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PubMed2002

Age and copper intake do not affect copper absorption, measured with the use of 65Cu as a tracer, in young infants.

BACKGROUND: Copper homeostasis involves a high degree of regulation in which changes in absorption and biliary excretion are the main mechanisms. Whether neonates and small infants can make these changes efficiently is unknown. OBJECTIVE: We evaluated the effect of age and copper intake on copper absorption in infants during the first 3 mo of life. DESIGN: Thirty-nine healthy infants (19 infants aged 1 mo and 20 infants aged 3 mo) were selected. One-half of the subjects were randomly assigned to receive oral supplementation of 80 mg Cu (as copper sulfate). kg body wt(-1). d(-1) for 15 d. At the end of the trial, copper absorption was measured by using orally administered (65)Cu as a tracer and fecal monitoring of recovered (65)Cu. RESULTS: Mean (+/- SD) copper absorption at 1 mo of age was 83.6 +/- 5.8% and 74.8 +/- 9.1% for the unsupplemented and supplemented infants, respectively. The corresponding figures at 3 mo of age were 77.6 +/- 15.2% and 77.7 +/- 11.3%. A two-way analysis of variance showed that age, copper supplementation, and the interaction between age and copper supplementation did not have a significant effect on copper absorption. There was an inverse correlation between total fecal copper and the percentage of (65)Cu absorption (r = -0.50, P < 0.003). CONCLUSION: Copper absorption in young infants is high but does not respond to copper intake within the range tested.

Aging↗

PubMed1980

Abnormal copper-thionein synthesis and impaired copper utilization in mutated brindled mice: model for Menkes' disease.

The copper utilization in mutated Brindled mice is impaired. Copper accumulates in various tissues, e.g., the kidney, of the mutated mice. The renal copper binding protein is characterized as copper-thionein--metallothionein to which copper is bound. The L-[35S]cystine incorporation experiments without prior induction with copper revealed an abnormal synthesis of metallothionein in the mutated mice. Two models are proposed which link the abnormal metallothionein synthesis with an impaired copper utilization. Model 1 is an unrestrained translation of renal mRNA which codes for metallothionein. Model 2 is an impaired renal copper reabsorption resulting in a toxic intracellular copper concentration which induces metallothionein synthesis to sequester copper. The impaired copper utilization results in a fatal copper deficiency in "Menkes" Brindled mice.

Animals↗

PubMed1983

Effects of zinc on mucosal copper binding and on the kinetics of copper absorption.

The kinetics of serosal copper transfer and the distribution of copper between metallothionein (MT) and a high-molecular-weight protein fraction (HMWPF) within the mucosal cells were examined, using isolated duodenal segments from rats fed different amounts of zinc. No difference in the Vmax or Km for serosal transfer could be detected between the different zinc groups, suggesting that zinc did not affect this aspect of copper absorption. When intestinal segments from rats fed the low zinc diet were incubated in high copper media, the majority of the copper was associated with the HMWPF, while those from rats fed the high zinc diet had the largest proportion bound to MT. All the intestines incubated in the low copper media, regardless of rat zinc status, had the majority of copper associated with MT. These results suggested that with the low zinc diet, the limited amount of MT present was saturated, and the excess copper was bound to the HMWPF. With larger intakes of zinc, MT synthesis was induced, and the larger amount of this protein was not as readily saturated, resulting in less copper binding to the HMWPF and more to MT. It is suggested that zinc interferes with copper absorption by inducing MT, which sequesters copper in the mucosal cells, making it unavailable for serosal transfer. The copper bound to the HMWPF is available for transfer.

Animals↗

PubMed1990

Effects of cellular copper content on copper uptake and metallothionein and ceruloplasmin mRNA levels in mouse hepatocytes.

The intracellular copper content of mouse hepatocytes has been altered by incubating with either increasing amounts of extracellular copper or increasing amounts of diamsar, a copper chelator. Metallothionein 1 (MT1) and MT2 mRNA levels in the cells increased in proportion to the intracellular copper concentration. The degree of stimulation was similar for both MT1 and MT2, with mRNA levels increasing approximately fourfold for a six- to eightfold increase in intracellular copper levels. In contrast, neither copper uptake nor ceruloplasmin mRNA showed any response to intracellular copper levels. Unlike the situation in the rat, there was no clear evidence for saturation of copper uptake. Incubating cells with increasing amounts of 64Cu resulted in a linear increase in the amount taken up over 2 h. The amount of 64Cu accumulated was the same in control and copper-depleted cells, which suggests that neither ceruloplasmin production nor copper uptake is regulated by intracellular copper levels. However, other possibilities, such as the chelators not being able to deplete the pool(s) responsible for the control of ceruloplasmin production or copper uptake, must also be considered.

Animals↗

PubMed1992

Cardiac ultrastructural and electrophysiological abnormalities in postweanling copper-restricted and copper-repleted rats in the absence of hypertrophy.

Cardiac ultrastructural and functional characteristics were determined in copper-depleted and copper-repleted rats. Male weanling rats were randomized into five groups that were fed either copper-adequate or copper-deficient diets. After 5 wk, one group fed each diet was studied to obtain baseline values. At this time, one copper-adequate postweanling group continued to receive the adequate diet as control, one deficient postweanling group was fed the adequate diet to evaluate the effect of copper repletion and one postweanling adequate group was fed the deficient diet to evaluate copper depletion in relatively older rats. These dietary treatments were continued for six additional weeks. Copper-depleted rats of both ages exhibited significant cardiac ultrastructural pathology and electrocardiogram abnormalities and the postweanling copper-depleted rats exhibited these abnormalities in the absence of hypertrophy and anemia. Increased mitochondrial volume density, disarranged cristae, and nonaligned myofibrils with disturbances at Z-bands were displayed. Additionally, all copper-depleted rats demonstrated fragmented basal laminae at capillary-myocyte interface. Increased QRS amplitude and notching and greater QT intervals were displayed. Copper-repleted rats exhibited some, but not total, reversal of these abnormalities. These results suggest that capillary-myocyte interface changes may play an important role in the developing pathology of copper depletion.

Animals↗

PubMed2003

Copper deficiency induces the upregulation of the copper chaperone for Cu/Zn superoxide dismutase in weanling male rats.

The most commonly used indices for determining copper deficiency in humans are reduced serum/plasma copper concentration and decreased activity of ceruloplasmin and Cu/Zn superoxide dismutase (SOD1). However, these indicators are influenced by many factors unrelated to copper status and lack the sensitivity required to detect marginal deficiency, limiting their usefulness in many situations. In vivo, the insertion of copper into SOD1 is dependent on the copper chaperone for SOD1 (CCS). In this study, we explored the possibility that the expression level of CCS may reflect copper status and thus serve as a useful marker of copper nutriture. Weanling male Wistar rats were fed either a normal (5.3 mg Cu/kg diet), moderately deficient (0.84 mg Cu/kg diet) or deficient (0.34 mg Cu/kg diet) copper diet for 6 wk. Rats fed moderate and deficient diets showed differences (P < 0.05) in several hematological measurements, indicating varying degrees of copper deficiency in these groups. Copper-deficient rats had reduced (P < 0.05) liver and erythrocyte SOD1 activity and body weight. Western blot analysis revealed a dose-dependent increase (P < 0.05) in CCS expression in liver and erythrocytes of copper-deficient rats. We report CCS protein level as a novel marker for assessing copper status.

Animals↗

PubMed1998

Copper in infant nutrition: safety of World Health Organization provisional guideline value for copper content of drinking water.

BACKGROUND: Copper is an essential nutrient for humans. Recently, a limit of 31.48 micromol/l (2 mg/l) was proposed by the World Health Organization as the provisional guideline value for copper content of drinking water. The objective of the study was to determine the tolerance of chronic exposure to drinking water with low or high copper content in infants. METHODS: Healthy infants (n = 128) were randomly assigned to receive drinking water with less than 1.57 micromol/l (<0.1 mg/l) (n = 48) or 31.48 micromol/l (2 mg/l) of copper (n = 80) from 3 to 12 months of age. At 6, 9, and 12 months of age, serum concentrations of copper, ceruloplasmin, and superoxide dismutase; erythrocyte metallothionein; bilirubin; transaminases; and gamma-glutamyl transferase were measured. RESULTS: Small differences in biochemical indexes of copper nutrition were observed between the groups, but there was no evidence of adverse or toxic effects. These findings may be explained by an adaptive response to the higher copper intake, limiting copper absorption, and increasing biliary secretion, as well as by an increase in copper storage. It is also possible that the sensitivity of the biochemical indicators employed to detect differences in copper status is limited. CONCLUSION: No acute or chronic adverse consequences of consuming water with copper content of 31.48 micromol/l (2 mg/l) were detected in infants during the first year of life. The results support the safety of the World Health Organization's provisional guideline value for copper in drinking water during infancy.

Alanine Transaminase↗

PubMed1999

Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase.

The copper chaperone for the superoxide dismutase (CCS) gene is necessary for expression of an active, copper-bound form of superoxide dismutase (SOD1) in vivo in spite of the high affinity of SOD1 for copper (dissociation constant = 6 fM) and the high intracellular concentrations of both SOD1 (10 microM in yeast) and copper (70 microM in yeast). In vitro studies demonstrated that purified Cu(I)-yCCS protein is sufficient for direct copper activation of apo-ySOD1 but is necessary only when the concentration of free copper ions ([Cu]free) is strictly limited. Moreover, the physiological requirement for yCCS in vivo was readily bypassed by elevated copper concentrations and abrogation of intracellular copper-scavenging systems such as the metallothioneins. This metallochaperone protein activates the target enzyme through direct insertion of the copper cofactor and apparently functions to protect the metal ion from binding to intracellular copper scavengers. These results indicate that intracellular [Cu]free is limited to less than one free copper ion per cell and suggest that a pool of free copper ions is not used in physiological activation of metalloenzymes.

Apoenzymes↗

PubMed2005

Gene expression profiling and phenotype analyses of S. cerevisiae in response to changing copper reveals six genes with new roles in copper and iron metabolism.

Exhaustive microarray time course analyses of Saccharomyces cerevisiae during copper starvation and copper excess reveal new aspects of metal-induced gene regulation. Aside from identifying targets of established copper- and iron-responsive transcription factors, we find that genes encoding mitochondrial proteins are downregulated and that copper-independent iron transport genes are preferentially upregulated, both during prolonged copper deprivation. The experiments also suggest the presence of a small regulatory iron pool that links copper and iron responses. One hundred twenty-eight genes with putative roles in metal metabolism were further investigated by several systematic phenotype screens. Of the novel phenotypes uncovered, hsp12-Delta and arn1-Delta display increased sensitivity to copper, cyc1-Delta and crr1-Delta show resistance to high copper, vma13-Delta exhibits increased sensitivity to iron deprivation, and pep12-Delta results in reduced growth in high copper and low iron. Besides revealing new components of eukaryotic metal trafficking pathways, the results underscore the previously determined intimate links between iron and copper metabolism and mitochondrial and vacuolar function in metal trafficking. The analyses further suggest that copper starvation can specifically lead to downregulation of respiratory function to preserve iron and copper for other cellular processes.

Amino Acid Motifs↗

PubMed1991

Identification of proteins involved in intracellular copper metabolism. Low levels of a approximately 48-kDa copper-binding protein in the brindled mouse model of Menkes disease.

Little is known about copper metabolism at the cellular level. The brindled mouse is an animal model of Menkes disease which is an inborn error of copper metabolism. Control and brindled mice were used to identify copper-binding proteins with possible roles in normal copper metabolism that are affected by the defect in the brindled mice. When 64Cu-labeled hepatic or renal cytosols from control mice were applied to Mono Q or Superose columns, a approximately 48-kDa protein coeluted with the protein fractions which contained the radiolabeled copper. Large decreases in copper binding were detected in these fractions from the brindled mice. The same column fractions which showed decreased copper binding showed large decreases in the levels of the approximately 48-kDa protein. Decreased copper binding and approximately 48-kDa protein were not simply secondary to the abnormal hepatic and renal copper levels that are found in the brindled mice since although their liver copper levels are low, their kidney copper levels are high. Elevated levels of an approximately 80-kDa heat shock protein were also detected in the hepatic and renal cytosols from the brindled mice. Consistent with expression of the primary defect in both the liver and kidney, the levels of the approximately 48- and approximately 80-kDa proteins were affected similarly in both organs. Irrespective of how the low levels of the approximately 48-kDa protein may be related to the basic defect in the brindled mice, the data are consistent with an important role for the approximately 48-kDa protein in intracellular copper metabolism.

Animals↗

PubMed1985

Copper toxicosis and tolerance in the rat: IV. Renal tubular excretion of copper.

Male rats were fed a diet containing o.oo3% copper and killed sequentially up to 15 weeks. The kidney cortices were examined analytically and histochemically for copper. Urinary copper output was measured in one group of copper supplemented rats. Kidney copper concentration rose (mean+SEM, microgramCu/g) to 4238.0 +/- 475 at 4 weeks (control 59 +/- IO) and remained unchanged to 15 weeks. Urinary copper output rose (m +/- SEM, microgramCu/h) to 4.3 +/- 0.36 (control 0.3 +/- 0.04) at 4 weeks; it peaked temporarily IO.9 +/- 2.5, P less than o.o5, at 5 weeks and subsequently fell to 4.I +/- o.75 at 6 weeks and thereafter. Histochemically demonstrable copper accumulated in the renal proximal convoluted tubules up to 4 weeks during which it was excreted into the lumen by exocytosis and cellular exfoliation. Widespread sloughing of necrotic copper-containing tubule cells became marked at 5 weeks but declined subsequently as regeneration occurred. Urinary copper output reflects the changes in kidney copper turnover and is apparently derived from this source. Renal tubular excretion of copper probably serves a protective function in the copper-loaded rat.

Animals↗

PubMed1983

Use of erythrocyte copper:zinc superoxide dismutase activity and hair or fleece copper concentrations in the diagnosis of hypocuprosis in ruminants.

Changes in the activity of superoxide dismutase, a copper-containing enzyme in erythrocytes (ESOD), and changes in copper in hair or fleece were compared with the changes in plasma copper during copper depletion and repletion in steers, lambs and ewes. During depletion the decline in ESOD began later than the decline in plasma copper: the lag varied from 0 to 80 days in individual steers and it was least evident when young rapidly growing lambs were subjected to severe depletion. ESOD activity eventually declined at only one-third to one-seventh of the rate shown by plasma copper, the difference being particularly marked in severely depleted lambs. Repletion of ESOD began after repletion in plasma copper and continued more slowly particularly in growing animals. Hair and fleece copper also responded relatively slowly to depletion and repletion. Low values of ESOD and hair or fleece copper may have diagnostic significance, indicating a more prolonged or intense deficiency of copper and a higher probability of clinical and production responses to copper therapy than low plasma or liver copper values.

Animals↗

PubMed2004

Quantitative evaluation of d-pi interaction in copper(I) complexes and control of copper(I)-dioxygen reactivity.

Crystal structures of the copper(I) complexes 1(X), 2, and 3 of a series of tridentate ligands L1(X), L2, and L3, respectively (L1(X): p-substituted derivatives of N,N-bis[2-(2-pyridyl)ethyl]-2-phenylethylamine; X=H, Me, OMe, Cl, NO(2); L2: N,N-bis[2-(2-pyridyl)ethyl]-2-methyl-2-phenylethylamine; L3: N,N-bis[2-(2-pyridyl)ethyl]-2,2-diphenylethylamine) were solved to demonstrate that all the copper(I) complexes involve an eta(2) copper-arene interaction with the phenyl ring of the ligand sidearm. The Cu(I) ion in each complex has a distorted tetrahedral geometry consisting of the three nitrogen atoms (one tertiary amine nitrogen atom and two pyridine nitrogen atoms) and C(1)-C(2) of the phenyl ring of ligand sidearm, whereby the Cu-C distances of the copper-arene interaction significantly depend on the para substituents. The existence of the copper-arene interaction in a nonpolar organic solvent (CH(2)Cl(2)) was demonstrated by the observation of an intense MLCT band around 290 nm, and the magnitude of the interaction was evaluated by detailed analysis of the (1)H and (13)C NMR spectra and the redox potentials E(1/2) of the copper ion, as well as by means of the ligand-exchange reaction between the phenyl ring and CH(3)CN as an external ligand. The thermodynamic parameters DeltaH(o) and DeltaS(o) for the ligand-exchange reaction with CH(3)CN afforded a quantitative measure for the energy difference of the copper-arene interaction in the series of copper(I) complexes. Density functional studies indicated that the copper(I)-arene interaction mainly consists of the interaction between the d(z(2) ) orbital of Cu(I) and a pi orbital of the phenyl ring. The copper(I) complexes 1(X) reacted with O(2) at -80 degrees C in CH(2)Cl(2) to give the corresponding (micro-eta(2):eta(2)-peroxo)dicopper(II) complexes 4, the formation rates k(obs) of which were significantly retarded by stronger d-pi interaction, while complexes 2 and 3, which exhibit the strongest d-pi interaction showed significantly lower reactivity toward O(2) under the same experimental conditions. Thus, the d-pi interaction has been demonstrated for the first time to affect the copper(I)-dioxygen reactivity, and represents a new aspect of ligand effects in copper(I)-dioxygen chemistry.

Journal Article↗

PubMed1989

The effect of oral oxidised copper wire on liver copper in farmed red deer.

Twenty-two weaner red deer stags grazed on a marginally copper-deficient property were used to evaluate the effect on liver copper levels of log oxidised copper wire particles given orally. The deer were assigned to two groups on the basis of pre-trial liver copper levels, and grazed together for the duration of the trial from March to October. Liver biopsies were collected from treated and control deer on six occasions at monthly intervals and were analyzed for copper content. Mean liver copper in the treated group rose from pre-treatment levels of 101.8 micromol/kg to a peak of 849.6 micromol/kg two months after copper administration. Thereafter, levels fell steadily until six months after administration when they averaged 84.8 micromol/kg. The mean liver copper content of untreated deer rose from 102.7 micromol/kg at the commencement of the trial, peaked at 255.3 micromol/kg after two months, fell to 103 micromol/kg one month later and remained low thereafter. The liver copper content in treated deer was significantly higher than for control deer for the duration of the study (p<0.01 for months 14 and 6, p <0.05 for month 5). It is concluded that log oxidised copper wire particles acted to provide adequate liver copper stores for up to five months in deer grazed on a marginally copper-deficient property.

Journal Article↗

PubMed1987

The reaction of nitric oxide with copper proteins and the photodissociation of copper-NO complexes.

The reactivity with nitric oxide was investigated for a number of type-1, type-2 and type-3 copper proteins azurin from Pseudomonas aeruginosa (type-1 copper); bovine superoxide dismutase, diamine oxidase from pig kidney and galactose oxidase from Dactylium dendroides (type-2 copper); haemocyanin from Helix pomatia (type-3 copper); the blue oxidases ceruloplasmin from pig serum, and ascorbate oxidase from Cucurbita pepo medullosa. Type-1 copper formed complexes with NO in the oxidised state, which complexes were only fully formed at low temperatures and could be photodissociated at 77K. Complex formation led to the disappearance of the EPR signal of type-1 copper and of the optical absorbance band in the 600 nm region. In azurin, photodissociation caused the reappearance of the original 625 nm absorbance band, but in the blue oxidases, a new band with lower intensity was found at 595 nm instead of the original absorbance band at 610 nm. In all cases, the EPR signal of type-1 copper did not return. These results are best explained by the formation of a photolabile type-1 Cu1+-NO+ complex. They also indicate that in the complex formed, the type-1 copper structure is probably not disrupted, and that after illumination, the nitric oxide molecule is still in the near vicinity of the copper atom. Type-2 copper did not react at all with nitric oxide, and type-3 copper formed complexes with nitric oxide in both the oxidised and the reduced state, but photodissociation of these complexes could not be demonstrated.

Amine Oxidase (Copper-Containing)↗

PubMed2004

Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin.

BACKGROUND & AIMS: Copper transport in hepatocytes is regulated by the interaction of multiple pumps, chaperones, and accessory proteins. Intracellular chloride channels are essential for copper metabolism in yeast but their role in Cu transport in hepatocytes is unknown. The aim of this study was to determine whether chloride channels are modulators of copper incorporation into ceruloplasmin (CP). METHODS: The effects of chloride concentration and chloride channel expression on secretion of holoCp and apoCp was measured by gel electrophoresis and immunoblotting. ClC family chloride channel expression in hepatocytes was determined by Western blotting. The association of ClC-4 and the Wilson's disease protein (ATP7B) was determined by co-immunoprecipitation. RESULTS: Chloride substitution reduced total Cp secretion and the ratio of secreted holoCp to apoCp (P = 0.038). The role of specific chloride channels was examined by cotransfection of ceruloplasmin and the chloride channel. Overexpression of ClC-4 doubled copper incorporation into ceruloplasmin (P = 0.011), whereas identical overexpression of ClC-3 had no effect. The effect of ClC-4 was most pronounced under copper-limiting conditions in which it increased copper incorporation more than 4-fold (P = 0.037). ClC-4 protein was abundant in hepatocyte membranes and was localized in intracellular vesicles containing ATP7B. CONCLUSIONS: ClC-4 is an intracellular chloride channel that stimulates copper incorporation into ceruloplasmin, probably by improving the efficiency of the ATP7B copper pump. It is thus an important component of the regulation of hepatic copper transport and may modulate Cu transport rates during copper deficiency, Wilson's disease, and other copper toxicosis syndromes.

Adenosine Triphosphatases↗

PubMed2002

A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation.

Copper is an essential co-factor for several key metabolic processes. This requirement in humans is underscored by Menkes disease, an X-linked copper deficiency disorder caused by mutations in the copper transporting P-type ATPase, MNK. MNK is located in the trans-Golgi network where it transports copper to secreted cuproenzymes. Increases in copper concentration stimulate the trafficking of MNK to the plasma membrane where it effluxes copper. In this study, a Menkes disease mutation, G1019D, located in the large cytoplasmic loop of MNK, was characterized in transfected cultured cells. In copper-limiting conditions the G1019D mutant protein was retained in the endoplasmic reticulum. However, this mislocalization was corrected by the addition of copper to cells via a process that was dependent upon the copper binding sites at the N-terminal region of MNK. Reduced growth temperature and the chemical chaperone, glycerol, were found to correct the mislocalization of the G1019D mutant, suggesting this mutation interferes with protein folding in the secretory pathway. These findings identify G1019D as the first conditional mutation associated with Menkes disease and demonstrate correction of the mislocalized protein by copper supplementation. Our findings provide a molecular framework for understanding how mutations that affect the proper folding of the MNK transporter in Menkes patients may be responsive to parenteral copper therapy.

Adenosine Triphosphatases↗

PubMed1995

Gene amplification of the Menkes (MNK; ATP7A) P-type ATPase gene of CHO cells is associated with copper resistance and enhanced copper efflux.

Three copper-resistant variants of cultured Chinese hamster ovary (CHO) cells were isolated and each was shown to accumulate less intracellular copper than the parental cells when grown in copper-supplemented media. The reduced copper accumulation was related to enhanced copper efflux. As cultured cells from patients with Menkes disease (mutations in MNK; ATP7A gene) accumulate copper, probably due to defective copper efflux, we investigated the possible role of the MNK gene in the molecular basis of copper resistance. We found increased MNK mRNA and MNK protein in all three resistant variants. The MNK protein, which has not been previously demonstrated experimentally in mammalian cells, was observed to have an apparent molecular weight of 178 kDa on SDS gels. The degree of increase in MNK mRNA and protein correlated well with the level of copper resistance and extent of copper efflux. By Southern blot and FISH analysis we determined that the molecular basis for overexpression of MNK was genomic amplification of the MNK gene. These data, combined with the clinical and cellular phenotype in Menkes disease, provide strong evidence that the MNK protein is involved in transmembrane copper efflux, and demonstrate a new system of gene amplification in mammalian cells.

Adenosine Triphosphatases↗