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PubMed1977

Cadmium-induced enteropathy: comparative toxicity of cadmium chloride and cadmium-thionein.

In protecting the body against the noxious effects of dietary cadmium ions, cadmium is bound to metallothionein in the proximal intestine, and subsequently excreted into the lumen with desquamation of the epithelium. The purpose of this study was to determine the extent to which cadmium in the form of intestinal cadmium-thionein is absorbed from the intestinal lumen and to appraise the toxicity of cadmium-thionein on the intestinal mucosa. With open-ended duodenal perfusion, equivalent amounts of cadmium administered as CdCl2 or cadmium-thionein entered the mucosa, but significantly less cadmium from the perfusate of cadmium-thionein passed into the body. Exposure of the mucosa to CdCl2 for 1 hr led to minor abnormalities in the form of broadening of villi with pseudostratification of epithelium, and swelling of mitochondria, whereas cadmium-thionein produced extensive necrosis of absorptive cells. The results suggest that cadmium-thionein may play a paradoxical role, providing protection against the cadmium ion in the intracellular milieu, but promoting cadmium toxicity when it is present in sufficient amounts in the lumen of the intestine.

Animals↗

PubMedDate not supplied

Degradation of cadmium-thionein in rat liver and kidney.

[3 H] Cystine and 115mCd were incorporated into hepatic and renal Cd-thionein in response to sc administration of 4.4 mumol of Cd2+ containing 115mCd. Cd-thionein-bound 115mCd reached a plateau by 24 and 72 h after the Cd2+ injection in liver and kidney, respectively. The half-life (t1/2) of 3 H-labeled hepatic Cd-thionein was 3.5 d, whereas the average t1/2 of the soluble proteins was 3.7 d. The t1/2 of 3 H-labeled renal Cd-thionein was 3.7 d, whereas the average t1/2 of the soluble renal proteins was 3.8 d. In marked contrast, the 115mCd content of both hepatic and renal Cd-thionein was virtually unchanged, even 9 d after administration of this radionuclide. These data indicate that the protein moiety of metallothionein is degraded, although there appears to be a concomitant rebinding of Cd2+ to nascent thionein polypeptide chains. Thus the lack of metallothionein degradation per se does not account for the long-term retention of Cd2+ in liver and kidney during chronic exposure.

Animals↗

PubMed1977

Studies on the synthesis and metabolism of zinc-thionein in rats.

The objectives of this investigation were to study the role of zinc-thionein in the metabolism of excessive amounts of zinc and the re-utilization of zinc bound to this protein. Rats were injected ip with 5 mg Zn/kg body weight as zinc chloride for 5 days to induce the synthesis of zinc-thionein. Proteins with molecular weight of 10,000 with high affinity for zinc were synthesized in rat liver and intestine. These proteins were heat stable. Large scale isolation of this protein from rat liver was achieved by a simple method consisting of a heating step and sephadex gel fractionation. Intravenous injection of isolated 65Zn-thionein to rats resulted in similar organ distribution of zinc as that after 65ZnCL2 injection. Gel filtration experiments with liver supernatant from rats injected with 65Zn-thionein showed that a major portion of 65Zn was transfered to other protein fractions and was re-ultilized similar to inorganic salts of zinc. Morphological studies showed no toxic effects after injection of zinc-thionein. These results show that zinc-thionein is metabolically active and non-toxic.

Animals↗

PubMed1984

Effect of epinephrine and norepinephrine on zinc thionein levels and induction in rat liver.

Hepatic zinc metallothionein (MT) levels are increased in response to a variety of stresses. Glucocorticoid induction of zinc thionein is insufficient in accounting for the levels attained. The potential involvement of catecholamines in the modulation of rat hepatic zinc metabolism and zinc thionein levels has been systematically studied. Eleven hours after multiple injections (6) of epinephrine, norepinephrine, or isoproterenol, zinc thionein levels of 4.01 +/- 0.74, 6.83 +/- 0.67, and 11.75 +/- 0.96 micrograms Zn in MT/g liver, respectively, were attained (untreated, 1.04 +/- 0.14). The levels of hepatic zinc thionein thus reached the range of stress response-induced levels (4-10 micrograms Zn in MT/g liver), attained 11 h after the onset of the stress. Multiple injections of isoproterenol and norepinephrine induced the formation of isoforms MT-I and MT-II in roughly equal amounts. The alpha-adrenoceptor blocker phentolamine blocked the 11-h increase in norepinephrine-stimulated (6) zinc thionein levels by 88%. The beta-adrenoceptor blocker propranolol blocked the 11-h increase in isoproterenol-stimulated (6) zinc thionein levels by 55%. This inhibition could be increased to 72% by previous administration of both phentolamine and propranolol. Catecholamines stimulated increases in both the zinc and the protein of MT, the latter as assessed by [35S]cysteine incorporation. Both of these increases were blocked by cycloheximide, confirming the requirement for de novo protein synthesis in this induction response.

Animals↗

PubMed2000

Quantitative determination of Cu-thionein from human fluids with application of solid-phase extraction on covalent affinity chromatography with thiol-disulphide interchange support.

The aim of our investigation was to carry out quantitative isolation of Cu-thionein (Cu-Th) in human body fluids (urine, plasma and breast milk) in order to determine the level of exposure to heavy metals. In the experiment covalent affinity chromatography with thiol-disulphide interchange gel (CAC-TDI) was used as a solid phase extraction (SPE) support for preconcentration of Cu-thionein (Cu-Th) protein and Cu bonded with MT from water and human fluids samples. The present paper is a continuation of early experiments on the quantitation of Hg-thionein (Hg-Th), Cd-thionein (Cd-Th) and Zn-thionein (Zn-Th) in human body fluids such as urine, plasma and breast milk.

Animals↗

PubMed1996

Copper-release from yeast Cu(I)-thionein by hypothiocyanite (OSCN-).

In the course of an oxidative burst oxygen free radicals and hypothiocyanite (OSCN-), a transiently abundant derivative of thiocyanate (SCN-), are formed in the presence of activated polymorphonuclear leukocytes (PMNs). At the same time Cu(I)-thionein is present and the question arose whether or not thiocyanate and its oxidized form may transiently release highly Fenton active copper to improve the efficacy of the above mentioned oxidative burst. Thus, the reaction of yeast Cu-thionein with OSCN- was examined. Indeed, a release of copper from the Cu(I)-thiolate clusters of the protein was observed ex vivo. Both the chiroptic and luminescence emission signals of Cu-thionein essentially levelled off in the presence of a 15-fold molar excess of OSCN- expressed per equivalent of thionein-copper. The effective copper-releasing activity of this reagent was confirmed by equilibrium dialysis. The demetallized protein could be reconstituted under reductive conditions. SCN- did not affect the copper-thiolate bonding. It rather acts as a potent metabolic source for the transient copper release from Cu-thionein in the presence of activated PMNs.

Carrier Proteins↗

PubMed1989

Copper-thionein in leucocytes.

Upon incubation of peripheral leucocytes with copper sulphate a dramatic cellular copper uptake reaching levels of 25-50-fold compared to that of the natural copper content was measured. The orange-red fluorescence of the copper-treated white blood cells was assigned to the formation of Cu(I)-thiolate clusters in Cu(I)-thionein. A protein of 6-8 kDa was isolated from homogenized bovine leucocytes and characterized by its electronic absorption and amino acid composition to be identical to the above Cu(I)-thionein. More than 70% of the intracellular copper was attributed to this protein in its monomeric and polymeric form. Cu-thionein formation was more pronounced in monocytes than in granulocytes. As most intriguing phenomenon, the release of this Cu-thionein from leucocytes, was also noticed. The occurrence of Cu-thionein in leucocytes and the excretion of the intact Cu(I)-thiolate protein is of considerable interest with respect to the observed elevated copper levels in white blood cells and plasma during tumor malignancies and inflammatory processes.

Amino Acids↗

PubMed1978

Metabolism of 35S-labelled copper-, zinc-and cadmium-thionein in the rat.

A comparative study has been made of the metabolism in the rat of intravenously-administered hepatic copper-, zinc- and cadmium-thioneins. In all cases the 35S-labelled protein was rapidly removed from the circulation. About 20% of the 35S was present in the kidneys after 30 min byt only small amounts of 35S were found in the liver, intestinal mucosa or pancreas. In the case of copper-thionein, 30% of the injected 35S was recovered in the urine within 2 h, mainly as intact copper-thionein. The 35S which appeared in the kidneys was also present initially as metallothionein but this was degraded very rapidly, especially when zinc-thionein was give. Both copper and cadmium from the injected proteins accumulated in the kidneys as metallothionein, but there was no increase in renal zinc concentrations in the rats dosed with zinc-thionein. These findings are discussed in relation to the development of renal damage in chronic cadmium and copper toxicity.

Animals↗

PubMed1984

Effects of glucagon, Arg-vasopressin, and angiotensin II on rat hepatic zinc thionein levels.

Rat hepatic zinc thionein levels can be modulated by a variety of external and internal stimuli. Metals, such as zinc or copper, induce levels 20 to 50 fold over controls. Catecholamines can increase levels 10 to 20 fold, while glucocorticoids, such as dexamethasone, can increase levels modestly by 2-6 fold. We have investigated the ability of additional hormones, which have receptors on hepatocytes, to modulate the levels of hepatic zinc thionein. Glucagon, angiotensin II, and Arg-vasopressin were administered intravenously and intraperitoneally, one time and three times, over an 11 hour period. Zinc thionein levels in rat liver were increased 1.7 to 5.6 fold by glucagon and 1.7 to 3.6 fold by angiotensin II, but not at all by Arg-vasopressin, as compared to appropriate controls. Glucagon and angiotensin II, when administered in vivo, can modulate zinc thionein levels in rat liver to an extent similar to glucocorticoids. Hepatic zinc thionein levels must now be recognized to be affected in vivo by metals, glucocorticoids, catecholamines, and polypeptide hormones.

Angiotensin II↗

PubMed1975

A naturally occurring Cu-thionein in Saccharomyces cerevisiae.

A naturally occurring monodisperse Cu-thionein was prepared using ammonium sulfate precipitation followed by ion exchange (DEAE 23) and gel chromatography (Sephadex G-75). The chromatographic steps were repeated at least twice, or until the Cu-thionein remained homogeneous when subjected to analytical polyacrylamide disc electrophoresis. The molecular weight of this copper protein was 9500+/-500. Up to 24.3% cysteine residues were determined, indicating the relationship to the metallothioneins. Aromatic amino acids were virtually absent, while there were about three times as many acidic amino acid residues, including aspartate and glutamate, as in metallothioneins. 10 g atoms of Cu were measured per mole of protein. The copper binding strength of thionein was extremely high. Displacement by protons (pH 1.5) and gel chromatography or dialysis employing EDTA were not effective. Dialysis against diethyldithiocarbamate produced a protein essentially free of copper. Both the ultraviolet properties and the circular dichroism measurements proved identical with those properties reported for artificially prepared Cu-thionein (see ref.[1]. The major absorption was in the far ultraviolet region with a weak shoulder at 270 nm attributable to copper charge-transfer transititions. 6 Cotton extrema were seen at 213, 283 and 302 nm (negative) and 245, 328 and 359 nm (positive). The possible role of Cu-thionein as an electron transport system was discussed.

Amino Acids↗

PubMedDate not supplied

Degradation of cadmium-thionein in rat liver and kidney.

3H-cystine and 115mCd were incorporated into hepatic and renal cadmium-thionein in response to a subcutaneous administration of 4.4 micronmol of Cd2+ containing 115mCd. Cadmium-thionein bound 115mCd reached a plateau by 24 hrs. and 72 hrs. after the Cd2+ injection in liver and kidney, respectively. The half-life (t 1/2) of 3-H-labeled hepatic cadmium-thionein was 3.5 days, whereas the average t 1/2 of the soluble proteins was 3.7 days. The t 1/2 of the soluble renal proteins was 3.8 days. In marked contrast, the 115mCd content of both hepatic and renal cadmium-thionein was virtually unchanged even 9 days after administration of this radionuclide. These data indicate that the protein moiety of metallothionein is degraded, although there appears to be a concomitant rebinding of Cd2+ to nascent thionein polypeptide chains. Thus the lack of metallothionein degradation, per se, does not account for the long-term retention of Cd2+ in liver and kidney during chronic exposure.

Animals↗

PubMed1993

Reactive nitrogen intermediates, antinuclear antibodies and copper-thionein in serum of patients with rheumatic diseases.

Sera from 354 patients with various inflammatory and autoimmune rheumatic diseases were screened for the presence of reactive nitrogen intermediates, antinuclear antibodies and the anti-oxidase copper-thionein (Cu-thionein), and compared to sera from healthy donors and patients with non-rheumatic diseases including AIDS, various internal as well as neurological diseases and carcinoma of different organs. When compared to healthy individuals, the levels of nitric oxides in sera from patients with autoimmune rheumatic diseases were elevated by 240-600% (P < 0.01). The status of reactive nitrogen intermediates (NOx, RNI) in sera from donors with inflammatory rheumatic diseases was increased by 170-540%, but was also significantly enhanced in sera of patients with non-rheumatic diseases, indicating a general inflammatory mechanism that is predominantly triggered by inducible nitric oxide (NO) syntheses of phagocytes. All rheumatic sera were dramatically depleted of the anti-oxidase Cu-thionein (P < 0.001), a powerful consumer of hydroxyl radicals and singlet oxygen and an efficient superoxide dismutase. The NOx levels were positively correlated with the serum titers of antinuclear antibodies (r = 0.77) and negatively correlated with Cu-thionein levels (r = 0.94), reflecting a high steady-state concentration of free radicals generated during inflammatory and autoimmune rheumatic diseases.

Antibodies, Antinuclear↗

PubMed1989

Cu(I)-thionein release from copper-loaded yeast cells.

The release of intact Cu(I)8-thionein from copper-resistant copper-loaded yeast cells, strain X2180-1Aa, has been shown. This copper(I)-thiolate-rich protein was characterized and compared with the chemical and physiocochemical properties of intracellular yeast Cu-thionein. The same molecular mass and stoichiometry of 8 mol copper atoms/mol protein was found. No detectable difference between the Cu-thioneins was seen in luminescence emission, electronic absorption in the ultraviolet region, chiroptical data or amino acid composition. The importance of stable Cu(I)-thiolates in Cu-thionein as a safe vehicle for transporting copper in a non-reactive manner is confirmed.

Carrier Proteins↗

PubMed1985

Cobalt-(cysteinyl)4 tetrahedra in yeast cobalt(II)-thionein.

The conversion of yeast Cu(I)-thionein into the Co(II) derivative was successful. 2.6 Co atoms were incorporated per mole of protein yielding a Co : S ratio of 1 : 3. The electronic absorption of this highly air sensitive Co(II)-thionein is virtually identical to those of the Co(II) derivatives of other metallothioneins originating from vertebrates and N. crassa. Weaker Cotton extrema are noticed and the two doublet splittings of Cu-thionein disappeared. Throughout the molar ellipticities of the cobalt protein were markedly lower compared to those of the Cu-thionein. Owing to the characteristic charge transfer bands and d-d transitions a tetrahedral Co-thiolate coordination was deduced. The best fit proposal maintaining the above Co : S ratio of 1 : 3 was a six-membered ring with three bridging cysteine sulphurs.

Animals↗

PubMed1976

Cadmium-thionein and the protection by cadmium against the nephrotoxicity of mercury.

Uptake of Hg2+ into the renal and hepatic metallothioneins of rats is increased by pretreatment with Cd2+. This increased uptake occurs both by displacement of Cd2+ (and of Zn2+) from the presynthesized cadmium-thionein, and by further synthesis of thionein. The former mechanism predominates in the kidney of the male rat, which is more sensitive than the female to Hg2+. The latter mechanism, which occurs particularly in the kidney of the female, also is considered to involve an initial displacement of Cd2+ from cadmium-thionein, but is followed by further synthesis of the metalloprotein, which is induced by the liberated cation. Pretreatment with Cd2+ increases not only the incorporation of Hg2+ into the renal metallothionein, but also the uptake of Hg2+ into other components of the kidney. At dose levels of Hg2+ at which Cd2+-pretreatment gives complete protection against the nephrotoxicity in male and female rats, the increase in Hg2+-uptake into both the particulate components and into the soluble fraction of the kidney is greater than into metallothionein. It is concluded, therefore, that binding of Hg2+ by pre-induced cadmium-thionein alone cannot explain the protection by Cd2+ against the nephrotoxicity of Hg2+.

Animals↗

PubMed1991

Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp1.

A number of transcription factors contain so-called zinc finger domains for the interaction with their cognate DNA sequence. It has been shown that removal of the zinc ions complexed in these zinc fingers abrogates DNA binding and transcription activation. Therefore we wanted to test the hypothesis that the activity of transcription factors could be regulated by physiological chelators of zinc. A prominent candidate for such a chelator is the Cys-rich protein thionein (apometallothionein) that is inducible by heavy metal loads, and by other environmental stimuli. Here we show with DNA binding and in vitro transcription assays that thionein indeed can inactivate the zinc finger-containing Sp1 in a reversible manner. By contrast, transcription factor Oct-1, which binds DNA via a homeo-domain, i.e. a helix-turn-helix motif not involving zinc ions, is refractory to thionein action. We propose that modulation of intracellular thionein concentration is used for the coordinated regulation of a large subset of genes whose transcription depends on zinc finger proteins.

Animals↗

PubMed1998

Cadmium removal from human plasma by Cibacron Blue F3GA and thionein incorporated into polymeric microspheres.

Poly(2-hydroxyethylmethacrylate-ethyleneglycoldimethacrylate) [poly(HEMA-EGDMA)] microspheres carrying Cibacron Blue F3GA and/or thionein were prepared and used for the removal of cadmium ions Cd(II) from human plasma. The poly(HEMA-EGDMA) microspheres, in the size range of 150-200 microm in diameter, were produced by a modified suspension copolymerization of HEMA and EGDMA. The reactive triazinyl dye-ligand Cibacron Blue F3GA was then covalently incorporated into the microspheres. The maximum dye incorporation was 16.5 micromol/g. Then, thionein was bound onto the Cibacron Blue F3GA-incorporated microspheres under different conditions. The maximum amount of thionein bound was 14.3 mg/g. The maximum amounts of Cd(II) ions removed from human plasma by poly(HEMA-EGDMA)-Cibacron Blue F3GA and poly(HEMA-EGDMA)-Cibacron Blue F3GA-thionein were of 17.5 mg/g and 38.0 mg/g, respectively. Cd(II) ions could be repeatedly adsorbed and desorbed with both types of microspheres without significant loss in their adsorption capacity.

Cadmium↗

PubMed1997

A photo-activated, protein-based, NO/H2O2 generating system with tumoricidal activity composed of the nitric oxide derivative of apo-metallothionein (thionein-NO) and glucose oxidase.

The S-nitroso derivative of apo-metallothionein (thionein) was prepared by transnitrosation with S-nitrosoglutathione. The thionein-NO thus formed has an absorption maximum at 334 nm. Light-induced NO release from thionein-NO was demonstrated by flash photolysis. This system produces peroxynitrite at neutral pH as evidenced by nitrotyrosine formation. The cytotoxic potential of this protein-based, light-activated NO/H2O2 generating system was demonstrated by exposing human colon adenocarcinoma cells (SW 948) in culture to thionein-NO and glucose oxidase in the presence and absence of light. The cell density of the samples, 72 h subsequent to receiving 1 h of light exposure, decreased by approximately 98%, relative to controls. In comparison, cell density of the samples that were incubated in the presence of catalase and did not receive light treatment, decreased by only approximately 22% after 72 h.

Glucose Oxidase↗