Elevation of 8-hydroxydeoxyguanosine and cell proliferation via generation of oxidative stress by organic arsenicals contributes to their carcinogenicity in the rat liver and bladder

Monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV) and trimethylarsine oxide (TMAOV) are well-documented inorganic arsenic (iAs) methylated metabolites. In our previous studies, DMAV and TMAOV were shown to exert carcinogenicity in the rat bladder and liver, respectively. Furthermore, MMAV, DMAV and TMAOV exhibited promoting activity on rat hepatocarcinogenesis. To clarify mechanisms of arsenical carcinogenicity and compare biological responses in the liver and bladder, male F344 rats were sequentially treated for 5, 10, 15, 20 days with MMAV, DMAV and TMAOV in their drinking water at a dose of 0.02%. Significant increase of P450 total content and generation of hydroxyl radicals in the liver were observed from 10 and 15 days of treatment with arsenicals, respectively, with the highest levels induced by TMAOV. Similarly, elevation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation was found in the DNA with significant increase by TMAOV treatment in the liver at days 15 and 20, and DMAV in the bladder after 20 days treatment. In addition, cell proliferation and apoptosis indices were significantly increased by TMAOV in the liver and by DMAV in the bladder of rats. These events were accompanied by differential up-regulation of phase I and II metabolizing enzymes, cyclins D1 and E, PCNA, caspase 3 and FasL. The results indicate that early elevation of 8-OHdG and cell proliferation via generation of oxidative stress by TMAOV and DMAV contributes to their carcinogenicity in the rat liver and bladder.