RT Journal Article SR Electronic T1 Structural Requirements for the Metabolic Activation of Benzo[a]pyrene to Mutagenic Products: Effects of Modifications in the 4,5-, 7,8-, and 9,10-Positions JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1116 OP 1125 VO 13 IS 6 A1 A. W. WOOD A1 W. LEVIN A1 A. Y. H. LU A1 D. RYAN A1 S. B. WEST A1 H. YAGI A1 H. D. MAH A1 D. M. JERINA A1 A. H. CONNEY YR 1977 UL http://molpharm.aspetjournals.org/content/13/6/1116.abstract AB 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. ACKNOWLEDGMENTS The authors thank Ms. Candace Caso and Ms. Arlene Ott for their assistance in the preparation of this manuscript.