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METHYLATED ASIII COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC
Citation:
Mass, M J., A H. Tennant, B. Kundu, B C. Roop, K H. Brock, A D. Kligerman, D M. DeMarini, M Styblo, W. R. Cullen, C. Wang, AND D J. Thomas. METHYLATED ASIII COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC. Presented at Int'l Symposium on Environmental Toxicology of Metals & Metaloids, Great Barrier Reef, Australia, 7/1-5/2001.
Description:
METHYLATED Asm COMPOUNDS AS POTENTIAL PROXIMATE/ULTIMATE GENOTOXIC METABOLITES OF INORGANIC ARSENIC.
The methylation of inorganic arsenic has typically been viewed as a detoxification process. Genotoxicity tests have generally shown that arsenite has greater mutagenic potential than arsenate or the methylated As v species. Arsenic has been considered to act indirectly without binding or reacting with DNA, as none of the chemical species above are electrophilic. Methylated As111 species have been postulated to be present along the reaction pathway to the methylated As v species. Recently advanced analytical techniques have detected methyl- and dimethyl-As111 in urine from individuals exposed to inorganic arsenic in drinking water. These species have been shown to be more cytotoxic and more potent as enzyme inhibitors than either arsenite or arsenate.
In this study, synthetic-methyl- and dimethyl-As111 species, methyloxoarsine [As111MeO] and iododimethylarsine [As111Me2I], were subjected to in vitro analyses including a supercoiled plasmid unwinding assay that detects nicks and breaks in DNA, a single cell gel (comet) assay in human lymphocytes that detects single stranded breaks and alkaline labile sites, the Ames Salmonella assay in strains T A 98, lOO, and 104, 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 the methylated As111 species are capable of nicking DNA and causing single- and double-stranded breaks, and inducing alkaline labile sites in DNA at concentrations significantly lower than seen with arsenite, or seen at all (Comet) assay, 2 hr exposure; doublIng of tail moment at 1 uM for AsMe2I, 5 uM for As11MeO; arsenite response at 40 uM; arsenate response at 300 uM. The methylated As111 species are not point mutagens in the Ames test; preliminary indications are that they induce an SOS repair response in the prophage induction assay. Results from the mouse lymphoma L5178Y assay are still pending.
We conclude that As111MeO and As111Me2I are potent DNA damaging agents with activities many-fold greater than arsenite; they are candidates for model proximate or ultimate genotoxic fonns of arsenic. The activities of these As111 methylated species suggest that the methylation of arsenic is not necessarily a detoxification process but can be a mutagen activation process.
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