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Mutagenicity of the Dihydrodiols and Bay-Region Diol-Epoxides of Benzo(c)phenanthrene in Bacterial and Mammalian Cells

Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [A. W. W., R. L. C., W. L., D. E. R., P. E. T., A. H. C.], and Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Bethesda, Maryland 20205 [M. C-D., Y. I., H. Y., D. M. J.]

The mutagenic activity of benzo(c)phenanthrene and some of its known and potential metabolites was evaluated in bacterial and mammalian cells either in the presence or absence of a metabolic activation system. trans-3,4-Dihydroxy-3,4-dihydrobenzo(c)phenanthrene [benzo(c)phenanthrene 3,4-dihydrodiol] was metabolized by a cytochrome P-450-dependent monooxygenase system to products which were severalfold more mutagenic to strains TA98 and TA100 of Salmonella typhimurium than were the metabolic products formed from benzo(c)phenanthrene or its 1,2- or 5,6-dihydrodiols. When the double bond in the 1,2-position of benzo(c)phenanthrene 3,4-dihydrodiol was replaced by a single bond, the resulting tetrahydrodiol could not be metabolically activated, suggesting that one or both diastereomeric bay-region diol-epoxides was the bioactivated metabolite of the 3,4-dihydrodiol of benzo(c)phenanthrene. Both of these bay-region diol-epoxide diastereomers were highly mutagenic in bacterial and mammalian cells and were very poor substrates for epoxide hydrolase. (±)-3,4ß-Dihydroxy-1ß,2ß-epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene (diol-epoxide 1), in which the epoxide oxygen and the benzylic hydroxyl group are cis, induced histidine prototrophy in strains TA98 and TA100 of S. typhimurium at a mutation rate of 1000 and 2700 revertants/nmol, respectively. A 1 µM concentration of this diol-epoxide killed one-half of the treated Chinese hamster V79 cells and induced mutations in the surviving cells at a rate of 100 8-azaguanine-resistant cells/10⁵ surviving cells. (±)-3,4ß-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene (diol-epoxide 2), in which the epoxide oxygen and the benzylic hydroxyl group are trans, had from 80 to 250% of the mutagenic and cytotoxic activity of its diastereomer. These data strongly suggest that in species capable of the appropriate metabolic transformations of benzo(c)phenanthrene, the 3,4-dihydrodiol and one or both of its diastereomeric bay-region diol-epoxides are proximate and ultimate carcinogens, respectively.

¹ To whom requests for reprints should be addressed.

Received 3/14/80. Accepted 5/12/80.