Metallothioneins cadmium toxicity

Cadmium is nutritionally non-essential, toxic and a ubiquitous environmental pollutant. It is found in leafy vegetables, grains and cereals, and since it is present in substantial amounts in tobacco leaves, cigarette smokers on a packet a day can easily double their cadmium intake. It has a long biological half-life (17-30 years in man), accumulates in liver and kidneys and its toxicity involves principally kidney and bone (Goyer, 1997).While Cd interferes primarily with calcium, it also interacts with zinc and can induce the synthesis of metallothionein. Cadmium bound to metallothionein in liver or kidney is thought to be non-toxic, but cadmium in plasma... 

Primary hepatocyte cultures have been used as a tool to predict the hepatotoxicity of many compounds such as nonsteroidal anti-inflammatory drugs (Castell et ah, 1988), psychotropic drugs (Boelsterli et ah, 1987), immunosuppressant drugs (Boelsterli et ah, 1988), and salicylates (Tolman et ah, 1978). Rat primary hepatocyte cultures have also been shown to be a good model for examining the mechanisms of metallothionein-induced tolerance to cadmium toxicity (Liu et ah,... 

Liu, J., Kershaw, W.C. and Klaasen, C.D. (1990). Rat primary hepatocyte cultures are a good model for examining metallothionein-induced tolerance to cadmium toxicity. In Vitro Cell. Dev. Biol. 26 75-79. 

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. 

Deeds, J.R., and Klerks, P.L. (1999) Metallothionein-like proteins in the freshwater oligochaete Limnodrilis udekemianus and their role as a homeostatic mechanism against cadmium toxicity. Environ. Pollut. 106, 381-389. 

Klaassen, C. D., Liu, J., and Choudhuri, S. Metallothionein An intracellular protein to protect against cadmium toxicity. Annu. Rev. Pharmacol. Toxicol. 39, 267-294,1999. 

The apparent affinity for zinc metallothionein may someday be found to be useful as an antidote for cadmium toxicity. Antagonists to cadmium toxicity include a pretreatment with selenium and zinc. It is believed that this pretreatment allows cadmium to displace zinc in the zinc metallothionein. 

Misra, R.R., J.F. Hochadel, G.T. Smith, J.C. Cook, M.P. Waalkes and D.A. Wink. Evidence that nitric oxide enhances cadmium toxicity by displacing the metal from metallothionein. Chem. Res. Toxicol. 9 326-332, 1996. 

Solis, W.A., N.L. Childs, M.N. Weedon, L. He, D.W. Nebert and T.P. Dalton. Retrovirally expressed metal response element-binding transcripton factor-1 normalizes metallothionein-1 gene expression and protects cells against zinc, but not cadmium, toxicity. Toxicol. Appl. Pharmacol. 178 93-101, 2002. 

Wahba ZZ, Coogan TP, Rhodes SW, et al. 1993. Protective effects of selenium on cadmium toxicity in rats Role of altered toxicokinetics and metallothionein. J Toxicol Environ Health 38(2) 171-182. 

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. 

Cadmium was selected for laboratory experiments as its toxic eifects on insects were well proved (Martoja et al., 1983 Hopkin, 1989 Helidvaara and Vaisanen, 1993). Its effect on production of free radicals has been discussed above. By elimination of zinc from metallothioneins cadmium may indirectly stimulate reactive oxygen particles (Viarengo, 1989). Direct inhibitory effects on detoxifying enzymes have been well documented (Byczkowski and Sorenson, 1984 Palace and Kleverkamp, 1993). Enzyme activity pattern under cadmium stress shows a cumulative eifects of many interacting factors. 

Bakka A, Samarawickrama GP, Webb M (1981) Metabolism of zinc and copper in the neonate Effect of cadmium administration during late gestation in the rat on the zinc and copper metabolism of the newborn. Chem.-Biol. Interact. 34 161-171 Bakka A, Webb M (1981) Metabolism of zinc and copper in the neonate Changes in the concentrations and contents of thionein-bound Zn and Cu with age in the livers of the newborn of various mammalian species. Biochem. Pharmacol. 30 721-725 Bell JU (1980) Induction of hepatic metallothionein in the immature rat following administration of cadmium. Toxicol. Appl. Pharmcol. 54 148-155 Bremner J (1978) Cadmium toxicity Nutritional influences and the role of metallothionein. Wld. Rev. Nutr. Diet. 32 165-197... 

Leber AP, Miya TS (1976) A mechanism for cadmium and zinc-induced tolerance to cadmium toxicity involvement of metallothionein. Toxicol Appl Pharmacol 37 403-414... 

Scand J Work Environ Health 12 523-537 Oberddrster G, Cox C (1990) Carcinogenicity of cadmium in animals what is the significance for man Chem Environ Toxicol 27 181-195 Ochi T, Ishiguro T, Ohsawa M (1983) Participation of active oxygen species in the induction of DNA single-strand scissions by cadmium chloride in cultured Chinese hamster cells. Mutat Res 122 169-175 Ochi T, Otsuka F, Takahashi K, Ohsawa M (1988) Glutathione and metallothioneins as cellular defense against cadmium toxicity in cultured Chinese hamster cells. Chem Biol Interact 65 1-14... 

Cadmium (soft, Cd2+) Renal toxicity Blocks sulfhydryl groups in enzymes and competes with zinc. Stimulates metallothionein synthesis and interferes with Cu(II) and Zn(II) metabolism. 

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