Species-specific enhancement by 7,8-benzoflavone of hepatic microsomal metabolism of benzo[e]pyrene 9,10-dihydrodiol to bay-region diol epoxides.

Metabolism of benzo[e]pyrene 9,10-dihydrodiol to the bay-region 9,10-diol-11,12-epoxides by hepatic microsomes from human, rat, mouse, guinea pig, hamster, and rabbit has been examined in the presence and absence of 7,8-benzoflavone. In the absence of 7,8-benzoflavone, the formation of bay-region diol epoxides from benzo[e]pyrene 9,10-dihydrodiol was low in all species except the hamster. With hamster liver microsomes, greater than 60% of total metabolites formed were bay-region diol epoxides, whereas human and mouse liver formed less than 5% of total metabolites as bay-region diol epoxides. Addition of 7,8-benzoflavone to the microsomal incubations stimulated the formation of diol epoxides, but this stimulation was species dependent. The most dramatic stimulation was observed with human and rabbit liver microsomes. In a parallel study, metabolic activation of benzo[e]pyrene 9,10-dihydrodiol to mutagens toward Salmonella typhimurium strain TA 100 by hepatic microsomes from the above species was examined in the presence and absence of 7,8-benzoflavone. In the absence of 7,8-benzoflavone, hepatic microsomes from all the species only weakly activated benzo[e]pyrene 9,10-dihydrodiol to mutagens. 7,8-Benzoflavone enhanced the metabolic activation catalyzed by microsomes from all species except rats and hamsters. Particularly high stimulation was observed with human and rabbit liver microsomes. 9,10-Dihydroxy-9,10,11,12-tetrahydrobenzo[e]pyrene, a compound which cannot be metabolized to a bay-region diol epoxide, was not metabolically activated to mutagenic metabolites in the presence or absence of 7,8-benzoflavone by any of the species examined. These results indicated that the effect of 7,8-benzoflavone on the enhanced mutagenic activity of benzo[e]pyrene 9,10-dihydrodiol is mediated by bay-region diol epoxides, which is consistent with the metabolism studies.