| Evidence for Radical Species as Intermediates in Cadmium/Zinc-Metallothionein-dependent DNA Damage In Vitro Environ Health Perspect Key words: cadmium/zinc-metallothionein, DNA strand breaks, radicals
This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity held 10-17 January 1993 in Madonno de Campiglio, Italy.
The authors thank M. G. Cherian, The University of Western Ontario, London, Canada, for the generous gift of a sample of electrophoretically pure (Cd5Zn2) MT2 from rat liver, and to G. Oberdörster, University of Rochester, NY, for initiating this work. Thanks are further due to K. Hildenbrand, Max Planck Institut für Strahlenchemie, Mülheim/Ruhr, who provided us with the opportunity to perform the ESR investigations.
Address correspondence to Thomas Müller, INBIFO Institut für biologische Forschung, Fuggerstr. 3, D-51149 Köln 90, Federal Republic of Germany. Telephone 22 03 303 1. Fax 22 03 303 362.
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Toxicologic data on cadmium (Cd) indicate that intracellular metallothionein (MT) is protective for Cd exposure, whereas extracellular Cd-containing MT might be toxic. Moreover, Cd is suspected to be a carcinogen though the underlying mechanism is not known. Here we report on the genotoxic activity of cadmium/zinc-metallothionein (Cd/Zn-MT) in a cell-free test system: a concentration-dependent increase in DNA strand breaks was detected with increasing doses of Cd/Zn-MT, whereas no DNA strand breaks were observed in the presence of heat-denatured MT or Cd or Zn ions alone. Modifications of native Cd/Zn-MT by the metal ion-chelating agent EDTA or the sulfhydryl group alkylating agents N-ethylmaleimide and iodoacetamide suggest that the various cysteine residues of MT, together with the attached heavy metal ions, may be involved in the DNA cleavage reaction. Furthermore, DNA strand breaks caused by Cd/Zn-MT seem more likely to be random than sequence- or base-specific. Results from experiments with radical scavengers and electron spin resonance spectroscopy point to radical species formed by Cd/Zn-MT as mediators of the DNA damage. Thus, the actual activity of Cd/Zn-MT--whether protective or damaging--appears to depend on various parameters governed by the extra- and intracellular environment. --Environ Health Perspect 102(Suppl 3) :27-29 (1994) . Key words: cadmium/zinc-metallothionein, DNA strand breaks, radicals
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