Mechanisms of butylated hydroxytoluene-mediated modulation of 2-acetylaminofluorene mutagenicity in rat and human hepatocyte/Salmonella assays.
Salmonella typhimurium (TA98) mutagenesis assays were used to study the influence of the antioxidant butylated hydroxytoluene (BHT) on 2-acetylaminofluorene (2-AAF) mutagenesis, in search of the mechanism of the anticarcinogenic effects of BHT. Rats pre-treated with BHT in the diet (0.5% w/w for 10 days) provided hepatocytes and hepatocyte S9 which were more efficient in the activation of 2-AAF than were similar preparations from control rats. The increased release of mutagens from hepatocytes might explain the reported increase in the incidence of bladder tumours in BHT-treated rats. In contrast, the mutagenic activity of 2-AAF was inhibited by the in vitro addition of BHT into incubations where human or rat liver S9 and intact hepatocytes were used for metabolic activation. Both competitive and un-competitive inhibition by BHT of 7-ethoxycoumarin O-deethylation was observed in hepatocytes which suggested that the antimutagenic activity may be mediated by one or more mechanisms of cytochrome P-450 inhibition. BHT inhibition of the mutagenicity of N-OH 2-AAF and of rat urinary metabolites of 2-AAF indicated that effects other than those mediated by cytochrome P-450 also occur e.g. scavenging of reactive metabolites. It was concluded that BHT-modulation of 2-AAF metabolic activation and mutagenesis (which may relate to BHT-protection against hepatocarcinogenicity) involves multiple mechanisms.
D015073:2-Acetylaminofluorene / Q000494:pharmacology*; D000818:Animals; D001711:Biotransformation; D002084:Butylated Hydroxytoluene / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects
D009153:Mutagens; D002084:Butylated Hydroxytoluene; D015073:2-Acetylaminofluorene