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DIRECT-ACTING, DNA-DAMAGING AS (III)-METHYLATED SPECIES: IMPLICATIONS FOR A CARCINOGENIC MECHANISM OF ACTION OF ARSENICALS
Citation:
Mass, M J., B Roop, A H. Tennant, K H. Brock, D M. DeMarini, M Pimentel, S Nesnow, A D. Kligerman, D. Thomas, B. Kundu, M. Styblo, AND W. R. Cullen. DIRECT-ACTING, DNA-DAMAGING AS (III)-METHYLATED SPECIES: IMPLICATIONS FOR A CARCINOGENIC MECHANISM OF ACTION OF ARSENICALS. Presented at Third International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity, Stintino, Italy, 09/2-5/2001.
Description:
Direct-acting, DNA-damaging As (III)-methylated species: implications for a carcinogenic . mechanism of action of arsenicals
Inorganic arsenic (iAs, arsenite and arsenate) has been thought to act as a carcinogen without reacting directly with DNA; neither iAs nor the As(V) methylated metabolites are
classical electrophiles. In the last few years reactive methyl- and dimethyl-As(III) species have been detected in urine from individuals exposed to arsenic in drinking water; methylated As(III) derivatives have been shown to be highly toxic to cultured human cells, and a methylated As(III) derivative has been recently been shown to have a much lower LD5o in hamsters than arsenite. Additionally, methylated As(III) compounds are more cytotoxic and more potent as enzyme inhibitors than iAs. In this study, four synthetic methyl- and dimethyl-As(III) compounds, were assayed in vitro by a DNA-nicking assay, and a monomethyl- and dimethyl As(III) derivative were assessed in: the single cell gel (comet) assay in human lymphocytes that detects breaks and alkaline labile sites, the Ames assay in strains TA98, TA100, and TA104, a prophage-induction assay that detects SOS repair, and the mouse lymphoma L5178Y TK +/-assay that detects small and large scale genetic damage. We report that methylated As(III) species can nick (unwind) DNA, produce double-stranded breaks, and/or induce alkaline labile sites at concentrations much lower than seen with iAs. In the comet assay, exposure to As(III) methylated species doubled the tail moment at concentrations up to 400-fold less than did iAs. In the mouse lymphoma assay, mutation by a methylated As(III) compound was observed at 0.4 microM, about 30-fold more potent than arsenite. Methylated As(III) species were not point mutagens in the Ames test but methylated As(III) species induced slight, dose-responsive elevations ofSOS repair. Two methylated As(III) compounds were negative in a single-treatment protocol in the C3H10Tl/2 oncogenic transformation assay; however, the compounds were highly cytotoxic In total these results suggest that As(III)-methylated species have the ability to damage DNA, and lend additional evidence that methylation of arsenic is not solely a detoxification process. Their potential contribution to arsenic-induced cancer needs to be considered. Extrapolation of these results to low dose will be discussed.
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