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Marked Differences in the Skin Tumor-initiating Activities of the Optical Enantiomers of the Diastereomeric Benzo(a)pyrene 7,8-Diol-9,10-Epoxides¹

Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830 [T. J. S., W. M. B., G. G.]; Department of Biochemistry and Drug Metabolism, Hoffmann-LaRoche Inc., Nutley, New Jersey 07110 [W. L., A. H. C.]; and Section on Oxidation Mechanisms, Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, NIH, Bethesda, Maryland 20014 [H. Y., D. M. J.]

The abilities of the optically pure (+)- and (-)-enantiomers of the diastereomeric 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrenes derived from the enantiomeric trans-7,8-dihydrodiols to initiate skin tumors in mice were determined with a two-stage system of tumorigenesis. As a tumor initiator, (+)-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene 2 was approximately 60% as active as was benzo(a)pyrene, whereas (-)-7,8ß-dihydroxy-9ß,10ß-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene 2 was about 2% as active as was benzo(a)pyrene. The racemic mixture of the above diol-epoxide, in which the 9,10-epoxide is trans to the 7-hydroxyl group, was 25% as active as was benzo(a)pyrene as a tumor initiator. (-)-7ß,8-Dihydroxy-9ß,10ß-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene 1 and (+)-7,8ß-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene 1, in which the 9,10-epoxide is cis to the 7-hydroxyl group, were found to have little or no tumorigenic activity. The tumor-initiating ability of (+)-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene 2 was found to be greater when given daily for 6 days at a dose of 34 nmol/day than when given once at a 200-nmol dose level. Similar fractionated doses of benzo(a)pyrene or (-)-7,8ß-dihydroxy-9ß,10ß-epoxy7,8,9,10-tetrahydrobenzo(a)pyrene 2 did not increase their skin tumor-initiating activity. The data suggest that (+)-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene is an ultimate carcinogenic form of benzo(a)pyrene.

¹ Research jointly sponsored by NIH Grant CA-20076 and by the Division of Biomedical and Environmental Research, United States Department of Energy, under Contract W-7405-eng-26 with the Union Carbide Corporation.

² To whom requests for reprints should be addressed, at Biology Division, Oak Ridge National Laboratory, P. O. Box Y, Oak Ridge, Tenn. 37830.

Received 6/12/78. Accepted 10/ 3/78.

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