Effects of co-administration of butylated hydroxytoluene, butylated hydroxyanisole and flavonoids on the activation of mutagens and drug-metabolizing enzymes in mice.

Effects of co-administration of food additives and naturally occurring food components were studied on the activation of mutagens. Male mice (ddY) were given diets containing butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA) and flavone or flavanone (2,3-dihydroflavone) for two weeks and the ability of hepatic microsomes to activate aflatoxin B1, benzo[a]pyrene and N-nitrosodimethylamine was determined by the mutagenicity test. Co-administration of an antioxidant (0.1% BHT or 0.2% BHA in diet) and a flavonoid (0.1% flavone or 0.1% flavanone) resulted in additive effects on the activation of aflatoxin B1 and benzo[a]pyrene, while the activation of N-nitrosodimethylamine was not elevated significantly by the co-administration. To understand the mechanism for the additive effects, induction of specific isozymes of cytochrome P450 involved in the activation of the mutagens was studied. Co-administration of BHT (0.1%) and flavone (0.1%) increased markedly the levels of proteins and the activities of the enzymes related to the isozymes of CYP2A and CYP2B, while co-administration of BHA (0.2%) and flavanone (0.1%) elevated those related to CYP1A. Further, the activation of aflatoxin B1 and benzo[a]pyrene in hepatic microsomes was inhibited by the antibodies against these isozymes, which suggested that the enhanced activation of the mutagens by the co-administration might be mediated by the induction of these isozymes.