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 1000µg/kg for 10 days was well tolerated in Muta TM Mouse mice. Treating Muta TM 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 affects 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.

The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells

“…The DNA adducts can eventually lead to mutations. Indeed, in a variety of bacterial and mammalian systems PhIP was demonstrated to be a DNA damaging and mutagenic agent (Felton and Knize, 1991) YadollahiFarsani et al, 1996), (Boyce et al, 2004;Boyce, 2014). The DNA-damaging and mutagenic properties of PhIP are therefore one mechanism by which the chemical can cause cancer.…”

Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer

“…The genotoxicity of PhIP is well established (Boyce et al 2014 ; Brooks et al 1994 ; Lynch et al 1998 ; Yadollahi-Farsani et al 1996 ). In the present study, we have assessed genotoxicity using an adapted micronucleus assay and show that PhIP is a potent inducer of micronuclei in ER receptor-positive MCF-7 cells but not MDA-MB-231 cells (Table 1 ).…”

Protective effects of Vitis vinifera (grapes) and one of its biologically active constituents, resveratrol, against natural and chemical toxicities: A comprehensive review

“…In an in vivo study, PhIP produced mutation in the colon of male rats more obvious than females. It was also shown that the antimutagenic effects of RSV might be associated with metabolic activation of PhIP, because RSV strongly suppressed ethoxyresorufin‐O‐deethylase activity in vivo (Boyce, David, & Gooderham, ).…”