Abstract

The metabolism of benzo[a]pyrene and eight benzo[a]pyrene derivatives to products mutagenic to Salmonella typhimurium strain TA98 was evaluated with a highly purified, cytochrome P-448-dependent monooxygenase system free of epoxide hydrase. Metabolic activation of benzo[a]pyrene derivatives saturated in the 7,8-position of the molecule either by reduction (7,8-dihydrobenzo[a]pyrene) or by the cis or trans addition of hydroxyl groups (7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene) resulted in 10-20 times more mutations than occurred after metabolic activation of benzo[a]pyrene. Benzo[a]pyrene 7,8-quinone was not intrinsically mutagenic to the bacteria and could not be metabolically activated. 9,10-Dihydrobenzo[a]pyrene was metabolized to mutagenic products to the same extent as benzo[a]pyrene, but derivatives that were totally saturated in the benzo ring (7,8,9,10-tetrahydrobenzo[a]pyrene and trans-7,8-dihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene) could not be activated. 4,5-Dihydrobenzo[a]pyrene, which cannot be epoxidized in the 4,5-position (K-region), was also nonmutagenic in the presence of the purified monooxygenase system. Epoxide hydrase, incubated together with the purified monooxygenase system reconstituted with 0.08 nmole of cytochrome P-448, almost completely deactivated the mutagenic products formed from 9,10-dihydrobenzo[a]pyrene, but reduced the mutation frequency induced by the metabolism of benzo[a]pyrene by only 30%. Evaluation of the intrinsic mutagenic activity of 7,8,9,10-tetrahydrobenzo[a]pyrene 4,5-oxide, benzo[a]pyrene 4,5-oxide, and pyrene 4,5-oxide indicated that saturation or removal of the benzo ring of benzo[a]pyrene 4,5-oxide markedly reduces the intrinsic mutagenicity of this K-region arene oxide.