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PubMed2003

Regulation of copper absorption by copper availability in the Caco-2 cell intestinal model.

Relatively little is known about the individual steps in intestinal copper absorption and whether or how they may be regulated. Polarized Caco-2 cell monolayers with tight junctions offer an already tested model in which to study intestinal metal transport. This model was used to examine potential effects of cellular copper availability on copper absorption. Uptake and transport were determined on application of (64)Cu(II) to the brush border. In the range of 0.2-2 micro M, uptake was dose dependent and was approximately 20% of dose/90 min. Overall transport of (64)Cu across the basolateral surface was approximately 0.3%. When cellular copper levels were depleted 40% by 18-h pretreatment with the specific copper chelator triethylenetetraamine, uptake and overall transport were markedly increased, going to 80 and 65% of dose, respectively. Cellular retention of (64)Cu fell fourfold, from 6 to 1.5%. Depletion of copper with the chelator was rapid and preceded initial changes in uptake and overall transport by 4 h. A lesser depletion of cellular copper (13%) failed to enhance copper uptake but doubled the rate of overall transport, as measured with (64)Cu and by atomic absorption. As previously reported, preexposure of the cells to excess copper (10 micro M, 18 h) also enhanced copper uptake ( approximately 3-fold). In contrast, ascorbate (10-1,000 micro M) failed to significantly alter uptake and transport of 1 micro M (64)Cu. Our findings are consistent with the concepts that, in the low physiological range, copper availability alters the absorption capacity of the intestine to support whole body homeostasis and that basolateral transport is more sensitively regulated than uptake.

Absorption↗

PubMed1992

Increased blood and urine copper after residential exposure to copper naphthenate.

Despite widespread industrial use of copper naphthenate, there are no reports of the relationship of copper naphthenate and copper absorption in humans or animals. We report a family of three individuals who lived in a home where copper naphthenate was sprayed on the inner foundation. Subsequently, these individuals developed non-specific complaints. In two of these individuals, serum copper levels were elevated when first measured months after copper naphthenate was sprayed in the home. A gradual decline over several years in urine and serum copper levels was observed in the individual who maintained follow-up. It is not known if symptoms reflected exposure to naphthenate, the solvent vehicle, volatilized copper, or the stress of exposure to a malodorous compound perceived as toxic. Exposure to copper naphthenate may be another cause of an elevated serum and urine copper level but the interpretation of these levels as "normal" or "toxic" requires additional study for clarification. This report suggests the need for further study of the absorption and relative toxicity of copper naphthenate.

Absorption↗

PubMed1989

[Histochemistry of copper and copper-binding protein in liver with a comparison between histologic sections and biochemical evaluation].

A quantitative analysis of copper in liver tissue and a qualitative analysis of copper-binding protein in the histologic sections were subjected to correlative study. Liver sections, obtained from autopsies and surgical resections, were examined histopathologically by orcein staining, rhodanine staining, and other special stainings, in addition to hematoxylin eosin (HE) staining. The quantitative analysis was carried out by an atomic absorption spectrophotometry. Copper and copper-binding protein were not detectable by HE staining. The amount of orcein positive granules (OPGs) was graded semiquantitatively from negative (-) to three plus ( ). The average copper content was 24.9 micrograms/g dry liver weight (micrograms/g) in (-) group, 60.9 micrograms/g in (+) group, 158.9 micrograms/g in (++) group, and 299.3 micrograms/g in ( ) group respectively. Although the copper content and the amount of OPGs were relatively well correlated as mentioned above, standard deviations of copper contents were comparatively large in each group, especially in (++) or ( ) group. Based upon the comparative study of staining qualities of various dyes, rhodanine staining and orcein staining were specific for copper or copper-binding protein. Finally, orcein staining was thought to be the most excellent method from the viewpoints of sensitivity, specificity, contrast and simplicity. The distribution of excessive copper in pathologic conditions was fairly uneven. We recommend a histopathologic examination by using many liver sections stained by orcein, when the condition of copper overload is suspected.

Adult↗

PubMed1987

Effects of intravenously administered tetra-thiomolybdate on the distribution of copper in the liver and kidney of copper loaded sheep: a histochemical study.

The effects of intravenously administered thiomolybdate on the liver and kidney of copper loaded sheep were studied using 16 ewes in three groups. Copper, iron and molybdenum concentrations were determined by spectrophotometry and the distribution of copper in the liver and kidney was studied histochemically. Following thiomolybdate administration, the concentration of copper in the liver was reduced, that of molybdenum increased and the concentration of copper and molybdenum in the kidney increased. The reduction of copper concentration in the liver was associated with reductions in the number and size of granules in hepatocytes which stained positively for copper and in the number of Kupffer cells containing positively staining granules. The decrease in the amount of copper in hepatocytes appeared to be greater than that in Kupffer cells. This effect was greatest in the centrilobular zones and least in the periportal zones. The increased concentration of copper and molybdenum in kidney was associated with an increase in the number and size of granules staining positively for copper in the epithelial cells of the proximal convoluted tubules which suggested an uptake of copper-molybdenum complexes by the lysosomes of these cells.

Animals↗

PubMed1995

Tear copper and its association with liver copper concentrations in six adult ewes.

Tear and liver copper concentrations from 6 clinically healthy adult mixed-breed ewes were measured by Atomic Absorption Electrothermal Atomization (graphite furnace) Spectrometry and Flame Absorption Spectrometry, respectively, 7 times over 227 d to determine if their tears contained copper and if so, whether tear copper concentrations could reliably predict liver copper concentrations. To produce changes in liver copper concentration, the diet was supplemented with copper at concentrations that increased from 23 mg to 45 mg Cu/kg feed/day/sheep during the study. This regimen raised liver copper for all sheep to potentially toxic hepatic tissue concentration of greater than 500 mg/kg dry (DM) matter (tissue). The results of the study showed that copper was present in the tears of all sheep. The mean tear copper concentration showed a positive correlation with liver copper concentration (P = 0.003), increasing from 0.07 mg/kg DM at the start to 0.44 mg/kg DM at the end of the study, but could not reliably predict liver copper concentration (R2 = 0.222).

Animals↗

PubMed1997

[Photometric determination of copper content in the liver during experimental chronic copper poisoning in sheep].

15 castrated rams were exposed to an oral copper-dosage of 3.64 mg/d/kg body weight for 84 days. The control group consisted of 11 rams with a copper intake of 0.14 mg/d/kg bodyweight. Liver biopsies were taken percutaneously (100 samples), under laparoscopic control (53 samples) or post mortem (14 samples) before, during and up to 200 days after the controlled copper intake. Analysis of copper concentration in the liver tissue was done by a modified photometrical Bathocuproin-method after cold extraction with hydrochloric and trichloracetic acid. By using a parallel specimen blank with added EDTA, disturbing factors of the sample matrix were eliminated. The method was evaluated by the atom-absorption-spectroscopy after wet incineration as well as by standard addition of copper titrisol. The correlation with the reference method was very good (r > 0.99); the recovery rate after standard addition was 95 +/- 5.4%. The maximum copper concentrations in the liver were reached after the completion of the copper dosage. Blackheaded sheep showed significantly higher values (480 +/- 173 mg/kg wet tissue weight) than Merino sheep (338 +/- 103). The values of the control animals were 36 +/- 18 mg/kg. In the copper dosed rams the course of copper storage in the liver tissue could be described by an multiple regression with an accuracy of r2 > 0.75. The half-life of the copper concentration in the liver after exceeding maximum levels was 175 +/- 91 days. The pathogenetic role of the copper retention in the dosed animals was proven by regularly increased values of the hepatocellular enzyme glutamate dehydrogenase in the plasma.

Animals↗

PubMed2001

Binuclear homoleptic copper carbonyls Cu(2)(CO)(x) (x = 1-6): remarkable structures contrasting metal-metal multiple bonding with low-dimensional copper bonding manifolds.

Binuclear homoleptic copper carbonyls Cu(2)(CO)(x) (x = 1-6) have been studied using four different density functional theory methods (DFT) in conjunction with a basis set of extended double-zeta plus polarization quality, labeled as DZP. For each homoleptic binuclear copper carbonyl compound, several stationary point structures are presented, and these structures are characterized in terms of their geometries, thermochemistry, and vibrational frequencies. The optimal unsaturated Cu(2)(CO)(x) (x = 1-6) structures are generated by joining 18-electron tetrahedral, 16-electron trigonal, 14-electron linear copper carbonyl building blocks, and/or bare copper atoms with copper-copper single bonds rather than by joining 18-electron copper carbonyl units with multiple copper-copper bonds. For Cu(2)(CO)(6) the eclipsed and staggered ethane-like structure are virtually degenerate and lie significantly lower in energy than other possible structures. The eclipsed Cu-Cu single bond distance is predicted to be 2.61 A, while that for the staggered structure is 2.65 A. The lowest energy structure for Cu(2)(CO)(5) is the eclipsed ethyl radical-like structure, with r(e)(Cu-Cu) = 2.51 A. The staggered ethyl radical-like structure lies only 0.1 kcal/mol higher in energy, with a Cu-Cu distance shorter by only approximately 0.001 A. For Cu(2)(CO)(4) a methylcarbene-like structure is predicted to lie lowest, with Cu-Cu distance 2.40 A. However, twisted and planar ethylene-like structure lie only 3-5 kcal/mol higher. For Cu(2)(CO)(3) a surprising methylcarbyne-like structure with r(e)(Cu-Cu) = 2.38 A is predicted to lie lowest with all four DFT methods. However, a classical vinyl radical-like lies only 2-4 kcal/mol higher. For Cu(2)(CO)(2) theory predicts a vinylidene-like structure with r(e)(Cu-Cu) = 2.34 A to be essentially degenerate with cis and trans bent acetylene structures with copper-copper distances 2.33 A. Finally, and consistent with earlier theoretical studies, the linear end on Cu-Cu-CO structure with r(e)(Cu-Cu) = 2.27 A is the predicted global minimum for Cu(2)(CO).

Journal Article↗

PubMed1982

Corrosion of a new copper-gold or copper-platinum intrauterine device.

It has been shown previously that supplementing plastic intrauterine devices (IUDs) with copper wire enhances the antifertility effect of the device. The use of copper intrauterine contraceptive devices, however, is currently limited to two to three years, mainly because of wire fragmentation, which was observed as early as after eight months of use. In the resulting search for a long-lasting device, two new systems of duplex wire, with gold and platinum cores electrolytically coated with copper, were devised and studied. Initially, duplex wires and controls were exposed to physiological solution. Copper dissolution rate and corrosion morphology were studied by weight-loss measurements and optical metallography. Similar systems were then surgically implanted in rat uteri for varying periods of up to 26 weeks. Electron microanalysis of corrosion products, in addition to weight-loss measurements and metallography, was performed. The results showed that a uniform and ductile copper coating is obtainable by electroplating on gold and platinum wires. Rate of copper dissolution is similar to that of solid copper wire. No dissolution of gold and platinum in the controls or coated wires was detected by weight loss, metallography, or atomic absorption measurements. Microanalysis of the deposits and corrosion products on the wires in the uteri environment showed sulfur, chlorine, and calcium, in addition to copper. The results of this study suggest that supplementing IUDs with copper-coated gold or platinum wires may result in significant prolongation of the life span of the device by preventing uncontrolled loss of copper caused by wire fragmentation.

Animals↗

PubMed2000

Toxicity and bioavailability of copper herbicides (Clearigate, Cutrine-Plus, and copper sulfate) to freshwater animals.

In designing aquatic herbicides containing copper, an important goal is to maximize efficacy for target species while minimizing risks for nontarget species. To have a margin of safety for nontarget species, the concentration, duration of exposure (i.e., uptake), and form (i.e., species) of copper used for herbicidal properties should not elicit adverse effects on populations of nontarget species. To determine the potential for risk or adverse effects (conversely the margin of safety), data regarding the comparative toxicity of copper-containing herbicides are crucial. A series of comparative toxicity experiments was conducted, including baseline estimates of toxicity (LC50s, LOECs), sensitive species relationships (thresholds and exposure-response slopes), and bioavailability of toxic concentrations and forms of copper 7 days after initial herbicide application. Aqueous 48-h toxicity experiments were performed to contrast responses of Daphnia magna Strauss, Hyalella azteca Saussure, Chironomus tentans Fabricius, and Pimephales promelas Rafinesque to copper herbicides: Clearigate(R), Cutrine(R)-Plus, and copper sulfate. D. magna was the most sensitive aquatic animal tested for all three herbicides; 48-h LC50s for organisms exposed to Clearigate, Cutrine-Plus, and copper sulfate were 29.4, 11.3, and 18. 9 microg Cu/L, respectively. In terms of potency (calculated from the linearized portion of the exposure-response curves, which included 50% mortality), D. magna was the most sensitive animal tested. Organisms exposed to Clearigate, Cutrine-Plus, and copper sulfate had exposure-response slopes of 2.55, 8.61, and 5.07% mortality/microg Cu/L, respectively. Bioavailability of Clearigate and Cutrine-Plus was determined by comparing survival data (LC50s) of test organisms exposed to herbicide concentrations during the first and last 48-h of a 7-day exposure period. Even in these relatively simplified water-only exposures, a transformation of copper to less bioavailable species over time was observed with a 100-200% decrease in toxicity (i.e., an increase in 48-h LC50s) for all four test animals. This series of laboratory experiments provides a worst-case scenario for determining the risk associated with the manufacturer's recommended application rates of Clearigate (100-1,000 microg Cu/L), Cutrine-Plus (200-1,000 microg Cu/L), and copper sulfate (100-500 microg Cu/L) in natural waters for four nontarget freshwater animals.

Amino Alcohols↗

PubMed1993

Copper-64 metabolism in two patients with non-Wilsonian movement disorders and copper deficiency.

Copper-64 studies are presented of 2 patients with non-Wilsonian movement disorder and with abnormal copper handling. Both patients differed from the usual phenotype of non-Wilsonian low copper movement disorder as they had choreiform movement disorders with an onset in the first decade; one patient lacked significant intellectual impairment. Both patients had reduced serum total copper and marginal free copper and caeruloplasmin levels, and both patients were capable of incorporating 64Cu2+ into caeruloplasmin but the second case did so at markedly reduced level. Both showed slightly increased basal and stimulated urinary copper loss compared to normal controls with the rate in patient 1 being capable of leading to copper depletion. Liver copper content was normal in both cases. These 2 patients add to the reports of cases with copper deficiency and movement disorder in whom copper chelation therapy is unlikely to be beneficial.

Adult↗

PubMed1999

Characterization of the Menkes protein copper-binding domains and their role in copper-induced protein relocalization.

Menkes disease is a fatal X-linked disorder of copper metabolism. The gene defective in Menkes disease (ATP7A) encodes a copper transporting P-type ATPase (MNK or ATP7A) with six copper-binding domains at its N-terminus. MNK is normally localized to the trans -Golgi network in cultured cells, but relocates to the plasma membrane in the presence of elevated extracellular copper. In this study, the role of the six copper-binding domains on copper-induced redistribution is investigated. In a recombinant clone, when all the wild-type copper-binding motifs are mutated from GMXCXXC to GMXSXXS and the cells grown in medium containing elevated copper, relocalization of the recombinant protein to the plasma membrane was not observed. Using the same assay with any one of the six copper-binding domains intact, MNK moves to the plasma membrane in a way indistinguishable from the wild-type protein. Therefore, the copper-binding domains are vital for MNK trafficking and only a single domain is sufficient for this redistribution to occur.

Adenosine Triphosphatases↗

PubMed1998

Effect of copper supplementation on copper status of pregnant mares and foals.

Pregnant Thoroughbred mares (n = 21) were grazed on tall fescue pasture containing 4.4-8.6 mg Cu/kg dry matter (DM). Twelve mares were supplemented with approximately 0.5 mg Cu/kg liveweight (LW)/day as copper sulphate for the final 13-25 weeks gestation. Plasma copper concentration declined during the third trimester for all mares and was not affected by copper supplementation. Liver copper concentration of mares and foals was determined when the foals were 4-10-days-old. Copper supplementation of the mares tended to increase mare liver copper concentration (P<0.08) and increased foal liver copper concentration (P<0.01). There was a significant relationship between mare and foal liver copper concentration (P<0.001, r2 = 0.7). Increasing the copper intake of mares is effective in enhancing the copper status of foals.

Analysis of Variance↗

PubMed2004

The copper influx transporter human copper transport protein 1 regulates the uptake of cisplatin in human ovarian carcinoma cells.

Cells selected for resistance to cisplatin are often cross-resistant to copper and vice versa, and the major copper influx transporter copper transport protein 1 (CTR1) has been shown to regulate the uptake of cisplatin, carboplatin, and oxaliplatin in yeast. To further define the role of hCTR1 in human tumor cells, the ovarian carcinoma cell line A2780 was molecularly engineered to increase expression of hCTR1 by a factor of 20-fold. Enhanced expression of hCTR1 in the A2780/hCTR1 cells was associated with a 6.5-fold increase in basal steady-state copper content and a 13.7-fold increase in initial copper influx, demonstrating that the exogenously expressed hCTR1 was functional in altering copper homeostasis. The A2780/hCTR1 cells accumulated 46% more platinum after a 1-h exposure to 2 microM cisplatin, and 55% more after a 24 h exposure, than the control A2780/empty vector cells. The initial uptake of cisplatin was 81% higher in the A2780/hCTR1 cells when measured at 5 min. Thus, increased expression of hCTR1 had a substantially larger effect on the cellular pharmacology of copper than cisplatin. Interestingly, the increased uptake of copper and cisplatin was accompanied by only a marginal increase in sensitivity to the cytotoxic effect of copper and cisplatin, and there was no increase in the extent of cisplatin-DNA adduct formation. Thus, although increased expression of hCTR1 mediates greater cellular accumulation of copper and cisplatin, hCTR1 delivers these compounds into intracellular compartments from which they do not have ready access to their key cytotoxic targets.

Antineoplastic Agents↗

PubMed1989

Effect of chelators on copper metabolism and copper pools in mouse hepatocytes.

Disorders of copper storage are usually treated by chelation therapy. It is generally thought that the chelators act by mobilizing copper from the liver, hence allowing excretion in the urine. This paper has examined the effect of chelators on copper uptake and storage in mouse hepatocytes. Penicillamine, a clinically important chelator, does not block the uptake of copper or remove copper from hepatocytes. Two other copper chelators, sar and diamsar, which form very stable and kinetically inert Cu2+ complexes by encapsulating the metal ion in an organic cage, were shown to block copper accumulation by the cells and to remove up to 80% of cell-associated copper. They also removed most (approximately 80%) of the 64Cu accumulated by the cells in 30 min, but released only a small percentage (less than 20%) of that accumulated over 18 h. The results show that copper in the hepatocyte can be divided into at least two pools, an easily accessible one, and another, not removable even after long-term incubation with any of the chelators. Most of the copper normally found in the cell appeared to be associated with the former pool.

Animals↗

PubMed2006

Copper homeostasis in the CNS: a novel link between the NMDA receptor and copper homeostasis in the hippocampus.

Copper is an essential nutrient that plays a fundamental role in the biochemistry of the central nervous system, as evidenced by patients with Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the loss-of-function of a copper-transporting P-type adenosine triphosphatase (ATPase). Despite clinical and experimental data indicating a role for copper in brain function, the mechanisms and timing of the critical events affected by copper remain poorly understood. A novel role for the Menkes ATPase has been identified in the availability of an N-methyl-D-aspartate (NMDA) receptor-dependent, releasable pool of copper in hippocampal neurons, suggesting a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the evidence that copper acts as a modulator of neuronal transmission, and that the release of endogenous copper from neurons may regulate NMDA receptor activity. The relationship between impaired copper homeostasis and neuropathophysiology suggests that impairment of copper efflux could alter neuronal function and thus contribute to rapid neuronal degeneration.

Adenosine Triphosphatases↗

PubMed1996

Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis.

The cell surface protein repertoire needs to be regulated in response to changes in the extracellular environment. In this study, we investigate protein turnover of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p, in response to a change in extra-cellular copper levels. As Ctr1p mediates high affinity uptake of copper into the cell, modulation of its expression is expected to be involved in copper homeostasis. We demonstrate that Ctr1p is a stable protein when cells are grown in low concentrations of copper, but that exposure of cells to high concentrations of copper (10 microM) triggers degradation of cell surface Ctr1p. This degradation appears to be specific for Ctr1p and does not occur with another yeast plasma membrane protein tested. Internalization of some Ctr1p can be seen when cells are exposed to copper. However, yeast mutant strains defective in endocytosis (end3, end4 and chc1-ts) and vacuolar degradation (pep4) exhibit copper-dependent Ctr1p degradation, indicating that internalization and delivery to the vacuole is not the principal mechanism responsible for degradation. In addition, a variant Ctr1p with a deletion in the cytosolic tail is not internalized upon exposure of cells to copper, but is nevertheless degraded. These observations indicate that proteolysis at the plasma membrane most likely explains copper-dependent turnover of Ctr1p and point to the existence of a novel pathway in yeast for plasma membrane protein turnover.

Cation Transport Proteins↗

PubMed1998

[Atomic absorption spectrophotometry study of copper ion release by copper-bearing intrauterine devices].

Copper release from copper-bearing IUD's was studied in vitro and in vivo using atomic absorption spectrophotometry in deionized water, normal saline solution and normal ovulatory cervical mucus. In these media, copper release from a 375 mm2 DIU occurs without latency, showing comparable amounts for identical time intervals. Daily copper release was shown to be respectively 8 and 11 times higher in cervical mucus and normal saline solution than in deionized water. Although copper ions are detectable in ovulatory cervical mucus under physiological conditions, the copper content appears 5 to 6 times higher in women bearing a copper IUD. Obviously, the copper amount is dependent on the copper exposed surface: the daily in vitro release from a 250 mm2 IUD is 18% inferior to that observed from a 375 mm2 model. In vivo, the daily copper release in ovulatory mucus of 380 or 200 mm2 IUD users is respectively 5 and 3.5 times higher than in controls.

Adult↗

PubMed1982

Copper loss from the copper T model TCu22OC.

The effect of mineral deposits on the copper dissolution rate of the Copper T Model TCu22OC was examined. 118 Copper T22OC devices removed from subjects for various medical and personal reasons after 12 to 72 months in utero were examined and graded based on the proportion of the total copper area covered with mineral deposits. The deposits increased in average size during the first three years of IUD use and then remained relatively constant. Seventeen percent of the devices were in situ for four or more years. Copper analysis was performed on 30 Copper T 22OC devices from selected periods of use : 12-14, 22-26, 36-39 and 48-72 months of use. The mean daily copper loss was 29.4 micrograms and the range, 7.3 to 62.1 micrograms. An inverse correlation between the amount of mineral deposit on the copper surface and the rate of copper loss was observed.

Copper↗