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PubMed1990

Copper salicylate and copper phenylbutazone as topically applied anti-inflammatory agents in the rat and horse.

Topically applied copper phenylbutazone, phenylbutazone, copper salicylate, salicylate and dimethylsulfoxide glycerol (80:20) were investigated as anti-inflammatory agents in rats and horses. Dimethylsulfoxide and glycerol (80:20) or dimethylsulfoxide, ethanol and glycerol (60:20:20) were used as the drug solvents. Subcutaneously administered carrageenin was used to induce inflammatory oedema, either in the paws of rats or the alar fold of the horse. The severity of the oedema and the anti-inflammatory effect of the drugs were assessed by measuring changes in the paw or alar-fold diameters. Copper salicylate and copper phenylbutazone were effective inhibitors of the inflammatory oedema in both species, but dimethylsulfoxide:glycerol (80:20) was not. In the rat, copper salicylate and copper phenylbutazone were superior anti-inflammatory agents compared to either salicylate or phenylbutazone, respectively. Following the topical application of four times the recommended daily dose of copper phenylbutazone to the horse for 5 days, minor skin irritation occurred and trace concentrations of phenylbutazone (maximum 0.6 microgram/ml) and negligible concentrations of oxyphenbutazone and gamma-hydroxyphenylbutazone were detected in the plasma.

Administration, Topical↗

PubMed1993

Copper Hypersensitivity and Uptake in Pseudomonas syringae Containing Cloned Components of the Copper Resistance Operon.

Copper resistance in Pseudomonas syringae carrying the copABCD operon is associated with accumulation of copper in the periplasm and outer membrane, apparently as a function of the copper-binding activities of the copABC gene products. However, no specific function for copD has been determined. In this study, P. syringae cells containing copCD or copBCD cloned behind the lac promoter were hypersensitive to copper. An increased accumulation of copper was measured in cells containing several combinations of cop genes that included copC and copD. Our data suggest that CopC, a periplasmic copper-binding protein, and CopD, a probable inner membrane protein, may function together in copper uptake.

Journal Article↗

PubMedDate not supplied

Copper-binding protein in acute copper poisoning.

This paper presents a suicide case of copper sulfate ingestion. Post-mortem autopsy revealed mucous membrane necrosis of the esophagus and the stomach. Histological examination revealed centrilobular necrosis in the liver and renal insufficiency. The quantitative determination of copper, zinc and cadmium in various tissues showed that the copper concentrations in blood, liver, kidney and lung were 3.5-24-fold higher than those of the normal level, whereas zinc and cadmium concentrations were within normal range. Chromatographical patterns on Sephadex G-75 showed that most of the accumulated copper in the liver and kidney was bound to metallothionein (MT), a low molecular weight protein with high metal binding capacity which plays a role in the detoxification of heavy metals, while no copper bound to MT was found in the lung. These results suggest that the formation of Cu-induced MT in the liver and kidney occurred at the early stage in fatal acute copper poisoning.

Acute Disease↗

PubMed2004

Identification of the "missing domain" of the rat copper-transporting ATPase, atp7b: insight into the structural and metal binding characteristics of its N-terminal copper-binding domain.

Wilson disease is an autosomal disorder of copper transport caused by mutations in the ATP7B gene encoding a copper-transporting P-type ATPase. The Long Evans Cinnamon (LEC) rat is an established animal model for Wilson disease. We have used structural homology modelling of the N-terminal copper-binding region of the rat atp7b protein (rCBD) to reveal the presence of a domain, the fourth domain (rD4), which was previously thought to be missing from rCBD. Although the CXXC motif is absent from rD4, the overall fold is preserved. Using a wide range of techniques, rCBD is shown to undergo metal-induced secondary and tertiary structural changes similar to WCBD. Competition 65Zn(II)-blot experiments with rCBD demonstrate a binding cooperativity unique to Cu(I). Far-UV circular dichroism (CD) spectra suggest significant secondary structural transformation occurring when 2-3 molar equivalents of Cu(I) is added. Near-UV CD spectra, which indicate tertiary structural transformations, show a proportional decrease in rCBD disulfide bonds upon the incremental addition of Cu(I), and a maximum 5:1 Cu(I) to protein ratio. The similarity of these results to those obtained for the Wilson disease N-terminal copper-binding region (WCBD), which has six copper-binding domains, suggests that the metal-dependent conformational changes observed in both proteins may be largely determined by the protein-protein interactions taking place between the heavy metal-associated (HMA) domains, and remain largely unaffected by the absence of one of the six CXXC copper-binding sites.

Adenosine Triphosphatases↗

PubMed2005

Effects of metal ions in the CuB center on the redox properties of heme in heme-copper oxidases: spectroelectrochemical studies of an engineered heme-copper center in myoglobin.

The electrochemical properties of an engineered heme-copper center in myoglobin have been investigated by UV-visible spectroelectrochemistry. In the cyanide-bridged, spin-coupled heme-copper center in an engineered myoglobin, the presence of Zn(II) in the Cu(B) center raises the heme reduction potential from -85 to 49 mV vs NHE. However, in the cyanide-free, spin-decoupled derivative of the same protein, the presence of Zn(II) in the Cu(B) center exerts little influence on the heme reduction potentials (77 and 80 mV vs NHE, respectively, in the absence and in the presence of Zn(II)). Similar trends have also been observed when copper ion is present in the Cu(B) center, although on a smaller scale, due to reduction of Cu(II) to Cu(I) prior to heme reduction. These results show that the presence of a metal ion in the designed Cu(B) center has a significant effect on the redox potential of heme Fe only when the two metal centers are coupled through a bridging ligand between the two metal centers, indicating that spin coupling plays an important role in redox potential regulation. In addition, the presence of a single positively charged Cu(I) center in the Cu(B) center resulted in a much lower increase (16 mV) in heme reduction potential than that of two positively charged Zn(II) (118 mV). Therefore, the heme reduction potential must be lowered after the first electron transfer to reduce heme Fe(3+)-Cu(B)(2+) to Fe(3+)-Cu(B)(+). To raise the heme reduction potential to make the second electron transfer (i.e., reduction of Fe(3+)-Cu(B)(+) to Fe(2+)-Cu(B)(+)) to be favorable, most likely a proton or decoupling of the heme-copper center is needed in the heme-copper site. These findings provide a strong argument for a thermodynamic driving force basis for redox-regulated proton transfer in heme-copper oxidases.

Amine Oxidase (Copper-Containing)↗

PubMed2006

An in vitro study on the postinfection activities of copper hydroxide and copper sulfate against conidia of Venturia inaequalis.

The postinfection activities of copper hydroxide [Cu(OH)2] and copper sulfate (CuSO4) against apple scab (Venturia inaequalis) were evaluated in an in vitro study. Our intention was to support the aim of reducing copper application rates by appropriate timing of applications. Experiments were conducted at 20 degrees C with leaf disks and isolated cuticular membranes (CM) of Malus x domestica 'Gloster' and 'Elstar'. Conidia of V. inaequalis were used as the inoculum. In untreated controls, 7.9 and 33.2% of germinated conidia formed primary stromata 24 and 48 h after inoculation, respectively. Treatments with copper compounds were applied 24 and 48 h after inoculation, which was 16 and 40 h after infection had occurred. When working with CM and using fluorescein diacetate as a vital stain, vital and dead stromata could be distinguished. Treatment effects were assessed 72 h after inoculation by counting vital (fluorescing) primary stromata. With leaf disks, the number of stromata was counted using KOH-aniline blue fluorescence staining. Cu(OH)2 and CuSO4 showed postinfection activity and killed primary stromata, provided that the surface of the CM was kept wet. Cu(OH)2 was more effective than CuSO4 and was able to kill all primary stromata 24 h after inoculation at concentrations of 116 and 231 mg L(-1). When Cu(OH)2 was applied at 116 mg L(-1) to leaf disks 24 h after inoculation, the number of primary stromata did not significantly differ from the control. Results indicate different modes of action for the highly water soluble CuSO4 and the slightly soluble Cu(OH)2. This supports the hypothesis that spore exudates react with insoluble copper compounds and form highly toxic copper complexes. Application of Cu(OH)2 to dry CM did not kill primary stromata. Hence, for Cu(OH)2 to exert postinfection activity, leaves must be wet. In the field, this cannot be guaranteed and a postinfection application of Cu(OH)2 cannot be recommended.

Ascomycota↗

PubMed2003

Copper-binding proteins in human erythrocytes: searching for potential biomarkers of copper over-exposure.

The recognition that copper is essential but also potentially toxic to humans has prompted the search for biomarkers of copper excess. The experimental approach followed here involves the isolation and subsequent characterization of copper-binding molecules (CuBP) from human erythrocytes. Incubation (0-60 min) of freshly obtained erythrocytes in the presence of increasing concentrations of copper (10-50 microM; as 64Cu-histidine) led to time- and concentration-dependent uptake of the radioisotope. A near-maximal incorporation was attained after 20 min, with 45-55% of the radioactivity being recovered in 20,000 x g hemolysate supernatants (S-20). 64CuBP from S-20 were separated by size exclusion and metal-affinity chromatography. Most radioactivity loaded into a Sephadex G-75 column was recovered in association with molecules of MMr greater than 60 KDa (largely accounted for by hemoglobin; Hb). Only negligible amounts of radioactive Cu were associated with metallothionein. With further purification, the higher MMr 64Cu-binding fractions were resolved by Sephadex G-200 into two major peaks. The cpm/microg protein ratios of the first peak (high MMr) were proportional to the concentrations of copper presented to the erythrocytes. The second one contained mostly Hb molecules. Proteins from the first peak were concentrated in an affinity chromatography mini-column, suited to trap CuBP. The higher-affinity CuBP were eluted as a single peak which comprised around 60% of the load. An SDS-PAGE analysis of such peak reveals the presence of three bands, of which two are non-hemoglobin Cu-binding proteins. The latter, whose identity remains to be established, had MMr of approximately 30 and 40 KDa, respectively. Preliminary data indicate that the two bands bind 64Cu within a range of concentrations, relevant to those expected to occur during copper over-exposure conditions.

Biological Transport↗

PubMed1997

The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator.

Fre1p and Fre2p are ferric reductases which account for the total plasma membrane associated activity, a prerequisite for iron uptake, in Saccharomyces cerevisiae. The two genes are transcriptionally induced by iron depletion. In this communication, we provide evidence that Fre2p has also cupric reductase activity, as has been previously shown for Fre1p (Hassett, R., and Kosman, D.J. (1995) J. Biol. Chem. 270, 128-134). Both Fre1p and Fre2p enzymes are functionally significant for copper uptake, as monitored by the accumulation of the copper-regulated CUP1 and CTR1 mRNAs in fre1Delta, fre2Delta, and fre1Deltafre2Delta mutant strains. However, only Fre1p activity is induced by copper depletion, even in the presence of iron. This differential copper-dependent regulation of Fre1p and Fre2p is exerted at the transcriptional level of the two genes. We have shown that Mac1p, known to affect the basal levels of FRE1 gene expression (Jungmann, J., Reins, H.-A., Lee, J., Romeo, A., Hassett, R., Kosman, D., and Jentsch, S. (1993) EMBO J. 12, 5051-5056), accounts for both the copper-dependent induction of FRE1 and down-regulation of FRE2 gene. Finally, Mac1p transcriptional activation function is itself modulated by the availability of copper.

Carrier Proteins↗

PubMed1998

HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense.

HAH1 is a 68-amino acid protein originally identified as a human homologue of Atx1p, a multi-copy suppressor of oxidative injury in sod1 delta yeast. Molecular modeling of HAH1 predicts a protein structure of two alpha-helices overlaying a four-stranded antiparallel beta-sheet with a potential metal binding site involving two conserved cysteine residues. Consistent with this model, in vitro studies with recombinant HAH1 directly demonstrated binding of Cu(I), and site-directed mutagenesis identified these cysteine residues as copper ligands. Expression of wild type and mutant HAH1 in atx1 delta yeast revealed the essential role of these cysteine residues in copper trafficking to the secretory compartment in vivo, as expression of a Cys-12/Cys-15 double mutant abrogated copper incorporation into the multicopper oxidase Fet3p. In contrast, mutation of the highly conserved lysine residues in the carboxyl terminus of HAH1 had no effect on copper trafficking to the secretory pathway but eliminated the antioxidant function of HAH1 in sod1 delta yeast. Taken together, these data support the concept of a unique copper coordination environment in HAH1 that permits this protein to function as an intracellular copper chaperone mediating distinct biological processes in eucaryotic cells.

Amino Acid Sequence↗

PubMed1980

Copper nitrilotriacetate: a potent therapeutic agent in the treatment of a genetic disorder of copper metabolism.

Copper nitrilotriacetate (NTA) was evaluated for its ability to ameliorate effects of the recessive mutant gene crinkled (cr) in mice. Copper-NTA was superior to copper sulfate in increasing postnatal survival and body copper content of offspring of dams supplemented during pregnancy and lactation. Feeding of NTA alone during these periods had no effect on survival. Postnatal supplementation with copper did not increase survival of the mutants. The therapeutic use of copper-NTA, and the necessity for prenatal intervention for successful treatment of the mutant, are discussed in relation to Menkes' syndrome.

Animals↗

PubMed1985

Copper deficiency in the preterm infant of very low birthweight. Four cases and a reference range for plasma copper.

Four preterm infants of very low birthweight (less than 1500 g) developed signs of copper deficiency between age 8 and 10 weeks. All had required prolonged ventilatory support, parenteral nutrition, and nasojejunal feeding. The clinical features, which included osteoporosis, oedema, anaemia, neutropenia, and late apnoea improved when the oral copper intake was increased. Diagnosis was made more difficult because a suitable reference range for plasma copper was not available. Serial measurements of plasma copper in 39 preterm infants who had no important medical problems were used to produce a reference range for plasma copper from 30 weeks' gestation to term plus seven weeks. This information will aid recognition of hypocupraemia in the very low birthweight infant who is particularly at risk of copper deficiency.

Copper↗

PubMed1999

Expression of menkes copper-transporting ATPase, MNK, in the lactating human breast: possible role in copper transport into milk.

The Menkes copper ATPase (MNK) is a copper efflux ATPase that is involved in copper homeostasis. Little is known about the intracellular localization and cell-specific function of the MNK in human tissues. To investigate a possible role for this protein in lactation, we measured its expression in sections of tissue from nonlactating and lactating human breast. Western blot analysis showed that MNK expression was greater in lactating tissue than in nonlactating tissue. By confocal immunofluorescence, the MNK was detected in luminal epithelial cells of the alveoli and ducts but not in myoepithelial cells. In the nonlactating breast epithelial cells, the MNK had a predominantly perinuclear distribution. In lactating breast tissue, the distribution of the MNK was markedly altered. Lactating epithelial cells showed a granular, diffuse pattern, which extended beyond the perinuclear region of the cell. This pattern was similar to that observed in a previous study in which cultured CHO cells were exposed to high copper concentrations. Our results suggest that relocalization of the MNK is a physiological process, which may be mediated by copper levels in the breast or by hormones and other events taking place during lactation. A vesicular pathway for copper from the Golgi into milk, similar to that of calcium, is proposed.(J Histochem Cytochem 47:1553-1561, 1999)

Adenosine Triphosphatases↗

PubMed1975

Perforation of the uterus by the copper-t and copper-7 intrauterine contraceptive devices.

Uterine perforation in patients wearing the Copper-T and the Copper-7 intrauterine contraceptive devices has been studied. In Bollnäs, Sweden, three perforations occurred in 1 156 insertions of the Copper-7, and in New York, USA, six perforations occurred in 1 153 insertions of the Copper-T. Cervical perforation seems to be a special feature of the Copper-T, while the Copper-7 tends to perforate through the uterine wall. The perforations can be divided into "primary" perforations, related to the insertion procedure, and "secondary" perforations, caused by uterine contractions. The diagnosis and treatment of uterine perforations by intrauterine devices is discussed.

Adult↗

PubMed1987

Influence of choline and sulfate on copper and toxicity and substitution of and antagonism between methionine and copper supplements to chick diets.

Studies were conducted to determine if the deleterious affects on chick growth of the primary antagonism between methionine and copper involves the homocysteine moiety or labile methyl group of methionine. A .1% choline supplement resulted in performance response similar to that of a .2% L-methionine supplement in the absence but not in the presence of 500 mg/kg copper from cupric sulfate. Similar results were observed when the levels of methionine and choline were doubled. Sulfate, with or without choline, had little effect in the presence of cupric sulfate. When cupric acetate was used instead of cupric sulfate, a small but nearly significant (P = .08) response to potassium sulfate was observed. Maximum performance with .29% supplemental methionine and 188 mg/kg Cu was predicted from a response surface analysis. The methionine requirement was increased by feeding copper. However, the increase in methionine requirement was accompanied by an improvement in growth rate and feed efficiency. This may explain why levels used of methionine and total sulfur-containing amino acids appear to be higher under field conditions (with pharmacological levels of copper) than in laboratory conditions (without pharmacological levels of copper). The primary antagonism between methionine and copper involves the homocysteine moiety, not the labile methyl groups.

Animals↗

PubMed2000

DNA degradation by the mixture of copper and catechol is caused by DNA-copper-hydroperoxo complexes, probably DNA-Cu(I)OOH.

Free hydroxyl radicals (free (.)OH), singlet oxygen ((1)O(2)), or (. )OH produced by DNA-copper-hydroperoxo complexes are possible DNA-damaging reactive oxygen species (ROS) in the reaction system containing copper, catechol, and DNA. para-Chlorobenzoic acid (pCBA) degradation studies revealed that CuCl(2) mixed with catechol produced free (.)OH. In the presence of DNA, however, inhibition of the pCBA degradation suggested that another ROS is responsible for the DNA degradation. Of a series of ROS scavengers investigated, only KI, NaN(3), and Na-formate-all of the salts tested-strongly inhibited the DNA degradation, suggesting that the ionic strength rather than the reactivity of the individual scavengers could be responsible for the observed inhibition. The ionic strength effect was confirmed by increasing the concentration of phosphate buffer, which is a poor (.)OH scavenger, and was interpreted as the result of destabilization of DNA-copper-hydroperoxo complexes. Piperidine-labile site patterns in DNA degraded by copper and catechol showed that the mixture of Cu(II) and catechol degrades DNA via the intermediate formation of a DNA-copper-hydroperoxo complex. Replacement of guanine by 7-deazaguanine did not retard the DNA degradation, suggesting that the DNA-copper-hydroperoxo complexes do not bind to the guanine N-7 as proposed in the literature.

Catechols↗

PubMedDate not supplied

Hepatic lysosomal copper protein in dogs with an inherited copper toxicosis.

Hepatic copper overload inherited as an autosomal recessive trait in Bedlington Terriers is characterized by the presence of hepatocellular lysosomal granules of unusually high specific gravity and electron density which contain at least two thirds of the total hepatic copper. Fractionation of homogenates of liver from such affected Bedlington Terriers yielded a low-speed pellet which contained the lysosomal granules. This fraction was used for isolation of a copper-binding protein by alkaline-reduction, solubilization, fractional acetone precipitation, and gel filtration. The purified protein yielded a single band on polyacrylamide gel electrophoresis and resembled other metallothioneins in containing 15 cysteine residues and 7 to 8 atoms of copper (but no zinc) per 54 amino acid residues. No methionine, histidine, or any aromatic amino acid was present. The accumulation of this lysosomal copper protein appears to be related to the primary genetic defect which underlies the hepatic copper toxicosis of the Bedlington Terrier.

Animals↗

PubMed2006

Effects of copper pre-exposure routes on the energy reserves and subsequent copper toxicity in Daphnia magna.

The hypothesis was tested that copper uptake routes affect the tolerance of Daphnia magna to copper and influence the energy reserves. These were determined in D. magna juveniles that had been exposed for 4 days to water borne and/or dietary copper (algae Pseudokichneriella subcapitata loaded with copper) at nominal concentrations of 0, 10, and 100 nM. Tolerance increased with dietary copper pre-exposure reflected in 24 and 48 h LC50 values of 466 and 398 nM at 100 nM pre-exposure versus 301 and 254 nM in controls, respectively. Control animals (no copper added to their exposure medium and diet) had the lowest lipid content and consequently the lowest energy content. The current study stresses the importance of addressing dietary exposure routes in metal toxicity assessments.

Animals↗

PubMed1997

Effects of sublethal copper exposure on copper accumulation, food consumption, growth, energy stores, and nucleic acid content in common carp.

Juvenile common carp were exposed for 28 days to three different sublethal copper concentrations (0.20 microM, 0.55 microM, and 0.80 microM). Food consumption was monitored on a daily basis during the exposure period, while growth, copper accumulation, energy stores, and nucleic acid contents were assessed weekly. Copper exposure to 0. 80 microM affected both growth and feeding behavior in common carp. At 0.55 microM, growth was affected despite normal food consumption. Even at the lowest copper concentration (0.20 microM), metabolic demand for the fish increased, challenging the carp with an increased demand for food. Copper accumulation mainly occurred in the liver, reaching an equilibrium between uptake and excretion after 1 month of exposure. Substantial biochemical changes were observed at the two highest copper exposure concentrations, but the correlation between growth rate and RNA:DNA ratio was poor considering the substantial differences in growth rate. The use of the RNA:DNA ratio as a sensitive biomarker is questioned.

Animals↗