Molecular Mechanisms of Metal Toxicity and Carcinogenicity
Environmental Health Perspectives 102, Supplement 3, September 1994

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Induction of Lung-specific DNA Damage by Metabolically Methylated Arsenics via the Production of Free Radicals

Kenzo Yamanaka¹ and Shoji Okada²

¹Department of Biochemical Toxicology, Nihon University College of Pharmacy, Chiba, Japan; ²Department of Radiobiochemistry, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka Japan

Abstract

To clarify the genotoxicity of inorganic arsenics, we focused on the genotoxic effect of metabolically methylated arsenics in mammals. Oral administration to mice of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics, induced lung-specific DNA damage, i.e., DNA single-strand breaks and the clumping of heterochromatin. The lung-specific strand breaks were not caused by DMAA itself, but by dimethylarsine, a further metabolite of DMAA. An in vitro experiment indicated that DNA single-strand breaks by dimethylarsine were suppressed by the presence of superoxide dismutase and catalase, suggesting that the strand breaks were induced via the production of free-radical species including active oxygens. Dimethylarsenic peroxyl radical [(CH₃)₂AsOO] and superoxide anion radical produced from the reaction between molecular oxygen and dimethylarsine were detected by electron-spin resonance analysis using a spin-trapping agent and the cytochrome-c method, respectively. Of these two radicals, the dimethylarsenic peroxyl radical rather than the superoxide anion radical is assumed to play the dominant role in causing the DNA damage, at least for DNA single-strand breaks. -- Environ Health Perspect 102(Suppl 3):37-40 (1994).

Key words: DNA damage, single-strand breaks, methylated arsenics, free radicals, dimethylarsenic peroxyl radical, dimethylarsine

This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity held 10-17 January 1993 in Madonna di Campiglio, Italy.

We are grateful to Dr. M. Hoshino of the Institute of Physical and Chemical Research and Dr. M. Nakano of Chiba University for determination of radical species by ESR analysis and morphological evaluation by electron microscopic analysis, respectively. We thank Dr. A. Hasegawa and Dr. R. Sawamura of Nihon University for helpful discussion.

Address correspondence to Dr. K. Yamanaka, Nihon University College of Pharmacy, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274, Japan or
to S. Okada, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Shizuoka-shi, Shizuoka 422, Japan. Telephone 474 65 6077. Fax 474 65 6057.

Last Update: November 16, 1998