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PubMed2001

Lower copper, zinc-superoxide dismutase protein but not mRNA in organs of copper-deficient rats.

Copper deficiency was induced in Sprague Dawley rats by dietary restriction to confirm and extend studies on copper, zinc-superoxide dismutase (Cu,Zn-SOD). Male rats restricted from copper in two models, a traditional postweanling model examining 50-day-old rats fed a low copper diet for 32 days (postnatal) and a gestational-lactational model examining 23-day-old male offspring of dams started on copper deficiency at day 7 of gestation (perinatal), showed signs of severe copper deficiency including anemia, and cardiac hypertrophy. Compared to control rats, copper-deficient rats exhibited lower copper concentrations in the liver, heart, brain, and kidney and lower Cu,Zn-SOD activity in the same organs with the exception of the brain in the postnatal model. In addition, there was a significant reduction in Cu,Zn-SOD protein detected by Western immunoblot proportional (r = 0.96) to the reduction in Cu,Zn-SOD activity. In the liver the reduction in Cu,Zn-SOD protein was approximately 50%. The reduction in Cu,Zn-SOD protein is likely due to a post-transcriptional mechanism as steady-state Cu,Zn-SOD mRNA levels measured by Northern hybridization were not altered by copper deficiency in any organ studied (liver, heart, and brain). Perhaps apo-Cu,Zn-SOD is degraded faster than fully metal-loaded enzyme. The loss of Cu,Zn-SOD activity and protein reduces the antioxidant defense capacity of copper-deficient organs.

Animals↗

PubMed1978

[Copper and zinc contents in milk and plasma of cows after high nutritional copper supplements].

In three feeding trials with dairy cows over periods of six weeks each, it was studied whether very high nutritional supplements of copper alter the copper and zinc levels of milk and plasma. The supplemented groups with an average milk yield of 20 kg were given CuSO4 X 5H2O at levels varying from 250 to 550 mg copper per cow and day over and above the amount supplied by the commercial winter ration (300 mg copper and 1200 mg zinc). There was no significant influence of the copper supplementation on the copper and zinc contents of milk compared with the untreated control animals. On the average for all experimental weeks, copper contents of 0.15--0.20 mg and zinc content of 4.0--4.6 mg/kg milk were recorded for the various experimental groups. The mean copper contents in plasma varied from 1.00 to 1.18 microgram/ml in the copper-supplemented groups and from 0.93 to 1.09 mircogram/ml in the control groups. The corresponding mean values for zinc ranged from 0.93 to 1.18 microgram/ml. Analysis of variance did not show any significant differences between the experimental groups nor any interactions between the copper and zinc contents. These results were discussed in relation to the dietary supply status.

Animals↗

PubMed1991

The protective role of metallothionein in copper overload: I. Differential distribution of immunoreactive metallothionein in copper-loaded rat liver and kidney.

The cytotoxicity of copper is probably determined by its molecular association and subcellular localisation rather than its concentration within tissues. Metallothionein (MT) is a copper binding protein distributed between the particulate and soluble cellular components. The role of MT in conferring protection to the copper-loaded rat has been investigated by comparing the distribution of the immunoreactive protein between the soluble and particulate fractions of liver and kidney during the development of copper tolerance. Young male Wistar rats were fed a high copper (1 g/kg) diet for 16 weeks and killed sequentially during this period; liver and kidneys were retained. Pellet and supernatant preparations from homogenised, pooled samples of liver and kidney were subjected to chromatographic separation. Copper and zinc were analysed in whole tissue, homogenates and eluant fractions and MT identified likewise using an enzyme-linked immunoassay. Copper accumulated for 5 weeks in the liver falling subsequently accompanied by similar changes in MT content. Kidney copper and MT rose to maximum concentrations at 8 weeks and were maintained thereafter. Substantial differences were apparent in the relative distribution of MT between the two organs. MT was the major, predominantly cytosolic, copper-binding protein in the kidney but in the liver immunoreactive MT was pelleted and present in lower concentration than the high molecular weight cuproproteins. It was concluded that whilst MT plays a role in the detoxification and adaptation of rats to copper-loading the regulatory functions of liver and kidney may differ significantly in this respect.

Animals↗

PubMed1989

Cellular mechanisms of toxicity and tolerance in the copper-loaded rat. II. Pathogenesis of copper toxicity in the liver.

The distribution of copper has been studied in the liver of the copper-loaded rat at the ultrastructural level by X-ray electron probe microanalysis in order to clarify the pathogenesis of copper-induced damage. Male rats fed a high copper diet (1500 ppm) for 16 weeks were killed at intervals; their livers were removed and fixed in 4% paraformaldehyde and 2% glutaraldehyde for electron microscopy and were analyzed for copper by AA spectrophotometry. Three different forms of lysosomes were identified with respect to their morphology and X-ray emission profiles: Type I lysosomes appeared early and contained iron and zinc in addition to markedly elevated copper peaks, whereas later appearing Type II lysosomes included sulfur and phosphorus in addition to copper. Type III lysosomes were associated with the recovery period and contained much reduced elemental residue. Degenerative changes were not observed in any of the three types of lysosomes. Copper and other elemental residues, including sulfur, were also identified within the hepatic parenchymal cell nuclei and by contrast were associated with irreversible nuclear damage. Nuclear copper is directly injurious to this organelle and responsible for the subsequent cell death whereas copper contained within lysosomes is apparently innocuous.

Animals↗

PubMed1983

The role of lysosomes in the pathogenesis of copper-induced hepatotoxicity. II. Intracellular distribution of copper in hepatocytes.

The effects of altered lysosomal function on the pathogenesis of copper-induced hepatotoxicity were studied in C57B1/6 bg/bg (beige) and C57B1/6 bg/+ (conventional) mice. Copper loading was accomplished through daily ip injections of aqueous copper chloride at a dosage rate of 8 mg/kg body weight for 1, 2, and 4 weeks. The subcellular distribution of copper in copper-treated beige mice was significantly different than that in conventional mice. Beige mice had consistently higher levels of copper in the nuclear and cytosolic fractions with lower levels in the heavy and light mitochondrial fractions. The copper levels were lowest in the microsomal fractions of both groups of copper-treated mice and remained similar throughout the 4-week experiment. Levels of total hepatic copper were similar in both groups of mice receiving parenteral copper except at Day 14, when beige mice had higher levels.

Animals↗

PubMed1984

Distribution of copper atoms and binding of carbon monoxide in partially copper-depleted hemocyanin.

Binding of CO to single cuprous (half-apo) or cupric (met-apo) copper of hemocyanin is investigated by a new method which allows estimation of the total amount of CO bound to hemocyanin. Pure half-apo preparations could not be obtained with the molluscan hemocyanins from Helix pomatia and Octopus vulgaris, and a residual fraction of sites with coupled copper is always present. However, the determination of CO bound to the protein before and after addition of H2O2, used to oxidize selectively single copper sites, reveals that CO binds to half-apo Cu(I), and is released upon oxidation of copper to met-apo Cu(II). Binding of CO to half-apo is not associated to luminescence, proving that luminescence of native carboxyhemocyanin demands the presence of a second cuprous copper in the site. In addition, analysis of data indicates that the residual amount of coupled copper sites in partially copper-depleted hemocyanin is underestimated by the residual O2-copper band measured at 340 nm in air, while faithfully quantitated by the residual luminescence in the presence of CO. A distribution of the copper left in the site of three partially copper-depleted hemocyanins is depicted.

Animals↗

PubMed1991

Inverse correlation between resistance towards copper and towards the redox-cycling compound paraquat: a study in copper-tolerant hepatocytes in tissue culture.

The essential mediatory role of copper or iron in the manifestation of paraquat toxicity has been demonstrated (Kohen and Chevion (1985) Free Rad. Res. Commun. 1, 79-88; Korbashi, P. et al. (1986) J. Biol. Chem. 261, 12472-12476). Several liver cell lines, characterized by their resistance to copper, were challenged with paraquat and their cross-resistance to paraquat and copper was studied. Cell growth and survival data showed that copper-resistant cells, containing elevated copper, are more sensitive towards paraquat than wild type cells. Copper-deprived resistant cells did not have this sensitivity. Paraquat was also shown to cause a marked degradation of cellular glutathione in all cell lines. Albeit the fact that the basal glutathione levels are higher in copper-resistant than in wild type cells, there is more paraquat-induced degradation of cellular glutathione (GSH + GSSG) in resistant cells. It is suggested that in copper-resistant cells which contain elevated levels of copper, paraquat-induced cellular injury is potentiated even where glutathione levels are elevated. Additionally, in vitro experiments are presented that support the in vivo findings demonstrating a role for copper in glutathione degradation.

Animals↗

PubMed2005

Tolerance of Oocystis nephrocytioides to copper: intracellular distribution and extracellular complexation of copper.

Several mechanisms have been proposed to explain how algae can tolerate heavy metals. In order to better understand the mechanisms determining metal tolerance, we examined the interaction of copper with two strains of the copper-tolerant green algae Oocystis nephrocytioides, isolated from algal communities differing only in copper exposure. The strains were cultured in chemically-defined media containing 0.04 microM Cu(total) (pCu 12.4) or 2 microM Cu(total) (pCu 10.6). Growth, photosynthesis rate, content of chlorophyll a and b, copper accumulation, its cellular distribution and ultrastructural localization, as well as the influence of algal growth on extracellular copper complexation were determined. Both strains had comparable growth and photosynthesis rates. The cellular content of both chlorophyll a and b was reduced, by roughly the same extent, at pCu 10.6 compared to pCu 12.4. Copper titration of the media indicated the production of copper-complexing ligands by O. nephrocytioides cultured at pCu 12.4 that increased with increased algal density during cell growth. No additional ligands were detected at pCu 10.6. Copper-complexing ligands had a conditional stability constant of K = 10(13) at pH 7.3. The intracellular concentration of copper in O. nephrocytioides was 80 microM at pCu 12.4 and increased to 7.5mM at pCu 10.6. The proportion of intracellular Cu accumulated increased from 8% of total Cu content at pCu 12.4 to 60% at pCu 10.6. By electron spectroscopic imaging, intracellular Cu was detected in the thylakoids and the pyrenoid of O. nephrocytioides cells. The results indicate that the tolerance of O. nephrocytioides to Cu is constitutive and does not need to be induced by previous exposure to Cu. We propose that accumulation and sequestration of Cu in thylakoids and, to a lesser extent, adsorption of copper to the algal cell surface represent the most important tolerance mechanism, for O. nephrocytioides.

Chlorophyll↗

PubMed2004

Copper-induced hepatotoxicosis with hepatic stellate cell activation and severe fibrosis in North Ronaldsay lambs: a model for non-Wilsonian hepatic copper toxicosis of infants.

Copper-sensitive North Ronaldsay sheep represent a possible model for certain hepatic-overload syndromes of infancy and childhood that are clinically, pathologically and genetically distinct from Wilson's disease. The purpose of this study was to simulate in artificially reared lambs the syndrome produced by copper exposure in susceptible human infants. Twenty four North Ronaldsay lambs were assigned to three groups of eight animals, namely, an unsupplemented control group and two trial groups given milk replacer to which copper (CuSO4) had been added at the rate of 5 mg/litre and 10 mg/litre. Four lambs from each group were killed at 40 or 69 days. Livers were fixed in 10% formalin and analysed for copper by mass spectrometry. Paraffin wax-embedded sections were stained with rhodanine for copper and labelled immunohistochemically for alpha smooth muscle actin (ASMA). At 40 days the maximum amounts of copper in the livers of both copper-supplemented groups was 1466-1605 microg/g dry weight (control group 172-201 microg/g Cu dry weight). Histochemically, copper was demonstrated within hepatocytes, together with marked apoptosis. At 69 days there was a florid pericellular fibrosis complemented by strong ASMA immunolabelling, confirming phenotypic modulation of hepatic stellate cells. Such primary copper-induced fibrogenesis confirms the unique status of this animal model in respect of childhood copper toxicosis.

Animals↗

PubMed1976

X-ray photoelectron spectroscopy of copper(II), copper(I), and mixed valence systems.

X-ray photoelectron spectroscopy using copper(II), copper(I) and the mixed valence Cu(II)/Cu(I) compounds was employed as a means of studying electron transfer reactions in copper proteins. The X-ray photoelectron spectra of copper(II) compounds display characteristic satellites of both variable size and resolution. Some of these satellites could be assigned to specific ligand interactions. Unlike electron paramagnetic resonance spectroscopy, the X-ray photoelectron spectroscopic measurements of copper(I) compounds allowed the unequivocal assignment of this oxidation state. No satellites at all could be detected in the Cu(I) spectra. Furthermore, established mixed valence Cu(II)/Cu(I) complexes including Cu2SO3-CuSO3-2H2O and Cu4Cl5 (ethylenediamine)2 proved essentially a mixture of distinct portions of Cu(I) and Cu(II). This indicates that both oxidation states of copper survive in such complexes. In contrast, all Cu X-ray photoelectron signals of the more tentatively described mixed valence complexes Na2Cu3S3 and the mineral covellite, CuI4CuII2(S2)2S2, could be attributed exclusively to Cu(I). In view of the known binding of copper with sulfur in many copper proteins, it was of utmost importance to study the copper-sulfur interactions. We have demonstrated the absence of Cu(II) in CuS. This indicates strong metal-induced polarization of sulfur resulting in electron transfer to copper to yield Cu(I).

Amino Acids↗

PubMed2006

Modeling the mononuclear, dinuclear, and trinuclear copper(I) reaction centers of copper proteins using pyridylalkylamine ligands connected to 1,3,5-triethylbenzene spacer.

The structure and O2-reactivity of copper(I) complexes supported by novel ligands, Pye2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(2-(pyridin-2-yl)ethyl)-)aminomethyl)benzene), Pye3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(2-(pyridin-2-yl)ethyl))aminomethyl)benzene), MePym2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene), and MePym3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene) have been examined. The ligands are designed to construct mono-, di-, and trinuclear copper(I) complexes by connecting two or three pyridylalkylamine metal-binding sites to a 1,3,5-triethylbenzene spacer. Thus, the reaction of the ligands with [CuI(CH3CN)4]X (X = PF6, CF3SO3) or CuICl gave the expected mononuclear copper(I) complexes [CuI(Pye2)(CF3SO3)] (1) and [CuI(Pye3)](CF3SO3) (2), dinuclear copper(I) complex [CuI2(MePym2)(Cl)]CuICl2 (3), and trinuclear copper(I) complex [CuI3(MePym3)(CH3CN)3](CF3SO3)3 (4), the structures of which were determined by X-ray crystallographic analysis. The mononuclear copper(I) complexes, 1 and 2, exhibit a distorted three-coordinate T-shape structure and a trigonal planar structure, respectively, which are very close to the coordination geometry of the CuA site of PHM (peptidylglycine alpha-hydroxylating monooxygenase) and the CuB site of CcO (cytochrome c oxidase). Notably, 1 and 2 showed a significantly high oxidation potential (990 mV vs SCE), thus showing virtually no reactivity toward O2. On the other hand, the metal centers of the dinuclear and trinuclear copper(I) complexes, 3 and 4, exhibit a distorted trigonal planar geometry and a trigonal pyramidal geometry, respectively. In contrast to the mononuclear copper(I) complexes, these dinuclear and trinuclear copper(I) complexes reacted with O2 to induce an aromatic ligand hydroxylation reaction involving an NIH-shift of one of the ethyl substituents on the benzene spacer. The NIH-shift of the alkyl substituent on the aromatic ring is strong evidence of the electrophilic aromatic substitution mechanism, although the active oxygen intermediate could not be directly detected during the course of the reaction. The biological relevance of the copper(I) complexes is also discussed on the basis of structure and O2-reactivity.

Benzene Derivatives↗

PubMed1996

New insights into the pathogenesis of copper toxicosis in Wilson's disease: evidence for copper incorporation and defective canalicular transport of caeruloplasmin.

Previous studies have suggested that copper is incompletely incorporated into caeruloplasmin, the major plasma form of copper-transporting protein, in the genetic copper toxic condition, Wilson's disease. In this paper we have investigated the role of copper and caeruloplasmin in the abnormal biliary copper transport and characterizes Wilson's disease. Using SDS/PAGE and Western blotting, we have demonstrated the presence of holocaeruloplasmin in liver samples from patients with Wilson's disease (abnormal biliary copper excretion) and in control patients (normal biliary copper excretion). The presence of holocaeruloplasmin was also confirmed by measurement of caeruloplasmin oxidase activity using staining with o'Dianisidine. In contrast with the findings in liver tissue, holocaeruloplasmin was absent from bile from patients with Wilson's disease, but as expected it was present in the bile from control subjects. We have also identified and partially characterized a 189-200 kDa protein from purified human biliary canalicular membranes which binds copper and possesses caeruloplasmin-like activity when probed with a specific human anti-caeruloplasmin antibody. In conclusion, we have demonstrated that copper incorporation in caeruloplasmin is normal in patients with Wilson's disease contrary to previous reports. Secondly, we have shown that the defect in Wilson's disease appears to lie in the biliary canalicular excretion of holocaeruloplasmin resulting in its retention within the hepatocyte causing copper toxicosis. Finally we have identified and partially characterized a caeruloplasmin-binding protein from biliary canalicular membranes which may provide a link to the gene defect in Wilson's disease.

Apoproteins↗

PubMed1978

[Behavior of the trace elements copper, zinc and manganese in bovine rumen. 1. Trace element content of different fractions of rumen fluid and the effect of copper sulfate administration].

Two adult, rumen-fistulated steers were fed, over four consecutive 3-week periods, Cu-deficient and normal hays with and without copper sulphate supplementation. Their rumen liquor levels of copper, zinc and manganese were determined correspondingly. The rumen liquor samples were split into 3 fractions by way of centrifugation, sodium dodecyl sulphate treatment of the sediment and filtration. The fractionation of the rumen liquor showed copper to be contained mainly in the water-soluble supernatant (68%), whilst zinc and manganese are more strongly linked to the microbial fraction (57 and 46%, resp.). The plant residue did not average but 9, 24 and 22% of copper, zinc and manganese, respectively. Copper sulphate supplementation to normal hay resulted in a significantly increased copper content in the supernatant and in the microbial fraction. At the same time, the zinc and manganese content values in the microbial fraction were found increased. However, the same copper sulphate supplementation to Cu-deficient hay was found to reduce highly significantly the copper level in the microbial fraction. It is supposed that the excessively high molybdenum content of this hay (2.5 ng/kg) has prevented any effect of the copper sulphate supplementation. The positive effects of copper sulphate supplementation on the zinc and manganese levels in the bacterial fraction were maintained even when feeding Cu-deficient hay rich in Mo.

Animal Feed↗

PubMed2006

Evaluation of copper speciation and water quality factors that affect aqueous copper tasting response.

This study determined taste thresholds for copper as its speciation was varied among free cupric ion, complexed cupric ion, and precipitated cupric particles. The impact of copper chemistry on taste is important as copper is added to many beverages and can be present in drinking water as a natural mineral or due to corrosion of copper plumbing. A one-of-five test was used to define thresholds with solutions containing 0.025-8 mg/l Cu (from copper sulfate) in distilled or mineralized water of varying pH. The mineralized water was designed to mimic the composition of a typical tap water. Group thresholds for copper in either distilled-deionized water or mineralized water were not significantly different and ranged from 0.4 to 0.8 mg/l Cu. A difference from control test was used to assess the impact of soluble and particulate copper on taste. Soluble copper species, including free cupric ion and complexed copper species, were readily tasted, while particulate copper was poorly tasted.

Adult↗

PubMedDate not supplied

Examination of the cutaneous absorption of copper after the use of copper-containing ointments.

Because copper-containing ointments are frequently used in anthroposophical medicine, a phase I trial to investigate the cutaneous absorption of copper was conducted. Sixty-one volunteers were randomized [group A: 0.4% copper (I) oxide, 13 men and 18 women (19-55 years); group B: 20% elementary copper, 11 men and 19 women (18-70 years)]. The ointment was applied over a 4-week period followed by a 4-week wash-out phase. Serum and urine copper concentrations were measured by atomic absorption spectrometry and hair copper concentration by inductive coupled plasma mass spectrometry. For statistical analysis, the Student t test for related random samples was used; alpha = 0.05 was chosen for the standard error. In group A, an increase of copper in serum and scalp hair and a decrease in urine were found in the study period. The mean serum concentration in all premenopausal women using oral contraceptives was above normal. In group B, the serum copper concentration increased significantly; in urine, it decreased, and in scalp hair, it remained stable. A higher level of serum copper was found in female volunteers using hormonal contraception. Treatment with the 2 different ointments did not cause toxic irritations on the skin, and it can therefore be deduced that the appropriate application of ointment preparations containing copper in concentrations up to 20% do not present a toxic risk.

Administration, Cutaneous↗

PubMed2002

Structure and dynamics of copper-free SOD: The protein before binding copper.

The solution structure of the copper-free state of a monomeric form of superoxide dismutase (153 amino acids) was determined through (13)C and (15)N labeling. The protein contained two mutations at the native subunit-subunit interface (F50E and G51E) to obtain a soluble monomeric species and a mutation in the active site channel (E133Q). About 93% of carbon atoms, 95% of nitrogen atoms, and 96% of the protons were assigned. A total of 2467 meaningful NOEs and 170 dihedral angles provided a family of 35 conformers with RMSD values of 0.76 +/- 0.09 A for the backbone and 1.22 +/- 0.13 A for all heavy atoms. The secondary structure elements, connected by loops, produce the typical superoxide dismutase Greek key fold, formed by an eight-stranded beta-barrel. The comparison with the copper-bound monomeric and dimeric structures shows that the metal ligands have a conformation very close to that of the copper-bound forms. This feature indicates that the copper-binding site is preorganized and well ordered also in the absence of the copper ion. The active-site channel shows a sizable increase in width, achieving a suitable conformation to receive the copper ion. The histidines ring NH resonances that bind the copper ion and the region around the active-site channel experience, as found from (15)N relaxation studies, conformational exchange processes. The increased width of the channel and the higher mobility of the histidine rings of the copper site in the copper-free form with respect to the holoprotein is discussed in terms of the process of copper insertion.

Copper↗

PubMed1990

Role of albumin's copper binding site in copper uptake by mouse hepatocytes.

It is possible, in vitro, to label albumin with copper either exclusively on the specific binding site or partly on the specific site and also on other sites by altering the pH at which the two ligands are mixed. Copper attached exclusively to the specific site is taken up more rapidly than copper attached to that site and others on albumin. The effect is proportional to the amount of copper on the specific site. Additional histidine stimulates uptake irrespective of the copper binding site on albumin. The effect is related to the histidine on position 3 of the albumin, since it is not seen when dog albumin is labeled under the same conditions. The data suggest that the cell recognizes and presumably binds the copper-albumin (CuAlb) complex but may preferentially recognize the ternary complex formed by CuAlb and histidine. We suggest that, in vivo, copper is bound mainly as the ternary complex and that the structure formed, presumably similar to that formed by a copper-histidine complex, is what is actually recognized by the cell. After binding, the albumin and histidine are released, possibly by a reduction step, and the copper is transported across the membrane. If the copper cannot be transported (as occurs when the cells are incubated at 4 degrees C), it blocks further binding of the ternary complex.

Animals↗

PubMed1993

Serum ultrafiltrable copper, total copper and caeruloplasmin concentrations in gynaecological carcinomas.

Serum copper and caeruloplasmin concentrations are elevated in various carcinomas, but it is not known whether the rise in serum copper is due to elevation of caeruloplasmin alone or whether it is also due to the elevation of 'free' copper. We therefore determined ultrafiltrable copper to answer this question. Serum ultrafiltrate was prepared using the Amicon micropartition system and ultrafiltrable (free) copper was determined by flameless atomic absorption spectrophotometry. Serum total copper was determined by flame atomic absorption spectrometry and caeruloplasmin by rate nephelometry. There was no significant difference in the ultrafiltrable copper concentration between patients with gynaecological tumours and control subjects. However, total copper and caeruloplasmin concentrations were significantly elevated in cancer patients compared with control subjects. In contrast to total copper and caeruloplasmin concentrations, ultrafiltrable copper concentrations showed no significant increase with increase in the stage of the cancer.

Adult↗