Effect of Antioxidants on the Papilloma Response and Liver Glutathione Modulation Mediated by Arsenic in Tg.AC Transgenic Mice

Epidemiological studies indicate that inorganic arsenicals produce various skin lesions as well as skin, lung, bladder, liver, prostate, and renal cancer. Our laboratory previously demonstrated that low-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the number of skin papillomas in Tg.AC transgenic mice that received sodium arsenite in drinking water, an effect dependent on proinflammatory cytokines. Because proinflammatory cytokine expression can be modulated by free radicals and oxidative stress, we hypothesized that oxidative stress contributes to TPA-promoted papilloma development in Tg.AC mice exposed to sodium arsenite. To evaluate the contribution of oxidative stress to arsenic skin carcinogenesis, two free-radical scavengers were tested for their ability to suppress papilloma responses (e.g. induction, latency, and multiplicity) modulated by arsenite in Tg.AC mice. Data indicate that arsenite increased papilloma responses in TPA-promoted Tg.AC mice as compared to control animals (no arsenite). The antioxidant vitamin E or a water-soluble natural antioxidant fraction from spinach had no inhibitory effect on TPA-promoted papilloma responses following arsenite exposure. Although not conclusively defined by our studies, oxidative stress generated by arsenic may contribute to skin carcinogenesis; however, it is not likely to be the sole or primary mechanism that enhances papilloma responses following arsenite exposure and TPA promotion.