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PubMed1986

Unique properties of Cd-binding peptides induced in fission yeast, Schizosaccharomyces pombe.

Metallothioneins, a class of low molecular weight cysteine-rich proteins that bind heavy metal ions, have been found in various eucaryotic organisms. When fission yeasts are grown in the presence of high concentration of CdCl2, large amounts of Cd-binding peptides (Cd-BP1 and Cd-BP2) are synthesized. Cd-BP1 (MW 4000) contains 4 mole of small unit peptide (cadystin, MW 771), 6 mole of Cd2+, and 1 mole of the labile sulfide; on the other hand, Cd-BP2 (MW 1800) contains 2 mole of cadystin and 2 mole of Cd2+. While Cd-BP2 shows similarities to mammalian Cd-thioneins in UV and CD spectra, Cd-BP1 has a characteristic shoulder at 265 nm in the UV absorption spectrum and shows two marked Cotton bands at 257 nm (negative) and 275 nm (positive). These characteristics of Cd-BP1 are not found in the other Cd-thioneins. When Cd-BP1 is acidified (pH 2.0) and successively neutralized, a shoulder of 265 nm in the UV spectrum and a Cotton band at 275 nm disappear, and the molecular weight changes from 4000 to 1800, with simultaneous loss of the labile sulfide. While the reconstituted complex without labile sulfide showed the characteristics of Cd-BP2, the reconstituted complex in the presence of labile sulfide indicated partial reconstitution of Cd-BP1. The UV and CD spectra differences between reconstituted and native Cd-BP1 suggest the requirement for some additional molecular architecture including another peptide-Cd2+ interaction. Induction of cadystin synthesis is almost exclusive for Cd, but an exception is a small amount of cadystin also induced by the higher concentration of CuCl2 (2.5 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2000

Metal transfer as a mechanism for metallothionein-mediated metal detoxification.

High kinetic reactivity and high metal affinity of the metal-binding sites of metallothionein are characteristics that would facilitate involvement of the thionein-zinc metallothionein couple in metal transfer or exchange reactions. Studies demonstrating thionein-metallothionein-mediated activation or inhibition of various zinc metalloenzymes and transcription factors provide support for a potential role for metallothionein in metal transfer reactions with receptor molecules. Although a role in basal zinc regulation is currently a topic of debate, less controversial is a role for metallothionein in the detoxification of metals such as cadmium. The toxicity of metals can, in part, be due to adventitious binding to charged sites of target proteins or the displacement of zinc bound to zinc metalloproteins. Zinc metallothionein has the capability of repairing such structures through abstraction of a toxic metal in the former case or through a reciprocal metal transfer reaction that involves abstraction of the toxic metal and donation of the essential metal zinc in the latter. This would confer on metallothionein an active role in the protective response to metal toxicity, rather than a passive one that is solely dependent on the high metal affinity for binding free metal ions. The efficacy of such a mechanism for metal detoxification has been demonstrated with enzymes, actin and zinc finger proteins. With zinc finger proteins, zinc metallothionein can restore both altered secondary structure and inhibited DNA-binding function to functional states through a zinc for cadmium exchange.

Animals↗
PubMed1982

Domain nature of metallothionein.

Metallothionein purified from the livers of rats injected with CdCl3 was cleaved by proteolysis into a 32-residue polypeptide that contained 4 bound Cd ions. Appearance of this fragment designated alpha requires prior treatment of metallothionein with EDTA to remove the Zn ions and destabilize the 3-metal cysteine cluster in the other domain. The half-molecule domain was not efficiently produced by proteolysis of native metallothionein. The Cd4-alpha fragment is asymmetric in shape, as is the parent molecule. NH2-terminal sequence analysis revealed that the alpha fragment starts at Lys 30. Since the same amino acids are released from the COOH terminus of intact thionein and the alpha fragment by carboxypeptidase Y, the alpha domain generated by digestion with subtilisin therefore comprises residues 30 through 61. The amino acid composition of the alpha polypeptide is consistent with the structure of the 4-metal cysteine cluster proposed by Otvos and Armitage ((1980) Proc. Natl. Acad. Sci. U. S. A. 77, 7094-7098). Metallothionein appears to consist of a 3-metal cysteine domain in the NH2-terminal half of the thionein molecule and the 4-metal cysteine domain in the COOH-terminal half.

Amino Acid Sequence↗
PubMed1994

Neuropathologic changes of the temporal pole in Alzheimer's disease and Pick's disease.

OBJECTIVE: To describe the pattern of neuropathologic changes in temporal polar cortex in Alzheimer's disease (AD) in comparison with changes in Pick's disease (PD) and normal elderly cytoarchitecture. DESIGN: Examination of degenerative changes, neurofibrillary tangles, and senile plaques in the temporal poles of 10 patients with AD, three patients with PD, and five age-compatible control subjects, by means of thionein and thioflavine S stains and Alz-50 and ubiquitin immunocytochemistry. SUBJECTS: All patients had a documented history of dementia and AD or PD confirmed on neuropathologic examination. Control subjects were without a history of cognitive impairment or evident neuropathologic changes. OUTCOME MEASURES: Cytoarchitecture, neuronal loss, neurofibrillary tangles, senile plaques, and Pick bodies. RESULTS: All patients with AD showed atrophy of the temporal pole and marked neuronal loss, especially in layers III and V and, to a lesser degree, in layers II and VI. Heavy accumulation of neurofibrillary tangles was found in layers II, III, V, and VI. Patients with PD showed extensive neuron loss throughout, although this appeared to be most prominent in layer III. CONCLUSIONS: Both AD and PD pathologic changes severely affect the layers of the temporal pole that mediate widespread reciprocal connections with temporal and frontal cortices and limbic cortical and subcortical structures. Neural systems that interconnect temporal polar cortex with sensory association areas and memory-related limbic structures are, therefore, disrupted, and it is likely that these lesions play a role in the multifaceted cognitive and behavioral changes of AD and PD.

Adult↗
PubMed1983

Cadmium-metallothionein-induced nephropathy: a morphological and autoradiographic study of cadmium distribution, the development of tubular damage and subsequent cell regeneration.

A single intravenous dose of 0.8 mg thionein-bound cadmium (Cd) per kg body weight, as the isolated (Cd, Zn)-metallothionein (MT) from rat liver, in rats of the same strain is nephrotoxic, but not lethal. Apical vesiculation in epithelial cells of the renal proximal convoluted tubules is apparent within 1 h of dosing and, by 4 h, is extensive in some of these cells that surround the larger arteries in the cortex. The membranes of these cells appear undamaged. The lesion at first progresses with time; by 24 h, the initially affected cells show extensive necrosis and most proximal convoluted tubular epithelia in other regions of the cortex are hydropically or vacuolarly degenerated. The inner stripe of the outer zone of the medulla and other portions of the nephron (glomerulus, distal tubule and collecting duct), however, appear essentially unaffected. The necrotic changes are maximal at 48 h but, after this time, regeneration begins. By seven days, much of the cell debris has been eliminated and cells of the regenerating or regenerated epithelia are similar in morphology to those of the normal kidney. Electron microscopic autoradiography of kidney sections from rats after administration of 109Cd-metallothionein of high specific activity shows that Cd is not concentrated in endocytotic vesicles, lysosomes, or any other cellular organelle, even at early times after dosing, but is distributed evenly throughout the epithelial cell. Thus, although Cd-MT appears to be taken up endocytotically in the kidney tubules, it appears that liberation of Cd from the metalloprotein must occur very early in the reabsorptive process.

Animals↗
PubMed1979

The interaction of cadmium-binding proteins (Cd-bp) and progesterone in cadmium-induced tissue and embryo toxicity.

Previous work indicates that a dimer of Cd-thionein (Cd-bp-D, 19,000 MW) is involved in the hereditary resistance to Cd-embryotoxicity seen in the inbred NAW/Pr (NAW) mouse strain. Cd-bp-D is not detected in virgin females after Cd exposure and is detected only after the first 24 hours of exposure to Cd in an inbred strain (C57BL/10ChPr) susceptible to Cd-induced embryotoxicity (Wolkowski, '74; Wolkowski-Tyl, '78). Since progesterone (P) is critical for maintenance of pregnancy in mice, we have studied the possible relationship between this hormone and Cd-bp-D production. As a model system, was examined effects of Cd treatment on Cd-bp synthesis in NAW males. It was anticipated that this model could provide information bearing not only on the relationship between P and Cd-bp-D production, but also on that between Cd-bp-D and Cd toxicity, since a single sc injection of CdCl2 causes typical testicular hemorrhagic necrosis in NAW males, and these animals make only metallothionein and not Cd-bp-D. NAW males were, therefore, given P (0.1 g/Kg bw) and then exposed to Cd. Sephadex gel chromatography (G-200) of liver cytosol from animals killed 24 hours later detected only Cd-bp-D. Testes of these males did not show hemorrhagic necrosis. Since the adrenals of male mammals release P in response to stress, NAW males were stressed by repeated sesame oil or propylene glycol injections (5 ml/Kg bw), or the adrenal was stimulated directly with injections of ACTH (100 IU/Kg bw) for seven days prior to Cd exposure. All methods tested which significantly elevated serum P levels (as confirmed by radioimmunoassay), also resulted in production of Cd-bp-D and absence of testicular hemorrhage in Cd-treated NAW males. Suppression of P release by injection of dexamethazone or corticosterone or by adrenalectomy resulted in testicular hemorrhage and production of only metalicthionein after Cd exposure. The relevance of the interaction between P, Cd-bp-D and protection against Cd-induced toxicity seen in the model system was supported by analysis of serum P levels in pregnant females; elevated levels were seen in resistant (NAW dams on day 10 of gestation and significantly lower levels seen in dams from a Cd-sensitive strain.

Animals↗
PubMed2001

High yield expression and single step purification of human thionein/metallothionein.

Human metallothionein (MT), isoform 2, was expressed in Escherichia coli as an intein (protein splicing element) fusion protein in the absence of added metals and purified by intein-mediated purification with an affinity chitin-binding tag (IMPACT system). This procedure constitutes a novel and simple strategy to prepare thionein (T), the metal-free form, or MT when reconstituting T with metals in vitro. The yield was 8 mg of T or 6 mg of pure Cd(7)- or Zn(7)-MT from a 1-L culture, significantly higher than yields from any other expression system. Purified recombinant protein is indistinguishable from the native protein on the basis of its metal-binding ability, titration of its sulfhydryls, and UV and CD spectra. The MALDI-TOF mass spectrum is consistent with that of T with a free N-terminus.

Amino Acid Sequence↗
PubMed1987

Metallothionein gene expression and cadmium toxicity in freshwater fish.

Certain species of fish e.g. rainbow trout, are particularly susceptible to poisoning by cadmium in their aquatic environment whereas others e.g. roach and stone loach, are much more resistant. It is postulated that the vulnerability of the salmonids arises because 1) existing metallothionein (MT) in the tissues of these fish is unable to bind cadmium and 2) the toxic metal (in contrast to zinc) cannot switch on the gene(s) for apo-thionein production de novo. Consequently, cadmium is sequestered in the liver, kidney and gills of these fish by two low mol.wt. non-metallothionein proteins for which no excretion mechanism appears to exist.

Animals↗
PubMed1976

The interaction between cadmium, mercury and zinc--administered subcutaneously in a single injection.

The interaction between three heavy metals, cadmium, mercury and zinc was investigated. The metals were injected subcutaneously into the hind leg of male rats of approximately 200 g body weight in a volume of 0.2 ml either alone or in combination with another metal. It has been shown that interaction started at the site of injection, at which the retention of one metal was increased by the presence of the other over a 48 h period. Besides this local interaction, probably based on competition for a carrier compound, there were differences in distribution. Analysis of the data indicates that metals injected simultaneously can influence the distribution of each other and, although each of the studied metal is able to induce thionein, the observed interactions cannot be explained by a single mechanism.

Animals↗
PubMed1994

Ribosome-deficient plastids affect transcription of light-induced nuclear genes: genetic evidence for a plastid-derived signal.

Transcription of ten nuclear genes was analysed in the albostrians mutant of barley (Hordeum vulgare L.). The lack of plastid ribosomes in white seedlings of this mutant results in a complex alteration of nuclear gene expression at the transcriptional level. We found a strong reduction in the accumulation of mRNAs transcribed from nuclear genes encoding chloroplast enzymes involved in the Calvin cycle, the chlorophyll a/b binding protein, and the cytosolic enzyme nitrate reductase. In contrast, the levels of transcripts of the genes encoding the cytosolic glycolytic enzymes glyceraldehyde phosphate dehydrogenase and phosphoglycerate kinase were slightly enhanced. Accumulation of chalcone synthase mRNA even reaches much higher levels in white than in green leaves. Ribosome-deficient plastids were combined by crossing with a nuclear genotype heterozygous for the albostrians allele. Analysis of transcript levels in F1 plants having the same nuclear genotype and differing only with respect to their content of normally developed chloroplasts versus undifferentiated mutant plastids, provided strong genetic evidence for the plastid being the origin of a signal (chain) involved in regulation of nuclear gene expression. Results of run-on transcription in isolated nuclei demonstrated that the plastid signal acts at the level of transcription; it does not interfere with gene regulation in general. Mechanisms triggering nuclear gene expression in response to light operate in white mutant leaves: the very low levels of mRNAs derived from nuclear genes encoding chloroplast proteins and the strongly enhanced level of chalcone synthase mRNA were both light inducible. Also the negative regulation of leaf thionein gene expression by light is observed in white albostrians seedlings.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Nucleus↗
PubMed1988

Metallothionein induction by sodium selenite at two different ambient temperatures in mice.

The induction of metallothionein (MT) synthesis by sodium selenite was investigated in mice with regard to the hypothermic response known to be caused by sodium selenite. Mice received a subcutaneous injection of sodium selenite at two doses (20 and 45 mumol/kg) under two ambient temperature (22 and 33 degrees C) conditions. Hepatic MT concentration was significantly increased by an injection of sodium selenite compared to the control, whereas no significant effect of ambient temperature was observed. The distribution of radiolabeled selenium was examined in vivo and in vitro. When sodium selenite was injected into mice, radiolabeled selenium was mostly eluted in a fraction larger in molecular weight than MT and was not found in a fraction corresponding to MT. When sodium selenite was added to the hepatic supernatant of the mice that had been injected with zinc sulfate, zinc in zinc-thionein was not displaced by radiolabeled selenium.

Animals↗
PubMed1985

Effect of oral cadmium administration to female rats during pregnancy on zinc, copper, and iron content in placenta, foetal liver, kidney, intestine, and brain.

Cadmium chloride was administered in drinking water at a concentration of 50 ppm cadmium to female rats for 20 days of gestation. The foetuses were then removed from the uteri of the dams. Gestational exposure to oral cadmium resulted in decreased zinc, copper, iron, metallothionein, and thionein-bound zinc content in foetal liver as well as in reduced copper content in placenta and foetal intestine, brain and kidney. Subcellular fractionation of the foetal liver revealed decreased nuclear and cytoplasmic zinc content as well as decreased microsomal iron content. Pregnant rats exposed to oral cadmium revealed decreased serum zinc and iron concentration as well as reduced ceruloplasmin activity. The decreased zinc, copper, and iron content in foetal organs is suggested to be causally connected with the diminished availability of these metals in the maternal circulation.

Animals↗
PubMed1984

Histochemical changes in protein disulphide bonds in rat liver and kidney after chronic cadmium administration, and the possible relation to metallothionein.

After chronic exposure to low doses of CdCl2 an increase in disulphide bonds has been established in rat liver using a specific staining method for disulphide bonds and cytophotometric quantitation. This increase is dependent on doses and length of exposure time. Evidence is presented that this increase might be related to the accumulation of metallothionein or some other cadmium binding protein. Using the same staining method after long exposure to low doses of CdCl2 a large number of large dark blue stained granules were observed in the proximal tubule cells, with blue stained deposits in the lumen of the proximal and some renal medulla tubules of the kidney. Evidence is presented that this staining pattern corresponds to the destruction of the proximal tubule cell by the cadmium thionein complex.

Animals↗
PubMed1986

Acute renal dysfunction by cadmium injected with cysteine in relation to renal critical concentration of cadmium.

In order to study the critical concentration of cadmium (Cd) in acute renal dysfunction following Cd, male mice were injected IV with Cd complexed with cysteine. The critical concentration was 10 micrograms Cd/g wet weight in whole kidney and it was the same as that for Cd-thionein (Cd-Th), which may suggest that the toxicity of Cd-Th is due to Cd ions liberated from Cd-Th in the kidneys. Renal Cd concentration was at first higher than the critical concentration, but decreased to the critical concentration by 24 h after administration. As an index for renal dysfunction, the uptake of p-aminohippurate (PAH) by renal cortical slices in vitro was sensitive, and showed the different time-course from those of urinary protein and glucose levels. The results suggest the usefulness of PAH uptake as an index. Incidental to the renal dysfunction, renal calcium levels exhibited a marked increase.

Animals↗
PubMed1988

Cadmium, zinc, copper and metallothionein levels in human liver.

The concentrations of cadmium, zinc, copper and metallothionein in the autopsy samples of liver among the inhabitants of Lódź (Poland) were determined. The cadmium levels were low in the range of 1.5 to 5.8 micrograms/g. The concentration of metallothionein determined by the Hg-method was high (0.160-1.665 mumol Hg/g); it was mainly a Zn-thionein. The percentage of hepatic zinc bound in the MT-fraction increased with the overall content of zinc in the liver. The elevation of zinc in the liver occurs in the proportion required for the saturation of metal-binding ligands of metallothionein. The role of cadmium remains less clear. Our results suggest that the metallothionein level in the liver increase significantly in response to elevated cadmium concentrations. This response, however, is in high excess to the demand which is justified stoichiometrically.

Adult↗
PubMed1979

Fate and comparative toxicity of metallothioneins with differing Cd/Zn ratios in rat kidney.

Metallothioneins with differing Cd/Zn ratios were prepared in vitro from rat liver zinc-thionein by replacing zinc with cadmium and were injected intraperitoneally to female rats. The distribution of cadmium, zinc, and copper in the kidney supernatant fraction was determined using a Sephadex G-75 column. The distribution pattern of cadmium and zinc changed dramatically within 24 hr after the injection. The changes were explained by the degradation and re-synthesis of metallothionein in the kidneys. The necrotic changes of renal tubular lining cells were correlated to the amount of cadmium in the metallothionein but not to the amount of metallothionein (protein).

Animals↗
PubMed1981

Native and induced rat kidney metallothioneins and their relation to cadmium toxicity.

The concentrations of zinc, copper, iron, manganese, magnesium, and phosphorus in the kidneys were determined for control female rats of five different ages (4, 8, 12, 16, and 20 weeks old). The concentration of copper increased with age and it was attributed to three metallothionein peaks on a SW 3000 column. Parenteral administration of Cd-thionein caused swelling of kidneys to different degrees, depending on the age of the rats; the youngest rats were affected most. The concentrations of cadmium and the six metals in the kidneys at 12 hr and 7 days after injection were determined and compared with controls. The distribution among protein fractions of cadmium, zinc, and copper, which are related to metallothionein, were examined by gel permeation chromatography. The elution profiles of the three metals changed not only with the ages of the rats but also with time after injection. The changes were correlated with the copper content in the metallothioneins and with swelling of the kidneys. The changes also correlated with native metallothionein levels.

Aging↗
PubMed1990

An EXAFS study of the copper accumulated by yeast cells.

X-ray absorption spectroscopy has been applied to the in vivo examination of copper-resistant yeast cells. The in vivo structure of the metal-binding site of the accumulated copper has been compared to that of the purified yeast thionein. Analysis of the EXAFS spectra performed on intact yeast cells indicates that the accumulated copper is univalent and is exclusively coordinated to sulfur atoms at a distance of 219 pm with an average coordination number of 2. In contrast, the purified protein indicates a univalent copper trigonally coordinated to sulfur at a distance of 221 pm. These discrepancies are discussed in terms of copper location in the resistant yeast cells.

Carrier Proteins↗