DNA Damage Induced by Methylated Trivalent Arsenicals Is Mediated by Reactive Oxygen Species

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 (DMAIII) are genotoxic and can damage supercoiled φX174 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 MMAIII and DMAIII. Using the φX174 DNA nicking assay we found that the ROS inhibitors Tiron, melatonin, and the vitamin E analogue Trolox inhibited the DNA-nicking activities of both MMAIII and DMAIII at low micromolar concentrations. The spin trap agent 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) also was effective at preventing the DNA nicking induced by MMAIII and DMAIII. ESR sp...