The mutagenic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine in Muta™Mouse colon is attenuated by resveratrol

Abstract

Epidemiology studies show that consumption of certain naturally occurring chemicals (generally plant-derived) can protect against the development of cancer (chemoprevention). Resveratrol, a phytoalexin found in foods such as grapes and wine as a glucoside, is one such chemical. Our group has previously shown that treating mammalian cells with resveratrol aglycone can reduce the mutagenicity of the cooked meat-derived carcinogens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP). However, the anti-mutagenic effect of resveratrol in vivo has not been previously reported. In this study, daily treatment of resveratrol up to 1000 μg kg⁻¹ for 10 days was well tolerated in Muta™Mouse mice. Treating Muta™Mouse mice with the meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine induced mutation in the colon. Co-treatment of resveratrol and PhIP reduced the mutation frequency induced by PhIP in the colon by about 25% in a treatment group of mixed male and females. Analysing males and females separately revealed a sex difference in the response to PhIP and to the effect of resveratrol on PhIP-induced mutagenicity. In males compared to females, PhIP was a more potent colonic mutagen and resveratrol was more effective at attenuating the mutagenic response (∼35% in males but only 9% in females). The reason for this sex difference in both PhIP mutagenicity and response to resveratrol is not clear. However, resveratrol treatment was also shown to powerfully inhibit ethoxyresorufin-O-deethylase activity in vivo, indicating that the antimutagenic effects are likely linked to metabolic activation of PhIP. These data suggest that resveratrol has anti-mutagenic effects in vivo, supporting its potential to act as a chemopreventative.