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Species-specific Enhancement by 7,8-Benzoflavone of Hepatic Microsomal Metabolism of Benzo[e]pyrene 9,10-Dihydrodiol to Bay-Region Diol Epoxides

Section of Oxidation Mechanisms, Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Bethesda, Maryland 20205 [D. R. T., H. Y., D. M. J.]; Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [W. L., A. W. W., M. B., A. H. C.]; and Department of Chemistry, University of Oklahoma, Norman, Oklahoma 73019 [R. E. L.]

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.

¹ To whom requests for reprints should be addressed.

² Recipient of Grant R01 CA22985 from the National Cancer Institute for partial support of these studies.

Received 9/29/80. Accepted 12/29/80.

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