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Mutagenicity and Tumor-initiating Activity of Cyclopenta(c,d)pyrene and Structurally Related Compounds

Department of Biochemistry and Drug Metabolism, Hoffmann-LaRoche Inc., Nutley, New Jersey 07110 [A. W. W., W. L., R. L. C., M-T. H., D. E. R., P. E. T., A. H. C.]; Department of Chemistry, University of Oklahoma, Norman, Oklahoma 73019 [R. E. L., S. K.]; Laboratorie de Chimie, Ecole Normale Superieure, 75231 Paris Cedex 05, France [P. D.]; Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109 [M. K., H. A.]; and Laboratory of Bioorganic Chemistry, National Institutes cf Arthritis, Metabolism, and Digestive Diseases, NIH, Bethesda, Maryland 20205 [Y. I., H. Y., D. M. J.]

The biological activities of benzo(a)pyrene, cyclopenta(c,d)pyrene, and 12 other structurally related compounds were assessed by mutagenicity studies with bacterial and mammalian cells and/or skin tumorigenicity studies with mice. The ability of the parent hydrocarbons to be metabolically activated to mutagenic products was examined in strains TA98 and TA100 of Salmonella typhimurium, using 3 experimental protocols. In each case, cyclopenta(c,d)pyrene was metabolically activated to products mutagenic to the bacteria to a greater extent than was benzo(a)pyrene. However, 7,8-dihydrobenzo(a)pyrene and 9,10-dihydrobenzo(e)pyrene were the best substrates for metabolic activation to bacterial mutagens. Highly purified epoxide hydrase added to a purified and reconstituted monooxygenase system readily abolished the mutagenic activity observed in strain TA100 of S. typhimurium when cyclopenta(c,d)pyrene was the substrate, but not when benzo(a)pyrene was the substrate. Inherent mutagenicity of several epoxides of the hydrocarbons generally paralleled the ability of their potential metabolic precursors to be activated to mutagens. 1-Pyrenyloxirane and 10,11-dihydrocycloheptapyrene 8,9-oxide were highly mutagenic in strains TA98 and TA100 of S. typhimurium, and in the former strain these activities were comparable to that observed with 9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. 4-Pyrenyloxirane was significantly less mutagenic than was 1-pyrenyloxirane in both strains of bacteria and in mammalian cells. Benzo(a)pyrene was over 20 times more tumorigenic than was cyclopenta(c,d)pyrene, and it was the most potent of the 11 compounds tested for tumor-initiating activity in 2-stage initiation-promotion experiments on the skin of mice. Cyclopenta(c,d)pyrene had tumor-initiating activity comparable to that of benzo(a)anthracene, but it was significantly less active than chrysene. Thus, contrary to inferences made from its high mutagenic activity, cyclopenta(c,d)pyrene is a weak tumor initiator on mouse skin.

¹ To whom requests for reprints should be addressed.

² Recipient of National Cancer Institute Grant 5-RO1-CA-22985-02, which provided financial support for part of this study.

³ Recipient of NIH Grant C825185, which provided financial support for parts of this study.

Received 8/31/79. Accepted 11/20/79.