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DNA DAMAGE INDUCED BY METHYLATED TRIVALENT ARSENICALS IS MEDIATED BY REACTIVE OXYGEN SPECIES
Citation:
Nesnow, S. C., B C. Roop, G. R. Lambert, M. B. Kadiiska, R. P. Mason, W. R. Cullen, AND M J. Mass. DNA DAMAGE INDUCED BY METHYLATED TRIVALENT ARSENICALS IS MEDIATED BY REACTIVE OXYGEN SPECIES. CHEMICAL RESEARCH IN TOXICOLOGY 15(12):1627-1634, (2002).
Description:
Abstract
Arsenic is a human carcinogen; however; the mechanisms of arsenic's induction of carcinogenic effects have not been identified clearly. We have shown previously that
monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMA III) are genotoxic and can damage supercoiled thetaX174 DNA and the DNA in peripheral human lymphocytes in culture. These trivalent arsenicals are biomethylated forms of inorganic arsenic and have been detected in the urine of subjects exposed to arsenite and arsenate. We show here by molecular, chemical, and physical methods that reactive oxygen species (ROS) are intermediates in the DNA-damaging activities of MMA III and DMA III. Using the thetaX174 DNA nicking assay we found that the ROS inhibitors Tiron, melatonin, and the vitamin E analog Trolox inhibited the DNA-nicking activities of both MMA III and DMA III at low micromolar concentrations. The spin trap agent 5,5-dimethyl-I-pyrroline-N-oxide (DMPO) also was effective at preventing DNA nicking by MMA III and DMA III. ESR spectroscopy studies using DMPO identified a radical as a ROS intermediate in the DNA incubations with DMA III. This radical adduct was assigned to the DMPO-hydroxyl free radical adduct on the basis of comparison of the observed hyperfine splitting constants and line widths with those reported in the literature. The formation of the DMPO-hydroxyl free radical adduct was dependent on time and the presence of DMA III and was completely inhibited by Tiron and Trolox and partially inhibited by DMSO. Using electrospray mass spectrometry, micromolar concentrations of DMAv were detected in the DNA incubation mixtures with DMA III. These data are consistent with the conclusions that the DNA-damaging activities of DMA III are mediated by ROS formed concomitantly with the oxidation of DMA III to DMAv.