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PubMed1995

Copper binding to rabbit liver metallothionein. Formation of a continuum of copper(I)-thiolate stoichiometric species.

Circular dichroism and ultraviolet absorption spectral data have been used to probe the binding mechanism for formation and the structure of the copper(I)-thiolate binding clusters in rabbit liver metallothionein during addition of Cu+ to aqueous solutions of Zn7-metallothionein 2 and Cd5Zn2-metallothionein 2. Mammalian metallothionein binds metals in two binding sites, namely the alpha and beta domains. Spectral data which probe the distribution of Cu(I) between the two binding domains clearly show that both the site of binding (alpha or beta), and the structures of the specific metal-thiolate clusters formed, are dependent on temperature and on the nature of the starting protein (either Zn7-metallothionein or Cd5Zn2-metallothionein). CD spectra acquired during the addition of Cu+ to Zn7-metallothionein show that Cu+ replace the bound Zn(II) in a domain-distributed manner with complete removal of the Zn(II) after addition of 12 Cu+. Spectral and metal analyses prove that a series of Cu(I)-metallothionein species are formed by a non-cooperative metal-binding mechanism with a continuum of Cu(I):metallothionein stoichiometries. Observation of a series of spectral saturation points signal the formation of distinct optically active Cu(I)-thiolate structures for the Cu9Zn2-metallothionein, Cu12-metallothionein, and the Cu15-metallothionein species. These data very clearly show that for Cu(I) binding to Zn7-metallothionein, there are several key Cu(I):metallothionein stoichiometric ratios, and not just the single value of 12. The CD spectra up to the Cu12-metallothionein species are defined by bands located at 255(+) nm and 280(-) nm. Interpretation of the changes in the CD and ultraviolet absorption spectral data recorded between 3 degrees C and 52 degrees C as Cu+ is added to Zn-metallothionein show that copper-thiolate cluster formation is strongly temperature dependent. These changes in spectral properties are interpreted in terms of kinetic versus thermodynamic control of the metal-binding pathways as Cu+ binds to the protein. At low temperatures (3 degrees C and 10 degrees C) the spectral data indicate a kinetically controlled mechanism whereby an activation barrier inhibits formation of ordered copper-thiolate structures until formation of Cu12-metallothionein. At higher temperatures (> 30 degrees C) the activation barrier is overcome, allowing formation of new Cu(I)-thiolate clusters with unique spectral properties, especially at the Cu9Zn2-metallothionein point. The CD spectra also show that a Cu15-metallothionein species with a well-defined, three-dimensional structure forms at all temperatures, characterized by a band near 335 nm, indicating the presence of diagonal Cu(I).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Acute copper toxicity following copper glycinate injection.

We present a patient who developed multi-organ failure due to severe copper toxicity following attempted suicide by s.c. injection of copper glycinate. Acute copper toxicity is rare in the developed world, although it occurs more frequently in developing world countries, where it is a common mode of suicide. Acute toxicity usually results from oral ingestion and there are several local and systemic effects. Specific management can be difficult as there is little evidence regarding the efficacy of chelating agents in acute toxicity.

Adult↗
PubMed1984

Mobilization of copper(II) from plasma components and mechanisms of hepatic copper transport.

The effects of plasma Cu(II) ligands on the kinetics of Cu(II) transport by rat liver parenchymal cells were determined to examine how Cu(II) is mobilized from plasma and transported into liver cells. Albumin markedly inhibited Cu(II) uptake at Cu(II)-to-albumin molar ratios of 3:1 or less. Kinetic analyses showed that albumin inhibits Cu(II) uptake by reducing the concentration of free Cu(II) in solution. Under conditions of excess albumin to Cu(II), histidine facilitated albumin-inhibited uptake of Cu(II). Threonine, glutamine, and most other amino acids were without effect. Moreover, the facilitation effect of a low-molecular-weight plasma fraction (less than or equal to 5,000) was largely accounted for by its histidine concentration. The tripeptide Gly-His-Lys also inhibited Cu(II) uptake into hepatocytes by the same mechanism as albumin. The inhibitory effects of albumin and Gly-His-Lys were additive with or without histidine. The active species in the Cu(II), albumin, and histamine mixtures was shown to be the His2Cu(II) complex. Vmax for this complex was identical to the Vmax for free Cu(II), but the Km was slightly higher [15 microM vs. 11 microM for free Cu(II)]. Concurrent determinations of [3H]-histidine and 64Cu(II) uptake showed that histidine was not transported with Cu(II) from His X Cu(II) or His2Cu(II) complexes. The data are consistent with histidine mobilizing Cu(II) from albumin by competing for Cu(II), interaction of the His2Cu(II) complex with the putative hepatic copper transport protein, and transport of copper as free ionic copper.

Amino Acids↗
PubMed1988

Neonatal and adult copper-64 metabolism in the pig and the possible relationship between the ontogeny of copper metabolism and Wilson's disease.

The copper profiles of neonatal mammals differ from those of the adult; in man they are similar to those found in people with Wilson's disease (WD). WD patients handle an intravenous bolus of radioactive copper in a characteristic manner which aids diagnosis. In view of the similarity between neonatal mammals and WD patients, we have studied the fate of an intravenous bolus of 64Cu injected into neonatal and adult pigs. In adult pigs, plasma 64Cu activity fell for 10 h and then slowly increased over the next 14 h as newly synthesised caeruloplasmin was secreted. In the neonate a secondary rise in 64Cu activity was not observed. Gel filtration of the soluble supernatant revealed significant differences in the association of 64Cu with hepatic copper proteins. In adults 64Cu associated predominantly with superoxide dismutase whilst in the neonate the 64Cu associated with metallothionein and a protein of high molecular weight. This study indicates that 64Cu export from the neonatal pig liver is in many ways similar to that found in WD. Additionally, there are similarities in the profile of hepatic 64Cu-binding proteins.

Animals↗
PubMed1989

Effects of copper and molybdenum supplements on the copper and selenium status of pregnant ewes and lambs.

The aim of this work was to investigate whether Cu, alone or in combination with Mo, reduces the Se status of sheep. Thirty-six Hampshire ewes were separated prior to mating into four treatment groups of nine sheep each. The four groups consisted of 1) basal (alfalfa hay or legume-grass low-moisture silage, corn, oats), 2) basal plus 10 mg Cu/kg diet, 3) basal plus 10 mg Mo/kg and 4) basal plus Cu and Mo (each 10 mg/kg). Copper and Mo were added to both ewe and lamb diets. Treatments continued until lambs were weaned at 10 wk postpartum. The basal ewe diet contained, in mg/kg, 5.6 Cu, .05 Se and 1.0 Mo. The basal lamb diet contained, in mg/kg, 6.1 Cu, .07 Se and less than 1.0 Mo. Sulfur concentrations in the ewe and lamb diets were .24% and .20%, respectively. Copper supplements increased, and Mo supplements decreased, the concentration of Cu in the livers of ewes and lambs (P less than .05). Despite this, there were no effects of treatment on Se concentration or glutathione peroxidase activity in blood or tissues. Selenium levels in plasma of all ewes declined throughout pregnancy and lactation, indicating that .05 mg/kg Se was insufficient for the maintenance of Se status during pregnancy in Hampshire ewes. Copper and Se levels (mg/kg fresh weight) in the liver of lambs at weaning for Treatments 1 through 4 were 48 and .13, 158 and .10, 11 and .11, and 136 and .13, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Feed↗
PubMedDate not supplied

[Development of copper tolerance in cyanobacteria subjected to repeated copper intoxication].

Experiments on cyanobacterial cultures showed that initial exposure to copper at concentrations of 0.01-0.05 mg/l not only has a direct toxic effect, but also significantly modifies the copper tolerance of cyanobacteria for repeated exposure. The response to repeated exposure and the mechanism of tolerance depend on the strength of the initial effect of copper and the extent of heterogeneity of the initial cyanobacterial population.

Adaptation, Physiological↗
PubMed1992

X-band electron paramagnetic resonance spectra of bovine serum albumin-copper(II) and bovine serum albumin-copper(II)-aminoacid systems.

X-band electron paramagnetic resonance (epr) spectra of the binary systems, BSA-copper(II) (1:1 and 2:1), and the ternary systems, BSA-Cu(II)-aminoacid (1:1:1), are described. In the binary system, two distinct epr features have been observed. One of the features (towards the low pH), showing broad and overlapping epr signals, has been attributed to non-specific bonding of copper(II) to the albumin and other feature (towards higher pH), showing sharp intense epr signals, has been attributed to the specific bonding. The change from non-specific to specific binding is favoured by increase in pH as well as by increase in protein concentration. Specific binding of copper(II) in BSA-Cu(II) has been suggested to be similar to that in HSA-Cu(II). Spectra of BSA-Cu(II)-aminoacid (1:1:1) show simultaneous presence of binary BSA-Cu(II) and ternary BSA-Cu(II)-aminoacid.

Amino Acids↗
PubMed2004

Dietary copper restriction-induced changes in myocardial gene expression and the effect of copper repletion.

Dietary copper (Cu) restriction leads to cardiac hypertrophy and failure in mice, and Cu repletion (CuR) reverses the hypertrophy and prevents the transition to heart failure. The present study was undertaken to determine changes in myocardial gene expression involved in Cu deficient (CuD) cardiomyopathy and its reversal by CuR. Analysis was performed on three groups of mice: 4-week-old CuD mice that exhibited signs of cardiac failure, their age-matched copper-adequate (CuA) controls, and the CuD mice that were re-fed adequate Cu for 2 weeks. Total RNA was isolated from hearts and subjected to cDNA micro-array and real-time reverse transcription-polymerase chain reaction analysis. Dietary CuD caused a decrease in cardiac mRNA of beta-MHC, L-type Ca(2+) channel, K-dependent NCX, MMP-2, -8, and -13, NF-kappaB, and VEGF. The mRNA levels of ET-1, TGF-beta, TNF-alpha, and procollagen-I-alpha1 and III-alpha1 were increased in the CuD cardiac tissue. Copper repletion resulted in cardiac mRNA levels of most of the genes examined returning to control levels, although the K-dependent NCX and MMP-2 values did not reach those of the CuA control. In addition, CuR caused an increase in beta-MHC, L-type Ca(2+)channel, MMP-13 to levels surpassing those of CuA control, and a decrease in ET-1, and TNF-alpha mRNA levels. In summary, changes in gene expression of elements involved in contractility, Ca(2+) cycling, and inflammation and fibrosis may account for the altered cardiac function found in CuD mice. The return to normal cardiac function by CuR may be a result of the favorable regression in gene expression of these critical components in myocardial tissue.

Animals↗
PubMed1991

Copper K-extended x-ray absorption fine structure studies of oxidized and reduced dopamine beta-hydroxylase. Confirmation of a sulfur ligand to copper(I) in the reduced enzyme.

The structure of the copper sites in oxidized and reduced dopamine beta-hydroxylase has been studied by extended x-ray absorption fine structure spectroscopy using a restrained refinement approach to data analysis. An histidine-rich active site has been found to be present with an average histidine coordination of between two and three histidine ligands per copper. In the oxidized protein, the data support four-coordination, involving two to three imidazole groups at 1.99 A with additional ligands derived from water or exogenous O-donor groups at an average distance of 1.94 A. Studies on the reduced enzyme have focused on resolving the controversy in the literature (Scott, R. A., Sullivan, R. J., De Wolfe, W. E., Dolle, R. E., and Kruse, L. I. (1988) Biochemistry 27, 5411-5417; Blumberg, W. E., Desai, P. R., Powers, L., Freedman, J. H., and Villafranca, J. J. (1989) J. Biol. Chem. 264, 6029-6032) as to whether a S/Cl scatterer is a ligand to Cu(I). Five independent samples of reduced enzyme prepared under conditions designed to probe the Cu(I) ligand environment have been measured and analyzed. All five samples gave identical spectra and could be simulated by two to three imidazoles (1.93 A) and 0.5 S/Cl (2.25 A) per Cu(I). The spectra were insensitive to the presence of added bromide or to exclusion of chloride during preparation. The results establish that the heavy atom scatterer is derived from a sulfur donor. Some evidence was found for an additional O/N scatterer at 2.6 A in the reduced enzyme. A hypothesis for the structure of the copper sites has been proposed involving inequivalent CuA(His)3(H2O)...CuB-(His)2X(H2O) coordination in the oxidized enzyme, which upon reduction loses coordinated water and coordinates a sulfur probably from a methionine.

Amino Acid Sequence↗
PubMed1990

Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II): synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion.

Generator produced positron-emitting radionuclides could potentially expand the application of positron emission tomography (PET) to centers that do not have access to a local cyclotron. The zinc-62/copper-62 radionuclide generator system could serve as a source of positron-emitting copper-62 (62Cu) (t1/2 = 9.74 min) for physiologic imaging. Accordingly, we have prepared zinc-62/copper-62 generators capable of high output (greater than 300 mCi) and used the no-carrier-added eluate in a rapid high yield synthesis of [62Cu] Cu(PTSM) that provides the radiopharmaceutical in a form suitable for intravenous injection (where Cu(PTSM) = pyruvaldehyde bis(N4-methylthiosemicarbazonato) copper(II]. We then demonstrated in pilot studies that [62Cu]Cu(PTSM) provides high quality brain and heart images with PET, accurately delineating cerebral and myocardial perfusion in both experimental animals and in humans (corroborating results of previous experimental studies utilizing longer-lived copper isotopes). The results of this work demonstrate that 62Cu can be conveniently obtained from high-level generators and, when used to label Cu(PTSM), provides a generator-produced radiopharmaceutical capable of providing estimates of cerebral and myocardial perfusion independent of cyclotron-produced radionuclides.

Animals↗
PubMed1977

Copper toxicity in sheep: the effects of repeated intravenous injections of copper sulphate.

Four Clun Forest, Suffolk cross sheep were given daily intravenous injections of copper sulphate. Three similar sheep acted as controls. The copper dosed sheep developed haemolysis and showed liver, kidney and brain damage similar to that seen in chronic copper poisoning. All animals survived for 30 days and two would have lived longer. Reticulocytes were produced after four days and continued to be produced, sometimes in high number throughout the course of the experiment.

Animals↗
PubMed1981

Dermal copper drugs: the copper bracelet and cu(II) salicylate complexes.

A review is presented of both published work and unpublished observations concerned with: a) the 'efficacy' of copper bracelets for arthritis; b) the bio-reactivity of metallic copper (especially with human sweat); c) permeation of the skin by Cu(II) when complexed with certain ligands (such as salicylates); d) the pharmacological and clinical activity of AlcusalR and DermcusalR, two formulations of copper salicylate with ethanol and dimethyl sulphoxide respectively that can be applied to the skin. Topical application promises to be a superior alternative to orally ingested drugs.

Administration, Topical↗
PubMed1993

Decrease in biliary excretion of copper in Long-Evans cinnamon (LEC) rats causing spontaneous hepatitis due to a gross accumulation of hepatic copper.

The concentration of biliary Cu was 0.12 +/- 0.01 microgram/ml in male LEC rats aged 14 weeks and 0.43 +/- 0.09 micrograms/ml in Fischer rats of the same age. When copper chloride (170 micrograms/kg b.w. as Cu) was infused intravenously (i.v.), the concentration of biliary Cu increased to only 0.21 +/- 0.06 microgram/ml 30 min after the infusion in LEC rats. In contrast, Fischer rats showed a concentration about 10 times higher (4.02 +/- 2.2 micrograms/ml) than that before the infusion. In Fischer rats pretreated with cadmium chloride, the biliary Cu concentration was 1.04 + 0.43 micrograms/ml 30 min after infusion of copper. Horseradish peroxidase (E.C.1.11.1.7) infused iv along with copper chloride was excreted into bile at a low level in LEC rats compared to Fischer rats. Our results suggest that the gross accumulation of hepatic Cu in the new, mutant LEC rats is due to a low excretion of Cu into bile and that the hepatobiliary dysfunction is related to spontaneous hepatitis.

Animals↗
PubMed1981

A comparison of the initial pain response following insertion of the Copper 7 and combined Multiload Copper 250-short IUDs.

The immediate postinsertion and 3 minute postinsertion pain response in nulliparous women undergoing insertion of either the Copper 7 (Cu 7) or the Multiload Copper 250-short (ML Cu 250-short) IUD has been studied. 35 women were fitted with a Cu 7 device and 23 with the ML Cu 250-short. The immediate postinsertion pain scores were significantly higher in the ML Cu 250-short group than in the Cu 7 group. There was no significant difference between the 3 minutes postinsertion scores for the 2 groups. The 3 minute pain scores were significantly lower than the immediate pain scores for each individual device group. Immediate postinsertion IUD pain may be related to the presenting diameter and insertional mechanism of the device. This pain is of short duration and after 3 minutes, the level of pain is independent of the type of device which has been inserted. The rapid diminution of pain at 3 minutes postinsertion indicates that the routine use of certain analgesic techniques, e.g., paracervical block before IUD insertion, is not justified. Pain following IUD insertion may provide a useful model for the study of various types of peripheral and centrally acting analgesics.

Chemical Phenomena↗
PubMed2006

Solid-state NMR and EXAFS spectroscopic characterization of polycrystalline copper(I) O,O'-dialkyldithiophosphate cluster compounds: Formation of copper(I) O,O'-diisobutyldithiophosphate compounds on the surface of synthetic chalcocite.

A number of polycrystalline copper(I) O,O'-dialkyldithiophosphate cluster compounds with Cu4, Cu6, and Cu8 cores were synthesized and characterized by using extended X-ray absorption fine-structure (EXAFS) spectroscopy. The structural relationship of these compounds is discussed. The polycrystalline copper(I) O,O'-diisobutyldithiophosphate cluster compounds, [Cu8{S2P(OiBu)2}6(S)] and [Cu6{S2P(OiBu)2}6], were also characterized by using 31P CP/MAS NMR (CP = cross polarization, MAS = magic-angle spinning) and static 65Cu NMR spectroscopies (at different magnetic fields) and powder X-ray diffraction (XRD) analysis. Comparative analyses of the 31P chemical-shift tensor, and the 65Cu chemical shift and quadrupolar-splitting parameters, estimated from the experimental NMR spectra of the polycrystalline copper(I) cluster compounds, are presented. The adsorption mechanism of the potassium O,O'-diisobutyldithiophosphate collector, K[S2P(OiBu)2], at the surface of synthetic chalcocite (Cu2S) was studied by means of solid-state 31P CP/MAS NMR spectroscopy and scanning electron microscopy (SEM). 31P NMR resonance lines from collector-treated chalcocite surfaces were assigned to a mixture of [Cu8{S2P(OiBu)2}6(S)] and [Cu6{S2P(OiBu)2}6] compounds.

Journal Article↗