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PROXIMATE OR ULTIMATE GENOTOXIC FORMS OF ARSENIC: METHYLATED ARSENIC(III) SPECIES THAT REACT DIRECTLY WITH DNA
Citation:
Mass, M J., B C. Roop, A H. Tennant, B. Kundu, K H. Brock, M Pimentel, AND D. Thomas. PROXIMATE OR ULTIMATE GENOTOXIC FORMS OF ARSENIC: METHYLATED ARSENIC(III) SPECIES THAT REACT DIRECTLY WITH DNA. Presented at Environmental Mutagen Society, San Diego, California, March 16-21, 2001.
Description:
PROXIMATE OR ULTIMATE GENOTOXIC FORMS OF ARSENIC: METHYLATED ARSENIC(III) SPECIES THAT REACT DIRECTL Y WITH DNA.
Abstract:
Although inorganic arsenic (iAs), arsenite or arsenate, is genotoxic, there has been no demonstration that iAs or a methylated metabolite reacts significantly with DNA, however, at high concentrations dimethylarsenic acid (V) can form peroxyJ radicals at high concentrations that can damage DNA. Recently investigators have detected monomethyl- and dimethyl-As(III) in urine from people exposed to arsenic in drinking water. These forms of arsenic are more cytotoxic and potent as enzyme inhibitors than iAs. We report here that methyl- and dimethyl- As(III), as methyloxoarsine [AsMeO] and iododimethyJarsine [AsMe2I], were assayed for their ability to damage DNA in vitro by several methods: a supercoiled-DNA unwinding assay with Q)X174 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 assay in strains T A98, 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. Our investigations show 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. In the comet assay, exposure to As(III) methylated species doubled the tail moment at concentrations 30 to 300-fold less than did iAs. They are significantly more potent than any other As metabolite examined to date. In the mouse
lymphoma assay, mutation by AsMeO was seen down to 0.5 ~M, 30 to 100-fold more potent than arsenite. Methylated As(III) species were not point mutagens in the Ames test and are tentatively negative for prophage induction. Currently we are assessing the ability of the As(III)- methylated metabolites to produce morphological transformation in C3H10T1/2 cells. The existence of As(III)-methylated species that are directly genotoxic through interaction with DNA implies that methylated As(III) species could be proximate or ultimate genotoxic forms of iAs. Methylation of arsenic, therefore, can be viewed as a pathway to generate genotoxicants rather than to deactivate them.
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