat fetal liver in dietary and drug-induced copper deficiency.

The teratogenicity of copper deficiency is well known, but underlying mechanisms have not been delineated. One method of studying the biochemical lesions of copper deficiency is the use of chelating drugs with different chemical characteristics. The teratogenicity of a copper deficient diet and of diets containing either D-penicillamine or triethylenetetramine is quite different, although all three diets result in decreased fetal liver copper levels. Feeding D-penicillamine can result in decreased fetal liver zinc, while feeding triethylenetetramine can result in increased fetal liver zinc. The effect of these three diets on fetal liver copper and zinc molecular localization was determined. Gel filtration showed that fetal liver copper and zinc in controls was localized in 3 fractions with MWs of greater than 50,000 (H), 30,000 (I) and 8-10,000 (L). Independent of dietary treatment, as liver copper diminished, copper was missing first from the L peak, then the I peak and with severe deficiency, from the H peak. Drug induced increases and decreases in fetal liver zinc were reflected in the L peak. These data suggest that the absolute levels of copper in the liver of the term fetus determines the distribution of the element among its binding ligands.

Abnormalities, Drug-Induced↗

PubMed1977

Copper thionein in the kidneys of copper-poisoned sheep.

A study has been made of the distribution of copper in the kidneys of copper-poisoned sheep, containing up to 240 microgram copper/g fresh cortex. About 64% of the copper in the cortex was present in the cytosol and 75% of this occurred in a form with molecular weight of approx. 12 000. This was partially purified by gel filtration on Sephadex G-75 and Bio-Gel P.10 and ion exchange chromatography on DEAE Sephadex A-25 to give three sub-fractions, which also contained zinc. The amino acid composition, copper content and chromatographic behaviour of these proteins indicated that they were copper-thioneins. No significant amounts of the proteins were detected in the plasma or erythrocytes of the copper-poisoned sheep when they were undergoing the haemolytic crisis typical of this syndrome. It is concluded that metallothionein constitutes the major copper-binding protein in the kidneys of copper-poisoned sheep. However the rapid accumulation of the protein in the kidney, and the development of kidney damage, are unlikely to have arisen from the release of the intact copper-protein from the liver and its transport via the blood to the kidneys.

Amino Acids↗

PubMed1995

Copper metabolism in analbuminaemic rats fed a high-copper diet.

Copper metabolism in male Nagase analbuminaemic (NA) rats was compared with that in male Sprague Dawley (SD) rats fed purified diets containing either 5 or 100 mg Cu/kg diet. Dietary copper loading increased hepatic and kidney copper concentrations in both strains to the same extent, but baseline values were higher in the NA rats. There was no strain difference in true and apparent copper absorption nor in faecal endogenous and urinary copper excretion. NA rats had higher levels of radioactivity in kidneys at 2 hr after intraperitoneal administration of 64Cu. As based on the distribution of added 64Cu, about 70% of plasma copper appeared to be in the non-protein compartment in the NA rats, whereas in SD rats, it was only about 1%. It is concluded that the NA rats are able to maintain a relatively normal metabolism of copper, even after dietary copper challenge. In the NA rats, zinc concentrations in kidneys, liver and urinary zinc excretion were elevated when compared with SD rats. The high-copper diet did not affect tissue zinc concentrations and apparent zinc absorption in both strains of rats.

Administration, Oral↗

PubMed2006

Copper(II) interactions with non-steroidal anti-inflammatory agents. III--3-Methoxyanthranilic acid as a potential *OH-inactivating ligand: a quantitative investigation of its copper handling role in vivo.

Pharmacological activities of copper(II) complexes are a direct function of the nature of their ligands associated with the metal ion in vivo. Some of these, defined as *OH-inactivating ligands (G. Berthon, Agents Actions 39 (1993) 210-217), may act as specific "lures" for hydroxyl radicals at inflammatory sites and behave as pseudo-catalase-like agents. This property has been advanced for anthranilic acid (H. Miche, V. Brumas, G. Berthon, J. Inorg. Biochem. 68 (1997) 27-38). With a view to improve the chemical features required to render such inactive substances effective anti-inflammatory drugs through their association with copper(II), an in vitro investigation into copper(II) interactions with the anionic form of an anthranilic acid derivative, namely 3-methoxyanthranilate (Man), has been performed under experimental conditions pertaining in vivo. Copper(II)-Man complex equilibria have been determined using glass electrode potentiometry, then checked by UV-vis and mass spectrometries. Given the prime role of histidine as a copper(II) ligand in blood plasma, copper(II)-histidine-Man ternary equilibria have also been studied. Subsequent computer simulations of the distribution of copper(II) in the extracellular fluid revealed that Man can specifically mobilize Cu(II) ions under inflammatory conditions without affecting their distribution under normal physiological conditions. Thiobarbituric acid reactive substances (TBARS) tests conducted with respect to standardized copper-mediated Fenton-type reactions (P. Maestre, L. Lambs, J.P. Thouvenot, G. Berthon, Free Rad. Res. 20 (1994) 205-218) have shown that, like anthranilic acid, Man can effectively both increase the Fenton-like reactivity of copper and decrease the amount of TBARS detected in solution, i.e., act as a potential *OH-inactivating ligand.

Animals↗

PubMed2006

XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders.

X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis. Here, we describe a role for XIAP in copper metabolism. We find that XIAP levels are greatly reduced by intracellular copper accumulation in Wilson's disease and other copper toxicosis disorders and in cells cultured under high copper conditions. Elevated copper levels result in a profound, reversible conformational change in XIAP due to the direct binding of copper to XIAP, which accelerates its degradation and significantly decreases its ability to inhibit caspase-3. This results in a lowering of the apoptotic threshold, sensitizing the cell to apoptosis. These data provide an unsuspected link between copper homeostasis and the regulation of cell death through XIAP and may contribute to the pathophysiology of copper toxicosis disorders.

Apoptosis↗

PubMed2003

The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis.

BACKGROUND: Non-Wilsonian hepatic copper toxicosis includes Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and the non-Indian disease known as idiopathic copper toxicosis (ICT). These entities resemble the hepatic copper overload observed in livers of Bedlington terriers with respect to their clinical presentation and biochemical and histological findings. We recently cloned the gene causing copper toxicosis in Bedlington terriers, MURR1, as well as the orthologous human gene on chromosome 2p13-p16. AIM: To study the human orthologue of the canine copper toxicosis gene as a candidate gene for ICC, ETIC, and ICT. METHODS: We sequenced the exons and the intron-exon boundaries of the human MURR1 gene in 12 patients with classical ICC, one patient with ETIC, and 10 patients with ICT to see whether these patients display any mutations in the human orthologue of the canine copper toxicosis gene. RESULTS: No mutations in the MURR1 gene, including the intron-exon boundaries, were identified in a total of 23 patients with non-Wilsonian hepatic copper toxicosis. CONCLUSIONS: Our results demonstrate that copper toxicosis in Bedlington terriers is not an animal model for the non-Wilsonian hepatic copper toxicosis described in this study.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Exposure-effect model for calculating copper effect concentrations in sediments with varying copper binding properties: a synthesis.

An exposure-effects model is described for calculating copper effect concentrations for benthic organisms in sediments with varying copper-binding properties. It is based on a bioenergetic-based kinetic model that describes the rate of assimilation of copper by benthic organisms from dissolved and particulate phases. During acute exposures, the total copper assimilated by the organisms was used as a measure of the organisms' exposure to bioavailable copper, and toxicity occurs when the copper exposure exceeds a threshold value. Exposure-effects models were developed for nine benthic organisms and were used to predict the effect of sediment-water partitioning (Kd) and copper assimilation from ingested solids on toxic effects and how these factors will influence derived sediment quality guideline (SQG) concentrations. Species sensitivity distributions were used to calculate SQG concentrations for copper for sediments of varying copper binding properties. The modeling indicated that "single value" SQG concentrations would be ineffective for predicting the toxicity of metals in sediment. It is proposed that, for all contaminants (not just metals), a better approach would be to have SQG concentrations, or ranges, that are applied to different sediment types. SQGs should account for contaminant exposure from both water-filtration and particulate-ingestion exposure routes, as can be achieved by models of sediment-water contaminant partitioning (Kd) and the contaminant assimilation efficiency (AE) of ingested particles. The study indicates that improved mechanistic models of contaminant exposure, as influenced by both organism physiology and sediment properties, are needed to predict toxic effects in sediments.

Copper↗

PubMed1987

Regulation of aortic CuZn-superoxide dismutase with copper. Caeruloplasmin and albumin re-activate and transfer copper to the enzyme in culture.

Caeruloplasmin and albumin were compared as potential donors of copper to Cu2Zn2-superoxide dismutase (CuZn-SOD) in culture. Aortas from 15-day copper-deficient chicks were suspended in oxygenated, serum-free, Waymouth medium (752/1) for 24 h. SOD activity was restored when the medium was supplemented with CuCl2, a copper-albumin complex or caeruloplasmin, all present at a level equivalent to 5 microM-copper. Activation did not occur at 4 degrees C or with Cu-EDTA as the supplement. Mn2+ and Zn2+, alone or in combination, did not activate nor enhance the activation achieved by CuCl2. The activation with CuCl2 was not inhibited by cycloheximide or cordycepin. [67Cu]Caeruloplasmin and albumin when added to the medium transferred radioactive copper to at least three cytosolic protein fractions, one of which was determined by immunoprecipitation to be CuZn-SOD. The transfer of 67Cu from caeruloplasmin was inhibited by increasing amounts of unlabelled caeruloplasmin; disodium EDTA (1.0 mM) had no effect on the transfer of copper from caeruloplasmin. These data show that aortic SOD activity, suppressed in copper deficiency, can be restored by incubating the aortas in culture medium supplemented with copper salts. In this system, caeruloplasmin and Cu-albumin appear equally capable of activating aortic CuZn-SOD. Moreover, the transfer of copper into the enzyme structure appears to be the primary event restoring catalytic activity to the enzyme.

Animals↗

PubMed2002

Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery.

The N-terminal region of the prion protein PrP(C) contains a series of octapeptide repeats. This region has been implicated in the binding of divalent metal ions, particularly copper. PrP(C) has been suggested to be involved in copper transport and metabolism and in cell defense mechanisms against oxidative insult, possibly through the regulation of the intracellular CuZn superoxide dismutase activity (CuZn-SOD) or a SOD-like activity of PrP(C) itself. However, up to now the link between PrP(C) expression and copper metabolism or SOD activity has still to be formally established; particularly because conflicting results have been obtained in vivo. In this study, we report a link between PrP(C), copper binding, and resistance to oxidative stress. Radioactive copper ((64)Cu) was used at a physiological concentration to demonstrate that binding of copper to the outer plasma cell membrane is related to the level of PrP(C) expression in a cell line expressing a doxycycline-inducible murine PrP(C) gene. Cellular PIPLC pretreatment indicated that PrP(C) was not involved in copper delivery at physiological concentrations. We also demonstrated that murine PrP(C) expression increases several antioxidant enzyme activities and glutathione levels. Prion protein may be a stress sensor sensitive to copper and able to initiate, following copper binding, a signal transduction process acting on the antioxidant systems to improve cell defenses.

Animals↗

PubMed2003

Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis.

A major source of free radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. The Alzheimer's disease amyloid precursor protein (APP) is a major regulator of neuronal copper homeostasis. APP knockout mice have elevated copper levels in the cerebral cortex, whereas APP-overexpressing transgenic mice have reduced brain copper levels. Importantly, copper binding to APP can greatly reduce amyloid beta production in vitro. To understand this interaction at the molecular level we solved the structure of the APP copper binding domain (CuBD) and found that it contains a novel copper binding site that favors Cu(I) coordination. The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter.

Alzheimer Disease↗

PubMed2006

Disease-associated mutations at copper ligand histidine residues of superoxide dismutase 1 diminish the binding of copper and compromise dimer stability.

A subset of superoxide dismutase 1 (Cu/Zn-SOD1) mutants that cause familial amyotrophic lateral sclerosis (FALS) have heightened reactivity with (-)ONOO and H(2)O(2) in vitro. This reactivity requires a copper ion bound in the active site and is a suggested mechanism of motor neuron injury. However, we have found that transgenic mice that express SOD1-H46R/H48Q, which combines natural FALS mutations at ligands for copper and which is inactive, develop motor neuron disease. Using a direct radioactive copper incorporation assay in transfected cells and the established tools of single crystal x-ray diffraction, we now demonstrate that this variant does not stably bind copper. We find that single mutations at copper ligands, including H46R, H48Q, and a quadruple mutant H46R/H48Q/H63G/H120G, also diminish the binding of radioactive copper. Further, using native polyacrylamide gel electrophoresis and a yeast two-hybrid assay, the binding of copper was found to be related to the formation of the stable dimeric enzyme. Collectively, our data demonstrate a relationship between copper and assembly of SOD1 into stable dimers and also define disease-causing SOD1 mutants that are unlikely to robustly produce toxic radicals via copper-mediated chemistry.

Animals↗

PubMed2000

Copper--ligand interactions and the physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry in vitro.

With a view to the possible use of copper(II)-*OH inactivating ligand (OIL) complexes as regulators of inflammation, the reactivity of the copper(II)-ascorbate system with hydrogen peroxide has been investigated in the presence of three key substances: histidine (the main copper(II) low molecular mass ligand in extracellular fluid), salicylic acid (the well-known nonsteroidal antiinflammatory drug, previously shown to be potentiated by copper(II) in animal models of inflammation), and anthranilic acid (an inactive substance by itself, known to be activated by copper(II) in the same models) at physiological pH (7.4) and inflammatory pH (5.5). Such substances may affect the amount of TBARS detected in solution following copper-mediated Fenton-like reactions through three distinct mechanisms: (i) by decreasing the Cu(II)/Cu(I) redox potential, i.e. at the expense of *OH radical production, (ii) by scavenging *OH radicals in the body of the solution, and/or (iii) by acting as a true OIL, i.e. at the expense of *OH detection. Redox potential measurements of initial solutions have been performed in parallel to TBARS determinations to help discriminate between different ligand influences. Computer-aided speciation has been used to understand the role of copper(II) distribution on the ligand effects characterised. Contrary to previous interpretations, histidine has been found to mainly affect *OH production by lowering the redox potential of the Cu(II)/Cu(I) couple. Salicylate, which has no effect on *OH production, has been confirmed to mainly scavenge *OH radicals in the body of the solution. Anthranilate, which both increases *OH production and decreases *OH detection, behaves as a potential OIL. These results tend to confirm our previous hypothesis that copper potentiation of antiinflammatory substances is indirect, i.e. independent of any interaction between metal and drug, whereas copper activation of substances that are inactive by themselves results from specific metal-substance interactions taking place at inflammatory sites.

Copper↗

PubMed1986

Serum copper and ceruloplasmin levels and urinary copper excretion in thermal injury.

Conflicting reports regarding copper status in thermal injury patients have been published. We determined serial serum-copper and serum-ceruloplasmin levels and 24-h urinary excretion of copper in 23 patients with second- and third-degree thermal burns. Throughout hospitalization, mean serum-copper concentration was significantly depressed; lowest levels were found in patients with greater than 40% total body surface area burns. Serum ceruloplasmin was also depressed, an unexpected finding because this protein is a positive acute-phase reactant poststress. Mean urinary excretion of copper was elevated, reaching 2.5 times the upper limit of normal 2 wk postburn. Depressed serum-copper levels paralleled the serum-ceruloplasmin levels rather than the increased urinary-copper losses. Further studies are required to determine the mechanism(s) of this altered copper metabolism and whether physiological or biochemical evidence of copper deficiency accompanies the observed hypocupremia.

Adult↗

PubMed2001

Plasma zinc, copper, copper:zinc ratio, and survival in a cohort of HIV-1-infected homosexual men.

A prospective cohort study of 121 HIV-1-positive homosexual men was conducted in Miami, Florida, U.S.A. to evaluate the associations between plasma zinc and copper levels and mortality. Plasma zinc and copper levels were measured at baseline and then at semiannual visits. Zinc inadequacy and copper inadequacy were defined as plasma zinc levels <75 (microg/dl) and plasma copper levels <85 (microg/dl), respectively. HIV-1-related deaths were confirmed by review of death certificates. Cox proportional hazards regression models with time-dependent covariates were used to estimate the relative risks of zinc and copper inadequacy on mortality. Over the average course of the 3.3-year follow-up, 19 participants (16%) died of HIV-1-related causes. After adjustment for potential confounders, including low CD4+ cell counts and antiretroviral therapy, zinc inadequacy and copper:zinc ratio >1 (i.e., plasma copper level greater than plasma zinc level) were associated with increased mortality (relative risks [RRs]; 95% confidence intervals [CIs], 4.98, 1.30-19.00 and 8.28, 1.03-66.58, respectively). A negative association was also observed between plasma zinc levels and mortality (RR 0.94; 95% CI, 0.91-0.98). Plasma levels of copper were not significantly associated with mortality. These results suggest that plasma zinc inadequacy or the plasma copper:zinc ratio may be useful predictors of survival in HIV-1 infection. The latter appears to be a stronger predictor.

Adult↗

PubMed2007

Assessment of zinc and copper status in weaned piglets in relation to dietary zinc and copper supply.

The aim of the study was to determine the effect of weaning and the effect of increasing dietary zinc concentrations on the zinc and copper status of weaned piglets (study 1) and to study the effect of high concentrations of dietary zinc and/or copper on zinc and copper status of weaned piglets (study 2). Study 1 included 54 piglets (six litters of nine piglets). One piglet from every litter was killed 1 day before weaning. The remaining 48 piglets were allocated at weaning (28 days) to four dietary zinc treatments (100, 250, 1000 or 2500 ppm) and subsequently killed 1-2, 5-6 or 14-15 days after weaning. Study 2 included 48 piglets (six litters of eight piglets) allocated to four dietary treatments, consisting of low or high dietary zinc (100 or 2500 ppm) in combination with low or high dietary copper (20 or 175 ppm). All piglets in study 2 were killed 5-7 days after weaning. In both studies, the trace mineral status was assessed by zinc and copper concentrations and alkaline phosphatase (AP) activity in plasma and mucosal tissue. In study 2, lymphocyte metallothionein (MT) mRNA and intestinal mucosa MT mRNA concentrations were included as zinc status markers. The results showed that the zinc status, measured as zinc in plasma and mucosa, was not affected by weaning of the piglets. Plasma copper concentrations decreased during the first 2 weeks after weaning. High dietary copper concentrations did not affect the concentration of copper in plasma, but increased the concentration of copper in mucosa and the concentration of zinc in plasma. The dietary zinc treatments increased the zinc concentration in plasma as well as the zinc and MT mRNA concentration in mucosa. Lymphocyte MT mRNA concentrations did not reflect the differences in dietary zinc supplementation.

Administration, Oral↗