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PubMed1988

Copper and copper-binding protein in liver tumors.

The presence of copper and copper-binding protein was histochemically investigated in 39 hepatocellular carcinomas, 24 metastatic tumors of the liver, and eight benign hepatic tumors. None of the hepatocellular carcinomas was fibrolamellar. The presence of copper (demonstrated by rhodanine) and of copper-binding protein (demonstrated by modified orcein) was simultaneously observed in 11 of the 39 hepatocellular carcinomas (28%). Deposition was mild in three cases, moderate in two cases, and marked in six cases, and it was significantly related to the presence of bile within the tumor. Copper and copper-binding protein granules were not found in metastatic tumors of the liver, and were observed in two of the eight cases of benign hepatic tumors. These results suggest that the presence of copper and copper-binding protein in tumor cells may be found in all variants of hepatocellular carcinomas and not only in fibrolamellar carcinomas as previously suggested, and might be helpful in differentiating primary from secondary liver tumors.

Adult↗

PubMed2004

Copper-associated liver disease: a proteomics study of copper challenge in a sheep model.

Sheep display a variant phenotype with respect to their susceptibility to copper and derivative pathology. The North Ronaldsay sheep are acutely sensitive to environmental copper while the Cambridge breed is much more copper-tolerant. A study of protein expression in the liver of the two different breeds of sheep as a result of copper challenge would aid in the understanding of their differing pathophysiologies and contribute to knowledge of copper toxicosis in man. In this initial study, Cambridge breed sheep were challenged with oral copper and liver proteins were analyzed by two-dimensional (2-D) gel electrophoresis. Proteins whose expression pattern was modified by copper exposure were then identified by peptide mass fingerprinting using matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. In conclusion, the pattern of changes in protein expression were consistent with an early adaptive response to oxidative challenge. This was followed by evidence of an impaired ability of the liver to compensate as copper loading increased, accompanied by oxidative stress-induced injury.

Animals↗

PubMed2000

The structural role of the copper-coordinating and surface-exposed histidine residue in the blue copper protein azurin.

Copper K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy and (15)N NMR relaxation studies were performed on samples of a variant azurin in which the surface-exposed histidine ligand of the copper atom (His117) has been replaced by glycine. The experiments were performed to probe the structure of the active site and the protein dynamics. The cavity in the protein structure created by the His-->Gly replacement could be filled by external ligands, which can either restore the spectroscopic properties of the original type-1 copper site or create a new type-2 copper site. The binding of external ligands occurs only when the copper atom is in its oxidised state. In the reduced form, the binding is abolished. From the EXAFS experiments, it is concluded that for the oxidised type-1 copper sites the protein plus external ligand (L) provide an NSS*L donor set deriving from His46, Cys112, Met121 and the external ligand. The type-2 copper site features an S(N/O)(3) donor set in which the S-donor derives from Cys112, one N-donor from His46 and the remaining two N or O donors from one or more external ligands. Upon reduction of the type-1 as well as the type-2 site, the external ligand drops out of the copper site and the coordination reduces to 3-fold with an SS*N donor set deriving from His46, Cys112 and Met121. The Cu-S(delta)(Met) distance is reduced from about 3.2 to 2.3 A. Analysis of the NMR data shows that the hydrophobic patch around His117 has gained fluxionality when compared to wild-type azurin, which may explain why the His117Gly variant is able to accommodate a variety of external ligands of different sizes and with different chelating properties. On the other hand, the structure and dynamics of the beta-sandwich, which comprises the main body of the protein, is only slightly affected by the mutation. The unusually high reduction potential of the His117Gly azurin is discussed in light of the present results.

Amino Acid Substitution↗

PubMed1993

Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation.

The anti-inflammatory role of copper is well-known although still largely unexplained. On the other hand, the capacity of copper to induce the formation of damaging .OH radicals in vivo is no longer debated. These two aspects of the physiological activity of copper have been considered to be paradoxical. Arguments developed here show that they may actually derive from a single chemical process, the type of physiological effect observed depending on the ligand bound to the copper ions involved in Fenton chemistry. Both iron and copper are Fenton catalysts. Given its intrinsic coordination properties, however, copper induces more site-specific .OH damage to the ligands bound to it. It, therefore, appears that copper complexes with specific .OH-inactivating ligands (OILs) can be used as "lures" for the Fenton reaction, .OH radicals preferentially formed on these being immediately inactivated. The hypothesis is thus put forward here that copper-OIL complexes acting as effective Fenton catalysts are potential "catalase-like" anti-inflammatory drugs.

Animals↗

PubMed1991

A comparison of phenotype and copper distribution in blotchy and brindled mutant mice and in nutritionally copper deficient controls.

The murine mottled mutants brindled, Mo br, and blotchy, Mo blo, are valuable animal models for the study of mammalian copper metabolism. In this paper, we present data showing that a nutritionally copper deficient suckling mouse, Cu-, with strong phenotypic similarities to the brindled mutant can be produced by feeding genetically normal dams a copper deficient diet (0.1-0.4 ppm Cu2+) from the day of mating. Comparisons of copper distribution between the Cu- mice and brindled mutants indicate that when a small dose of copper (0.5-0.9 micrograms Cu2+) was administered by intracardiac injection, the copper was abnormally distributed, and that the pattern of tissue distribution was very similar in Cu- mice and brindled mutants 24 h after injection. When, however, a treatment dose (50 micrograms Cu2+) was injected subcutaneously, and tissues assayed 3 d after injection, copper distribution in Cu- mice and brindled mutants was clearly different. Copper deficiency in Cu- suckling mice is entirely derived from maternal effects. Evidence that maternal effects may also influence the survival and phenotype of the brindled and blotchy mutants was obtained by comparing the viability of mutants born to dams carrying mottled mutations on one or both X chromosomes.

Animals↗

PubMed2004

Responses of antioxidative enzymes to accumulation of copper in a copper hyperaccumulator of Commoelina communis.

Discovery of a copper hyperaccumulator is very important for phytoremediation of copper-contaminated soil. In the present study a link was established between the copper accumulation in hyperaccumulator and that in nonaccumulator species of Commelina communis and its responses of antioxidative enzymes, including superoxide dismutase, guaiacol peroxidase, and ascorbate peroxidase. It was verified that copper exerted little physiological damage to copper hyperaccumulator species of Commelina communis at copper accumulation of >1,000 microg/g in dry leaf tissue. However, in nonaccumulator species of Commelina communis superoxide dismutase, guaiacol peroxidase, and ascorbate peroxidase were activated, and malondialdehyde content was increased, which were symptoms of physiological damage by copper intoxication. Therefore, antioxidative enzymes can be used as an indicator of copper toxicity before the visible symptoms can be observed.

Ascorbate Peroxidases↗

PubMed1991

Developmental variation in copper, zinc and metallothionein mRNA in brindled mutant and nutritionally copper deficient mice.

The concentrations of copper, zinc and metallothionein-I (MT-I) mRNA were determined in the liver, kidney and brain of the brindled mutant mouse from birth until the time of death. Despite accumulation of copper in the kidney of the mutant, MT-I mRNA concentrations were normal. There was no difference between the MT-I mRNA in the brain of mutant and normal in the first 10 days of life, but after day 10 metallothionein mRNA levels were increased in the mutant. The concentration of copper was very low in the liver of the mutant, and on day 6 after birth the metallothionein mRNA was also reduced by about 50%. This reduction was not seen in copper-deficient 6-day-old pups, despite very low hepatic copper levels. This suggests that the lower hepatic MT-I mRNA in the day 6 brindled mouse was not simply due to the reduction in hepatic copper and also that hepatic copper is not regulating metallothionein gene expression the liver of neonatal mice. After day 12 hepatic MT-I mRNA levels were elevated in mutant and in copper deficient mice, both of which die at 14 to 16 days. These increases and the increase in brain MT-I mRNA in older mutant mice are likely to be caused by stress. Overall the results support the conclusions that the brindled mutation does not cause a constitutive activation of the metallothionein genes, and that the differences in metallothionein mRNA between mutant and normal are most probably secondary consequences of the mutation.

Animals↗

PubMed2006

Copper trafficking to the mitochondrion and assembly of copper metalloenzymes.

Copper is required within the mitochondrion for the function of two metalloenzymes, cytochrome c oxidase (CcO) and superoxide dismutase (Sod1). Copper metallation of these two enzymes occurs within the mitochondrial intermembrane space and is mediated by metallochaperone proteins. Cox17 is a key copper donor to two accessory proteins, Sco1 and Cox11, to form the two copper centers in the mature CcO complex. Ccs1 is the necessary metallochaperone for the copper metallation of Sod1 in the IMS as well as within the cytoplasm where the bulk of Sod1 resides. Copper ions used in the metallation of CcO and Sod1 appear to be provided by a novel copper pool within the mitochondrial matrix. This review documents copper ion shuttling within the mitochondrion and the proteins that mediate assembly of active CcO and Sod1.

Biological Transport↗

PubMed2005

Speciation and leachability of copper in mine tailings from porphyry copper mining: influence of particle size.

Mine tailing from the El Teniente-Codelco copper mine situated in VI Region of Chile was analysed in order to evaluate the mobility and speciation of copper in the solid material. Mine tailing was sampled after the rougher flotation circuits, and the copper content was measured to 1150 mg kg (-1) dry matter. This tailing was segmented into fractions of different size intervals: 0-38, 38-45, 45-53, 53-75, 75-106, 106-150, 150-212, and >212 microm, respectively. Copper content determination, sequential chemical extraction, and desorption experiments were carried out for each size interval in order to evaluate the speciation of copper. It was found that the particles of smallest size contained 50-60% weak acid leachable copper, whereas only 32% of the copper found in largest particles could be leached in weak acid. Copper oxides and carbonates were the dominating species in the smaller particles, and the larger particles contained considerable amounts of sulphides.

Adsorption↗

PubMed2006

Sulfidation treatment of copper-containing plating sludge towards copper resource recovery.

The present study is concerned with the sulfidation treatment of copper-containing plating sludge towards copper resource recovery by flotation of copper sulfide from treated sludge. The sulfidation treatment was carried out by contacting simulated or real copper plating sludge with Na(2)S solution for a period of 5 min to 24 h. The initial molar ratio of S(2-) to Cu(2+) (S(2-) to Me(2+) in the case of real sludge) was adjusted to 1.00, 1.25 or 1.50, while the solid to liquid ratio was set at 1:50. As a result, it was found that copper compounds were converted to various copper sulfides within the first 5 min. In the case of simulated copper sludge, CuS was identified as the main sulfidation product at the molar ratio of S(2-) to Cu(2+) of 1.00, while Cu(7)S(4) (Roxbyite) was mainly found at the molar ratios of S(2-) to Cu(2+) of 1.50 and 1.25. Based on the measurements of oxidation-reduction potential, the formation of either CuS or Cu(7)S(4) at different S(2-) to Cu(2+) molar ratios was attributed to the changes in the oxidation-reduction potential. By contrast, in the case of sulfidation treatment of real copper sludge, CuS was predominantly formed, irrespective of S(2-) to Me(2+) molar ratio.

Copper↗

PubMed2002

Thiourea protects against copper-induced oxidative damage by formation of a redox-inactive thiourea-copper complex.

Although thiourea has been used widely to study the role of hydroxyl radicals in metal-mediated biological damage, it is not a specific hydroxyl radical scavenger and may also exert antioxidant effects unrelated to hydroxyl radical scavenging. Thus, we investigated the effects of thiourea on copper-induced oxidative damage to bovine serum albumin (1 mg/ml) in three different copper-containing systems: Cu(II)/ascorbate, Cu(II)/H(2)O(2), and Cu(II)/H(2)O(2)/ascorbate [Cu(II), 0.1 mM; ascorbate, 1 mM; H(2)O(2), 1 mM]. Oxidative damage to albumin was measured as protein carbonyl formation. Thiourea (0.1-10 mM) provided marked and dose-dependent protection against protein oxidation in all three copper-containing systems. In contrast, only minor protection was observed with dimethyl sulfoxide and mannitol, even at concentrations as high as 100 mM. Strong protection was also observed with dimethylthiourea, but not with urea or dimethylurea. Thiourea also significantly inhibited copper-catalyzed oxidation of ascorbate, and competed effectively with histidine and 1,10-phenanthroline for binding of cuprous, but not cupric, copper, as demonstrated by both UV-visible and low temperature electron spin resonance measurements. We conclude that the protection by thiourea against copper-mediated protein oxidation is not through scavenging of hydroxyl radicals, but rather through the chelation of cuprous copper and the formation of a redox-inactive thiourea-copper complex.

Animals↗

PubMed2001

Influence of inositolhexaphosphori acid (phytic acid) on the copper distribution in tissues and the excretion of copper in rats.

The aim of the present study was to investigate the effect of the administration of phytic acid on copper (Cu) concentrations in several different rat tissues. The animals used were divided into three groups: Group A (received a diet supplemented with 2% phytic acid), group B (received a diet supplemented with 10% phytic acid) and group C (control). At the end of the experiment, the animals were sacrificed and the concentration of copper was determined in the different tissues. Phytic acid significantly increased Cu concentration in the duodenum of the animals of both groups as well as in the lungs and blood of the animals of group A. The copper concentration was also increased in the uterus and bone of the animals of group B. On the other hand, the stomach copper concentration of the animals of both groups, the heart and lung copper concentrations of the animals of group B as well as the jejunum, colon and hair copper concentrations of the animals of group A were significantly decreased. Copper excretion through feces was significantly decreased in the animals of both groups, while the excretion through urine was not significantly affected by the administration of phytic acid. In conclusion, the administration of phytic acid can produce translocation and/or elimination of copper in various tissues of rats.

Animals↗

PubMed2001

Leucocyte copper, a marker of copper body status is low in coronary artery disease.

To elucidate the relationship between leucocyte copper as a reliable, sensitive index of copper body status and extent of atherosclerosis in patients with Coronary Artery Disease (CAD) the present case-control study was carried out. 80 subjects were studied (23 females and 57 males), aged between 30-70, due to have a angiography. Individual angiograms were scored by combining the individual scores in all the major coronary arteries into one score of a scale 1.00 for patency to 0.00 for severe CAD. Serum and leucocyte copper and zinc were determined by GFAAS. No significant difference between patients with advanced CAD and relatively normal arteries were observed in the lipid profile and levels of plasma copper. Leucocyte copper had a significant link with the severity of atherosclerosis which was independent of sex. There was a linear relationship between the degree of decreasing leucocyte copper concentration and angiogram score. These findings give support to the hypothesis that marginal copper status, assessed by decreased leucocyte copper level, is associated with developing CAD.

Adult↗

PubMed2002

Cadmium, copper and zinc in tissues of deceased copper smelter workers.

Workers at a copper and lead smelter in northern Sweden have a multifactorial exposure to a number of heavy metals. The concentrations of cadmium, copper and zinc in liver, lung, kidney and brain tissues have been determined by atomic absorption spectrometry in 32 deceased long-term exposed male lead smelter workers, and compared with those of 10 male controls. Furthermore, copper and zinc levels in hair and nails were determined by energy-dispersive X-ray fluorescence. The highest cadmium concentrations among both workers and controls were observed in kidney, followed in order by liver, lung and brain. The levels in kidney, liver and lung were all significantly higher in the workers than in the controls (p < 0.03). Among the workers relatively strong positive correlations (p < 0.03) were observed between cadmium concentrations in liver and lung, liver and kidney, liver and brain, and lung and brain. In the exposed workers a positive correlation was observed between cadmium and zinc concentrations in the kidney (rs = 0.38; p = 0.034). This is probably mainly due to the protein metallothionein, which is stored in the kidney, binding equimolar amounts of these two metals. The highest concentrations of copper were found in hair and nails among both workers and controls, followed in order by liver, brain, kidney and lung. The tissue concentrations of copper in brain, lung and kidney were all significantly higher among the smelter workers than in the controls (p < 0.036). Copper levels in lung and age at time of death were positively correlated among the exposed workers (rs = 0.39; p = 0.029). In the same group, positive correlations between copper and zinc concentrations in kidney (rs = 0.45; p = 0.009) and nails (rs = 0.68; p < 0.001) were also observed, reflecting possible biological interactions between these two metals. Among both workers and controls, the highest zinc concentrations were found in hair, followed in order by nails, liver, kidney, brain and lung. Significantly higher tissue concentrations among the workers as compared with the reference group were noted in kidney, liver and brain (p < 0.033). Neither copper nor zinc concentrations in hair and nails seemed to provide a useful measure of the trace element status of the smelter workers.

Body Burden↗

PubMed1998

Electronic structural information from Q-band ENDOR on the type 1 and type 2 copper liganding environment in wild-type and mutant forms of copper-containing nitrite reductase.

Q-band ENDOR elucidated proton and nitrogen hyperfine features to provide spin density information at ligands of blue-green Type 1 and catalytic Type 2 copper centers in nitrite reductase. The blue-green Type 1 center of nitrite reductase has a redox, electron-transfer role, and compared to the blue center of plastocyanin, it has the following structural differences: a shortened Cu-Smet bond length, a longer Cu-Scys bond length, and altered ligand-copper-ligand bond angles (Adman, E. T., Godden, J. W., and Turley, S. (1995) J. Biol. Chem. 270, 27458-27474). The hyperfine couplings of the two Type 1 histidine (N delta) ligands showed a larger percentage difference from each other in electron spin density than previously reported for other blue Type 1 proteins, while the cysteine beta-proton hyperfine couplings, a measure of unpaired p pi spin density on the liganding cysteine sulfur, showed a smaller electron spin density. A mutation of the Type 1 center, M182T, having the copper-liganding Met182 transformed to Thr182, caused the center to revert to an optically "blue" center, raised its redox potential by approximately 100 mV, and led to the loss of activity (prior paper). Surprisingly, in M182T there was no change from native Type 1 copper either in the histidine or cysteine hyperfine couplings or in g values and Cu nuclear hyperfine couplings. The conclusion is that the optical and redox alterations due to changed Type 1 methionine ligation need not be concurrent with electron spin delocalization changes in the HOMO as reported from its essential cysteine and histidines. A detailed picture of the nitrogen couplings from the three histidine (N epsilon) ligands of the Type 2 center indicated a substantial ( approximately 200%) electronic hyperfine inequivalence of one of the histidine nitrogens from the other two within the Type 2 HOMO and thus provided evidence for electronic distortion of the Type 2 site. In the presence of the nitrite substrate, hyperfine couplings of all histidines diminished. We suggest that this nitrite-induced decreased covalency would correlate with an increased Type 2 redox potential to assist electron transfer to the Type 2 center. Dipole-coupled, angle-selected exchangeable proton features, observed over a range of g values, predicted a ligand-water proton distance of 2.80 A from copper, and these water protons were eliminated by nitrite. His287 is not a Type 2 ligand but is positioned to perturb an axial water or a nitrite of Type 2 copper. In the presence of nitrite the mutant H287E showed no evidence for the loss of water protons and no diminished ligand histidine covalency. H287E has vastly diminished activity (prior paper), and the ENDOR information is that NO2- does not bind to Type 2 copper of H287E. In summary, the electronic information from this study of native and suitably chosen mutants provided a test of the highest occupied molecular orbital (HOMO) wave function at Type 1 and Type 2 coppers and an intimate electronic insight into functional enzymatic properties.

Copper↗

PubMed2005

Copper toxicity to larval stages of three marine invertebrates and copper complexation capacity in San Diego Bay, California.

Temporal and spatial measurements of the toxicity (EC50), chemical speciation, and complexation capacity (Cu-CC) of copper in waters from San Diego Bay suggest control of the Cu-CC over copper bioavailability. While spatial distributions of total copper (CuT) indicate an increase in concentration from the mouth toward the head of San Diego Bay, the distribution of aqueous free copper ion (Cu(II)aq) shows the opposite trend. This suggests that the bioavailability of copper to organisms decreases toward the head of the bay, and is corroborated by the increase in the amount of copper needed to reach an EC50, observed for larval stages of three marine invertebrates (Mediterranean mussel, Mytilus galloprovincialis, sand dollar, Dendraster excentricus, and purple sea urchin, Strongylocentrotus purpuratus), and by the increase in Cu-CC heading into the head of the bay. The amount of Cu(II)aq required to produce a 50% reduction in normal larval development (referred to here as pCuTox,) of the mussel, the most sensitive of the three marine invertebrates, was generally at or above approximately 1 x 10(-11) mol L(-1) equivalents of Cu (i.e., pCuTox approximately 11 = -(log [Cu(II)aq])). These results suggest that the copper complexation capacity in San Diego Bay controls copper toxicity by keeping the concentration of Cu(II)aq at nontoxic levels.

Animals↗

PubMed2005

Tridentate copper ligand influences on heme-peroxo-copper formation and properties: reduced, superoxo, and mu-peroxo iron/copper complexes.

In cytochrome c oxidase synthetic modeling studies, we recently reported a new mu-eta2:eta2-peroxo binding mode in the heteronuclear heme/copper complex [(2L)Fe(III)-(O2(2-))-CuII]+ (6) which is effected by tridentate copper chelation (J. Am. Chem. Soc. 2004, 126, 12716). To establish fundamental coordination and O2-reactivity chemistry, we have studied and describe here (i) the structure and dioxygen reactivity of the copper-free compound (2L)FeII (1), (ii) detailed spectroscopic properties of 6 in comparisons with those of known mu-eta2:eta1 heme-peroxo-copper complexes, (iii) formation of 6 from the reactions of [(2L)FeIICuI]+ (3) and dioxygen by stopped-flow kinetics, and (iv) reactivities of 6 with CO and PPh3. In the absence of copper, 1 serves as a myoglobin model compound possessing a pyridine-bound five-coordinate iron(II)-porphyrinate which undergoes reversible dioxygen binding. Oxygenation of 3 below -60 degrees C generates the heme-peroxo-copper complex 6 with strong antiferromagnetic coupling between high-spin iron(III) and copper(II) to yield an S = 2 spin system. Stopped-flow kinetics in CH2Cl2/6% EtCN show that dioxygen reacts with iron(II) first to form a heme-superoxide moiety, [(EtCN)(2L)FeIII-(O2-)...CuI(EtCN)]+ (5), which further reacts with Cu(I) to generate 6. Compared to those properties of a known mu-eta2:eta1-heme-peroxo-copper complex, 6 has a significantly diminished resonance Raman nu(O-O) stretching frequency at 747 cm(-1) and distinctive visible absorptions at 485, 541, and 572 nm, all of which seem to be characteristics of a mu-eta2:eta2-heme-peroxo-copper system. Addition of CO or PPh3 to 6 yields a bis-CO adduct of 3 or a PPh(3) adduct of 5, the latter with a remaining FeIII-(O2-) moiety.

Copper↗

PubMed1998

Effect of stainless steel on corrosion behavior of copper in a copper-bearing intrauterine device.

Some copper-bearing intrauterine devices (Cu-IUDs) consist of pure copper and stainless steel. Corrosion of copper in the Cu-IUD was anticipated to be affected by galvanic action due to electrical contact between these two metals. Electrochemical measurements were carried out in physiological saline with or without indomethacin, which was introduced for bleeding control. In the copper/stainless steel couple, the open-circuit potential of stainless steel was found to play a decisive role. In most cases, when stainless steel was in the passive state and acted as the cathode, the contact accelerated copper corrosion. In addition, the area ratio of stainless steel to copper altered copper corrosion behavior. The larger the area of stainless steel, the greater the acceleration of copper corrosion. It was noted that the stainless steel surface might be activated due to improper handling of the IUD. In this case, copper became the cathode of the couple and its corrosion was suppressed.

Anti-Inflammatory Agents, Non-Steroidal↗