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METHYLATED TRIVALENT ARSENICALS AS CANDIDATE ULTIMATE GENOTOXIC FORMS OF ARSENIC: INDUCTION OF CHROMOSOMAL MUTATIONS BUT NOT GENE MUTATIONS
Citation:
Kligerman, A D., C L. Doerr, A H. Tennant, K H. Brock, J W. Allen, E. Winkfield, P. AllenPoorman, B. Kundu, K. Funasaka, B C. Roop, M J. Mass, AND D M. DeMarini. METHYLATED TRIVALENT ARSENICALS AS CANDIDATE ULTIMATE GENOTOXIC FORMS OF ARSENIC: INDUCTION OF CHROMOSOMAL MUTATIONS BUT NOT GENE MUTATIONS. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 42(3):192-205, (2003).
Description:
ABSTRACT
Arsenic is a prevalent human carcinogen whose mutagenicity has not been characterized fully. Exposure to either form of inorganic arsenic, AsIII or AsV, can result in the formation of at least four organic metabolites: monomethylarsonic acid, monomethylarsonous acid (MMAIII), dimethylarsinic acid, and dimethylarsinous acid (DMAIII). The methylated trivalent species, as well as some of the other species, have not been evaluated previously for the induction of chromosome aberrations, sister chromatid exchanges (SCE), or toxicity in cultured human peripheral blood lymphocytes; mutagenicity in L5178Y/Tk+/- mouse lymphoma cells or in the Salmonella mutagenicity assay; or prophage-induction in Escherichia coli. Here we have evaluated the arsenicals in these assays and found that MMAIII and DMAIII were the most potent clastogens of the six arsenicals in human lymphocytes and the most potent mutagens of the six arsenicals at the Tk+/- locus in mouse lymphoma cells. The dimethylated arsenicals also were spindle poisons, suggesting that they may be ultimate forms of arsenic that induce aneuploidy. Although the arsenicals were potent clastogens, none were potent SCE inducers, similar to clastogens that act via reactive oxygen species. None of the six arsenicals were gene mutagens in Salmonella TA98, TA100, or TA104; and neither MMAIII nor DMAIII induced prophage. Our results showed that methylated AsV was less cytotoxic and genotoxic than AsV, whereas methylated AsIII was more cytotoxic and genotoxic than AsIII. Our data support the view that MMAIII and DMAIII are candidate ultimate genotoxic forms of arsenic and that they are clastogens and not gene mutagens. We suggest that the clastogenicity of the other arsenicals is due to their metabolism by cells to MMAIII or DMAIII.