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ARSENIC (III) METHYLATED SPECIES REACT WITH DNA DIRECTLY AND COULD BE PROXIMATED/ULTIMATE GENOTOXIC FORMS OF ARSENIC
Citation:
Mass, M J., B Roop, A H. Tennant, K H. Brock, B. Kundu, M Pimentel, D M. DeMarini, A. Kligerman, S Nesnow, C. Wang, D. Thomas, M Styblo, AND W. R. Cullen. ARSENIC (III) METHYLATED SPECIES REACT WITH DNA DIRECTLY AND COULD BE PROXIMATED/ULTIMATE GENOTOXIC FORMS OF ARSENIC. Presented at Annual American Association Cancer Research Mtg, New Orleans, LA, March 24-28, 2001.
Description:
ARSENIC(III) METHYLATED SPECIES REACT WITH DNA DIRECTL Y AND COULD BE PROXIMATE/ULTIMATE GENOTOXIC FORMS OF ARSENIC
Arsenite and arsenate (iAs, inorganic arsenic) have been thought to act as genotoxicants without reacting directly with DNA; neither iAs nor As(V) methylated metabolites have the characteristics ofelectrophiles. Recently, methyl- and dimethyl-As(III) have been detected in urine from individuals exposed to arsenic in drinking water. These agents are more cytotoxic and potent as enzyme il1hibitors than iAs. In this study, synthetic monomethyl- and dimethyl-As(III), as methyloxoarsine [AsMeO] and iododimethylarsine [AsMe2I], were assayed in vitro by a supercoiled-plasmid unwinding assay that detects nicks and breaks in DNA, a single cell gel (comet) assay in human lymphocytes that detects breaks and alkaline labile sites, the Ames Salmonella assay in strains TA98, TAIOO, 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 are able to interact directly with DNA. They can nick(unwind) DNA, produce double-stranded breaks, and/or induce alkaline labile sites at concentrations much lower than seen with iAs, or seen at all. In the comet assay exposure to As(III) methylated species doubled the tail moment at concentrations 30 to 300-fold less than did iAs. In the mouse lymphoma assay, mutation by AsMeOwas seen down to 0.5 uM which is 30 to 100-fold more potent than arsenite. Methylated As(III) species were not point mutagens in the Ames test but AsMe2I induced SOS repair at 0.5 ulM. In transformable mouse C3HlOT1/2 cells these As(III) methylated species are cytotoxic in the range of 0.3 to 3 ulM and are currently being assessed for oncogenic transformation potential using morphologic cell transformation. In total, results above are consistent with As(III)-methylated species that are genotoxic through direct interaction with DNA. Methylated As(III) species could be proximate or ultimate genotoxic forms of iAs.
This is an abstract of a proposed presentation and does not represent US EPA policy.