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PubMed1985

Cellular localization of metallothionein in the lung following repeated cadmium inhalation.

Cadmium and metallothionein (MT) levels were measured in lungs derived from Lewis rats exposed 0, 5, 10, 15, 20, 24, or 30 times to a Cd acetate aerosol (1.6 mg/m3). Cd burden rose from 2.21 micrograms in control lungs to 42.55 micrograms in lungs of animals exposed 30 times to the Cd aerosol. Pulmonary MT, expressed as nmoles Cd-thionein, paralleled Cd retention. Levels increased from 7.5 nmol in control animals to a value of 340.5 nmol in animals exposed 30 times to Cd. Energy dispersive X-ray microanalysis and the laser micro-probe analyzer were used to localize Cd within the lung. Lung tissue was prepared by a variety of chemical and physical fixation procedures. Cd localization proved unsuccessful by these techniques, presumably because the cellular Cd levels were below the limits of detectability. Using a immunohistochemical procedure which employed an antibody to MT, pulmonary MT was found in alveolar epithelial cells, fibroblasts, and lymphocytes. The MT was restricted to the nuclei of these cells.

Aerosols↗
PubMed1986

D-penicillamine induces rat hepatic metallothionein.

Intraperitoneal injection of D-Penicillamine (D-PA) at a dose range of 20-500 mg/kg increased rat hepatic but not renal and pancreatic metallothionein (MT). Elevated MT predominantly contained Zn. Maximal induction was obtained 18 h after a single injection of 200 mg D-PA/kg resulting in 148 +/- 18 micrograms MT/g liver which was 16.4-times the control level of 9 +/- 2 micrograms MT/g. At 48 h after injection, MT declined to 18 +/- 9 micrograms MT/g liver. At maximal MT increase the content of total hepatic Zn but not of Cu was elevated. Increased amounts of Zn in liver homogenate, cytosol and MT could be detected approximately 4 h after injection of 200 mg D-PA/kg. Concomitantly there was a decrease in Zn bound to cytosolic non-MT ligands. All Zn changes reversed at 18 h. These data show that already single doses of D-PA cause induction of Zn-thionein in rat liver and lead to synchronous redistribution of Zn from endogenous sources to newly synthesized MT.

Animals↗
PubMed1986

Concentrations of metallothionein and metals in malignant and non-malignant tissues in human liver.

Concentration of metallothionein in the malignant and non-malignant tissues of the human liver was determined by the Cd-hem method. The concentration of metallothionein was high in the non-malignant tissue (471 +/- 306 micrograms/g). Metallothionein in the non-malignant tissue was mainly Zn-thionein and metallothionein-bound Zn was a major chemical form of Zn in the non-malignant tissue. The concentration of metallothionein in the malignant tissue was 75.6 +/- 79.6 micrograms/g, and significantly lower than that in the nonmalignant tissue. A strong, positive relationship was observed between the Zn and metallothionein concentrations, and the regression equation was MT (microgram/g) = -94.7 + 11.9 Zn (micrograms/g).

Adult↗
PubMed1991

Induction of metallothionein in mouse liver by valproic acid.

Intraperitoneal injection of valproic acid (VPA) induces metallothionein (MT) in mouse liver. There was a clear-cut dose-dependency and the maximal amount of MT induced by VPA was about 6 times the basal level. The hepatic MT level reached the peak value at 24 h after VPA injection. Neither Cu nor Zn concentrations showed any significant changes after VPA administration in either the whole liver, or in the mitochondrial or supernatant fractions of the liver homogenate. Gel filtration profiles for the supernatant of the liver homogenate of the VPA-treated mice, however, clearly showed that induced MT was chiefly Zn-thionein. Therefore, Zn molecules necessary for the elevated MT levels seem to originate mainly from cytosolic Zn-containing proteins except for MT.

Animals↗
PubMed1993

Metallothionein in human lung carcinoma.

Eleven pairs of surgically resected lung cancers and corresponding non-neoplastic lung tissue were evaluated for metallothionein (MT) and metal content (cadmium and copper) by the heme/109Cd binding assay and atomic absorption spectroscopy, respectively. Tissue samples, obtained from patients ranging in age from 51 to 79, included six adenocarcinomas, two small cell carcinomas, one mixed cell carcinoma, one squamous cell carcinoma, and one carcinoma of non-primary origin (i.e., melanoma). Paired t-tests showed that metallothionein and copper concentrations in lung tumor tissue were significantly elevated when compared to non-malignant lung tissue. Cu was the major metal associated with the 10 kDa MT fraction in lung tumors whereas Cd was the primary metal bound to MT from non-neoplastic lung tissue. Since Cu-thionein is also known to be elevated in fetal lung tissue, the possibility exists that MT might represent an oncodevelopmental product which is useful as a biomarker for the early detection of lung carcinoma.

Adenocarcinoma↗
PubMed1983

Isolation and characterization of hepatic metallothionein from rainbow trout (Salmo gairdneri).

1. A low molecular weight (7,700) Zn- and Cu-containing protein was isolated from the livers of Zn-injected rainbow trout by gel filtration and ion exchange chromatography. Purity of the isolated protein was assessed by native and denaturing polyacrylamide gel electrophoresis and isoelectric focusing. 2. The purified protein was positively identified as a metallothionein on the basis of its molecular size, high metal content (3.6 g atoms Zn and 2.6 g atoms Cu per mole; 5.2% metal), heat stability, u.v. absorption spectrum, charge and amino acid composition (25% cysteine, no histidine and tryptophan, and trace tyrosine and phenylalanine). 3. The relatively high Cu content of this protein was unexpected and may be attributed to the presence of high levels of Cu, as Cu-thionein, in the livers of non-injected fish. 4. The comparative differences in the metal content of hepatic MT in trout and other animals are discussed.

Amino Acids↗
PubMed1983

Heavy metal detoxication in Mytilus kidney--an in vitro study of Cd- and Zn-binding to isolated tertiary lysosomes.

Uptake of Cd and Zn by isolated lipofuschin granules (tertiary lysosomes) has been studied. Freshly isolated granules contain Zn and approx 85% is immobilised. The granules take up ionic Cd and Zn from the surrounding medium. The metals are weakly and reversibly bound by a passive, non-concentrative adsorption process. Multiple, non metal-specific binding sites with a pKapp approximately equal to 6 and stability constant approximately equal to 5 were found. Metals can be sequestered from proteins with weakly bound metal but not from Cd-thionein. The results are discussed in relation to intracellular control of heavy metal concentrations in the cell and the pathway of Cd metabolism.

Animals↗
PubMed1984

Chronic exposure of coho salmon to sublethal concentrations of copper--III. Kinetics of metabolism of metallothionein.

Juvenile coho salmon (Oncorhynchus kisutch) 3-8 g body weight were exposed to sublethal concentrations of copper acetate in water of hardness 280 mg/l (as CaCO3) using flow-through conditions. Concentrations of copper were approximately 1, 50, 100 or 150 micrograms Cu/l. Uptake of copper into blood, gills, kidney and liver was measured using 67Cu and into hepatic metallothionein. Chromatography on Sephadex G-75 was used to separate the protein from the cytosol. Copper was determined using atomic absorption spectrophotometry. The ratio of rates of uptake of copper and synthesis of metallothionein was consistent with published values for the copper content of copper-thionein, i.e. 7 to 1. After 4 weeks of continuous exposure the concentrations of copper and hepatic metallothionein levelled off at concentrations that were a function of the copper concentration in the water. After the plateau or steady-state had been reached, the rate of loss of metallothionein was measured by determining the change in specific-activity of isotope with time after incorporation of 35S-L-cysteine or 3H-L-lysine into the protein. The half-life for loss of metallothionein was a function of the exposure to copper, being about 13 days for control fish and 30 days for fish exposed to the greatest concentration of copper. Salmon that had been exposed to copper for 8 weeks neither gained hepatic metallothionein in a further 4 week exposure to copper, nor lost it when transferred for 4 weeks to clean water. Tolerance to copper exhibited by fish that continued to be exposed to it was partially lost after 4 weeks depuration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Metallothionein present or induced in the three species of frogs Bombina orientalis, Bufo bufo japonicus and Hyla arborea japonica.

A low molecular weight copper (Cu)- and/or zinc (Zn)-binding protein was present in the livers (and kidneys) of the three species of frogs Bombina orientalis, Bufo bufo japonicus and Hyla arborea japonica. Cadmium (Cd) accumulated in the livers (and kidneys) after repeated i.m. injections of Cd2+ was mostly bound to the same metal-binding protein as Cd, Zn- or Cd, Zn, Cu-thionein. Concentrations of Cd and several essential elements in the livers and kidneys of the three species of frogs were determined by inductively coupled plasma-atomic emission spectrophotometry. Metallothionein in the three species of frogs consists of a single isoform both in control and Cd-injected animals.

Animals↗
PubMed1989

Cadmium disposition following repeated exposure in the pregnant hamster.

Pregnant Syrian hamsters were given a dose of 3.9 micromoles cadmium ion/kg (radiolabelled with 109cadmium) on days 7, 8, 9, and 11 of gestation. Animals were sacrificed on day 13 of gestation and maternal blood, liver, kidney, placentas, and fetuses collected. No pathology was observed in placentas or fetuses. Maternal liver accounted for 61% of the total cadmium injected (15.6 micromoles/kg dam), maternal kidney 4%, and placentas 0.24%. Maternal blood and fetuses contributed negligibly to the total body burden of cadmium. Gel filtration experiments indicated two major cadmium fractions in maternal liver, maternal kidney, and placental cytosols, one at the excluded volume and another nearly twice the excluded volume. Further purification and characterization of the cadmium fraction eluting at twice the excluded volume in the gel filtration experiments showed it to be cadmium metallothionein. Ion exchange chromatography on DEAE Sephacel revealed two forms of cadmium metallothionein in the cytosols of maternal liver and placentas. Maternal kidney cytosols contained one cadmium metallothionein. Amino acid analyses suggest that the thionein components of placental cytosols are synthesized in situ.

Amino Acids↗
PubMedDate not supplied

A digital three-dimensional atlas of structure/function relationships.

The techniques and issues relevant to the development of a digital three-dimensional atlas of brain structure and function are discussed. The goals were to develop the appropriate methods for an interactive and quantitative stereotactic atlas to describe both anatomy and physiology. The work presented here used serial sections from unstained, thionein-stained and 2-deoxyglucose autoradiographic data sets.

Animals↗
PubMed2000

Toxic action/toxicity.

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a

Animals↗
PubMed1981

Zinc(II), cadmium(II), and mercury(II) thiolate transitions in metallothionein.

The metal-specific absorption envelopes of zinc-, cadmium-, and mercury-metallothioneins and of complexes of these metal ions with 2-mercaptoethanol have been analyzed in terms of Jørgensen's electronegativity theory for charge-transfer excitations by using the spectra of zinc(II), cadmium(II), and mercury(II) tetrahalides as references. By Gaussian analysis the difference absorption spectra of the various forms of metallothionein vs. thionein and of the corresponding 2-mercaptoethanol complexes vs. 2-mercaptoethanol were resolved into three components. For each metal derivative the location of the lowest energy band is in good agreement with the position of the first ligand-metal charge-transfer (LMCT) transition (type t2 leads to a1) predicted from the optical electronegativity difference of the thiolate ligands and of the central metal ion by assuming tetrahedral coordination. There is also a correspondence between the effects of the metal ion on the position of the first LMCT band and the binding energy of the 2p electrons of the sulfur ligands as found by X-ray photoelectron spectroscopic measurements [Sokolowski, G., Pilz, W., & Weser, U. (1974) FEBS Lett. 48, 222]. Due to the lack of exact structural information, the assignment of the two other resolved metal-dependent bands remains conjectural, but it is likely that they include a second LMCT transition (type t2 leads to a1) analogous to that occurring in tetrahalide complexes of group-2B metal ions. The simplicity of the resolved thiolate spectra and their correspondence to those of tetrahedral models support the view that the various metal-binding sites of metallothionein are chemically similar and that the coordination environment of the metal ion has a symmetry related to that of a tetrahedron [Vasák, M. (1980) J. Am. Chem. Soc. 102, 3953].

Animals↗
PubMed1980

Investigation of the structure of metallothioneins by proton nuclear magnetic resonance spectroscopy.

The proton nuclear magnetic resonance spectra of metallothioneins from horse, human, and sheep livers were investigated. The spectra of the metallothioneins from the three species are similar as are the two isoproteins from any one species. The spectra indicate that metallothioneins possess a well-defined tertiary structure. Zinc(II) and calcium(II) ions induce similar but not identical tertiary structures. Confirmatory evidence was obtained for the involvement of cysteine residues in metal binding, but no evidence was obtained for the involvement of any other amino acid residue in metal binding. The apoprotein thionein was found to exist essentially in a random-coil conformation with perhaps some residual segmental structure.

Animals↗
PubMed2002

The ATP/metallothionein interaction: NMR and STM.

We have previously established that ATP binds to mammalian metallothionein-2 (MT). The interaction between ATP and MT and the associated conformational change of the protein affect the sulfhydryl reactivity and zinc transfer potential of MT [Jiang, L.-J., Maret, W., and Vallee, B. L. (1998) The ATP-metallothionein complex. Proc. Natl. Acad. Sci. U.S.A. 95, 9146-9149]. NMR spectroscopic investigations have now provided further evidence for the interaction. (35)Cl NMR spectroscopy has further identified chloride as an additional biological MT ligand, which can interfere with the interaction of ATP with MT. (1)H NMR/TOCSY spectra demonstrate that ATP binding affects the N- and C-terminal amino acids of the MT molecule. Scanning tunneling microscopy recorded images of single MT molecules in buffered solutions. Moreover, this technique demonstrates that the otherwise nearly linear MT molecule bends by about 20 degrees at its central hinge region between the domains in the presence of ATP. These results may bear on the development of mild obesity in MT null mice and the role of MT in the regulation of energy balance. The interaction suggests a mechanism for the cellular translocation, retention, and reactivity of the ATP*MT complex in the mitochondrial intermembrane space. Both MT and ATP are localized there, and MT and thionein alternately bind and release zinc, thereby affecting mitochondrial respiration.

Adenosine Triphosphate↗
PubMed2000

Copper-release from yeast Cu(I)-metallothionein by nitric oxide (NO).

The reaction of yeast Cu-MT with nitric oxide (NO) was examined. A release of copper from the Cu(I)-thiolate clusters of the protein by this remarkably important reagent was observed in vitro. The characteristic spectroscopic signals of the Cu(I)-thiolate chromophores levelled off in the presence of a two-fold molar excess of NO expressed per equivalent of thionein-copper as monitored by UV-electronic absorption, circular dichroism and luminescence emission. At the same time all of the copper became EPR detectable. The oxidized metal ions could easily be removed from the protein moiety by gelfiltration. The reversibility of the copper releasing process is of special interest. The specific fluorescence and dichroic properties of the previously demetallized protein could be recovered up to 85% under reductive conditions. Moreover, no difference in the electrophoretic behaviour was seen compared to the untreated Cu-MT. Thus, NO may act as a potent metabolic source for the transient copper release from Cu-MT. In the course of an oxidative burst this highly Fenton active copper is able to improve the efficacy of biological defence mechanisms.

Copper↗
PubMed1994

Reduction of focal cerebral ischemic damage by delayed treatment with nitric oxide donors.

We studied whether delayed posttreatment with the nitric oxide donor 3-morpholinosydnonimine (SIN-1) is effective in reducing the size of the infarct produced by occlusion of the middle cerebral artery (MCA) in spontaneously hypertensive rats (SHRs). SHRs were anesthetized with halothane and intubated transorally. The left MCA was occluded at the level of the inferior cerebral vein. Cerebral blood flow (CBF) was monitored in the ischemic hemisphere by a laser-Doppler flowmeter, and an electroencephalogram (EEG) was recorded. SIN-1 was infused into the left internal carotid artery for 60 min starting 3, 15, 30, 60 or 120 min after MCA occlusion. The hypotension associated with SIN-1 administration was controlled by i.v. administration of phenylephrine. At the end of the infusion, rats were extubated and allowed to recover. Infarct size was measured 24 h later on thionein-stained coronal brain sections by computer-assisted planimetry. SIN-1 infusion 3 min after MCA occlusion enhanced the recovery of CBF and EEG amplitude and reduced the size of the infarct by 30 +/- 11% (p < 0.05, analysis of variance). The reduction in infarct size by SIN-1 was still seen when SIN-1 was administered 15, 30, and 60 min after MCA occlusion (p < 0.05). However, administration of SIN-1 2 h after MCA occlusion did not affect the size of the infarct (p > 0.05). We conclude that posttreatment with SIN-1 is effective in reducing focal ischemic damage if this agent is administered up to 60 min after MCA occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

The induction of metallothionein in rat liver by zinc injection and restriction of food intake.

The isolation of two forms of hepatic zinc-thioneins after either zinc injection into rats or partial restriction of their food intake is described. The proteins differed slightly in their amino acid composition and electrophoretic mobilities. Increases in liver zinc content after both treatments were synchronous with, and associated almost completely with, increased zinc-binding to these proteins. The time-course for the appearance and disappearance of the zinc proteins is shown. It is suggested that metallothionein is involved in the normal metabolism of zinc, perhaps in some temporary storage or detoxication capacity.

Amino Acids↗