Metallothioneins cadmium

Liu, X.Y., T.Y. Jin, G.F. Nordberg, S. Ranner, M. Sjostrom, and Y. Zhou. 1992. A multivariate study of protective effects of Zn and Cu against nephrotoxicity induced by cadmium metallothionein in rats. Toxicol. Appi. Pharmacol. 114 239-245. 

The binding of cadmium to metallothionein decreases toxicity to the testes but increases the nephrotoxicity, possibly because the complex is preferentially, and more easily, taken up by the kidney than the free metal. Dosing animals with the cadmium-metallothionein complex leads to acute kidney damage, whereas exposure to single doses of cadmium itself does not. 

Pseudomonas putida growing on 3 mM cadmium synthesizes three cysteine-rich proteins of molecular weight 4000 to 7000, containing four to seven cadmium, zinc and copper atoms per molecule. The use of I13Cd NMR on the major cadmium protein shows it to be related to cadmium metallothionein, but with some significant differences.I223b... 

Liu JX, Nordberg GF. 1995. Nephrotoxicities of aluminum and/or cadmium-metallothionein in rats Creatinine excretion and metabolism of selected essential metals. Pharmacol Toxicol 77 155-160. 

High, K.A., Azani, R., Fazekas, A.F., Chee, Z.A. and Blais, J.-S. (1992) Thermospray-microatomizer interface for the determination of trace cadmium and cadmium-metallothioneins in biological samples with flow injection- and high-performance liquid chromatography-atomic absorption spectrometry. Anal. Chem., 64, 3197-3201. 

Cadmium (Cd) is a non-essensial metal used in industry as an anti-corrosive agent, and is found as a contaminant in food and also in cigarette smoke. The most serious consequence of chronic Cd poisoning is lung- and prostate cancer but the first effect during chronic intake is kidney damage, manifested by marked proteinuria [164]. Under chronic exposure, cadmium is primarily taken up by the liver, where it induces synthesis of metallothionein (MT) and induces formation of cadmium-metallothionein complexes. 

Abbreviations P-Gty. P-gtycoprotein GGT gamma glutamyl transpeptidase AmB. amphotericin B DMTI. divalent metal transporter OAT. organic anion transporter Ctrl, copper transporter TEER. transepithelial electrical resistance ROS. reactive oxygen species GST glutathione-S transferase GSH. glutathione Gd-MT cadmium-metallothionein. 

Wolff NA, Abouhamed M, Verroust PJ, and Thevenod F. Megalln-dependent Internalization of cadmium-metallothionein and cytotoxicity In cultured renal proximal tubule cells. J Pharmacol ExpTher 318 782-791,2006. 

Abouhamed M, Wolff NA, Lee WK, Smith CP, and Thevenod F. Knockdown of endosomal/lysosomal divalent metal transporter 1 by RNA interference prevents cadmium-metallothionein-1 cytotoxicity in renal proximaltubulecells.AmJ Physiol Renal Physiol 293 F705-712, 2007. 

Fowler BA, Nordberg GF. Renal toxicity of cadmium metallothionein morphometric and X-ray microanalytical studies. Toxicol AppI Pharmacol 1978 46 609-623. 

Bernard AM, OuledAA,Lauwerys RR.The effects of lowdoses of cadmium-metallothionein on the renal uptakeofPj-microglobulin in rats.Toxicol AppI Pharmacol 1987 87 440-445. 

Buchet JP, Eauwerys R, Roels El, Bernard A, Bruaux P, Claeys F, DucofFre G, De Plaen P, Staessen J, Amery A, Eijnen P, Thijs L, Rondia D, Sator F, Saint-Remy A, Nick L. Renal effects of cadmium body burden of the general population. Eancet 1990 336 699-702. Nordberg GF, Goyer RA, Nordberg M. Comparative toxicity of cadmium metallothionein and cadmium chloride on mouse kidney. Arch Pathol 1975 99 192-197. 

Squibb KS, Pritchard JB, Fowler BA. Cadmium metallothionein nephrotoxicity ultrastructural/biochemical alterations and intracellular cadmium-binding. J Pharmacol Exp Ther 1984 229 311-321. 

CdMT cadmium-metallothionein DISC death inducing signaling complex... 

Cadmium inhibits plasma membrane calcium channels and Ca -ATPases. It also inhibits repair of DNA damaged by various chemicals, an effect which is believed to be associated with the induction of tumors. Although cadmium forms a metallothionein, the preformed cadmium metallothionein is nephrotoxic (toxic to the kidneys) it is suggested that effects occur when, at some stage in the kidney, the cadmium is dissociated from the metallothionein. In Itai-Itai disease (see Chronic Toxicity, Human section), patients were found to have chromosome abnormalities. 

Cadmium metallothionein has also been studied extensively. This metalloprotein is high in the amino acid cysteine ( 30%) and is devoid of aromatic amino acids. Metallothionein itself may function to help detoxify cadmium. For some experimental tumors, cadmium appears to be anticarcinogenic (e.g., it reduces the induction of tumors). 

Cadmium, zinc, and copper bind to metallothioneins in different oxidation states and stoichiometries. In class I metallothioneins, 20 cysteine residues occur all of which participate in metal-ion binding. In zinc-metallothionein, seven Zn2+ ions are coordinated by three cysteine ligands each. A similar stoichiometry occurs in cadmium-metallothionein [54, 55], Additionally, basic amino acids (lysine and arginine) are in the close neighborhood of the cysteine residues and it had been suggested that they participated in the metal-binding as well [56,57]. Two cysteine residues occur in a Cys-x-Cys motive while the third cysteine residue is offset by some amino acids [58]. 

The metal content is mainly zinc, but an appreciable fraction is cadmium. Metallothionein is the only biological material known to contain cadmium. 

Cadmium occurs only in one valency state (2 ) and does not form stable alkyl compounds or other organometallic compounds of known toxicological significance. Cadmium initially is distributed to the liver and then redistributes slowly to the kidney as cadmium-metallothionein (Cd-MT), with 50% of the total-body burden in the liver and kidney after distribution. Cadmium and several other metals induce the expression of metallothionein, a cysteine-rich protein with high affinity for metals such as cadmium and zinc. Metallothionein protects cells against cadmium toxicity by preventing the interaction of cadmium with other proteins. 

Tallkvist J, Persson E, Henriksson J, Tjalve H (2002) Cadmium-metallothionein interactions in the olfactory pathways of rats and pikes. Toxicol Sci 67 108-113... 

Placental metallothionein binds zinc and copper as well as cadmium. Zinc and copper are essential nutrients for the fetus whereas cadmium is toxic to the fetus and retained rather than transferred to the fetus. There is a question, therefore, as to how the essential metals are preferentially transported to the fetus while the toxic metal, cadmium, is retained. One possibility is that there is a greater sensitivity for zinc and copper metallothionein than cadmium metallothionein to the action of proteolytic enzymes present in trophoblasts. Degradation of the zinc and copper metallothionein complex facilitates the release of these metals to fetal blood, whereas cadmium metallothionein is resistant to this effect. 

McKim JM Jr, Choudhuri S, Klaassen CD (1992) In vitro degradation of apo-, zinc-, and cadmium-metallothionein by cathepsins B, C, and D. Toxicol Appl Pharmacol 116 117-124... 

Merchant S, Hill K, Howe G (1991) Dynamic interplay between two copper-titrating components in the transcriptional regulation of cyt c6 (published erratum appears in EMBO J (1991) 10 23201). EMBO J 10 1383-1389 Miller J, McLachlan AD, Klug A (1985) Repetitive zinc-binding domains in the protein transcription factor III A from Xenopus oocytes. EMBO J 4 1609-1614 Min KS, Nakatsubo T, Fujita Y, Onosaka S, Tanaka K (1992) Degradation of cadmium metallothionein in vitro by lysosomal proteases. Toxicol Appl Pharmacol 113 299-305... 

De SK, McMaster MT, Dey SK, Andrews GK (1989) Cell-specific metallothionein gene expression mouse decidua and placentae. Development 107 611-621 De SK, Enders GC, Andrews GK (1991) High levels of metallothionein mRNAs in male germ cells of the adult mouse. Mol Endocrinol 5 628-636 Dorian C, Gattone II VH, Klaassen CD (1992) Renal cadmium deposition and injury as a result of accumulation of cadmium-metallothionein (Cd-MT) by the proximal convoluter tubules. Toxicol Appl Pharmacol 114 173-181 Dudley RE, Gammal LM, Klaassen CD (1985) Cadmium-induced hepatic and renal injury in chronically exposed rats likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharmacol 77 414-426 Ershoff BH (1948) Conditioning factors in nutritional disease. Physiol Rev 28 107-137... 

Koropatnick J, Leibbrandt M, Cherian MG (1989) Organ-specific metallothionein induction in mice by x-irradiation. Radiat Res 119 356-365 Lehman-McKeeman LD, Kershaw WC, Klaassen CD (1991) Species differences in metallothionein regulation a comparison of the induction of isometallothioneins in rats and mice. In Klaassen CD, Suzuki KT (eds) Metallothionein in biology and medicine, CRC, Boca Raton, pp 121-132 Lui EMK (1987) Metabolism of copper and zinc in the liver and bone of perinatal guinea pig. Comp Biochem Physiol 86 173-183 Maitani T, Cuppage FE, Klaassen CD (1988) Nephrotoxicity of intravenously injected cadmium-metallothionein critical concentration and tolerance. Fund Appl Toxicol 10 98-108... 

Nordberg GF, Goyer RA, Nordberg M (1975) Comparative toxicity of cadmium-metallothionein and cadmium chloride on mouse kidney. Arch Pathol 99 192-197... 

Suzuki KT, Ebihara Y, Akitomi H, Nishikawa M, Kawamura R (1983) Change in ratio of the two hepatic isometallothioneins with development from prenatal to neonatal rats. Comp Biochem Physiol 76 33-38 Templeton DM, Cherian MG (1984a) Effects of zinc deficiency on pre-existing cadmium-metallothionein in the pancreas. Toxicology 29 251-260 Templeton DM, Cherian MG (1984b) Chemical modification of metallothionein. Biochem J 221 569-575... 

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