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Tumorigenicity of the Diastereomeric Bay-Region Benzo(e)pyrene 9,10-Diol-11,12-Epoxides in Newborn Mice

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

The tumorigenic activities of benzo(e)pyrene, 9,10-dihydrobenzo(e)pyrene, 9,10-epoxy-9,10,11,12-tetrahydrobenzo(e)-pyrene, the diastereomeric bay-region 9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrenes, and the K-region benzo(e)pyrene 4,5-oxide were assessed in newborn mice. Swiss-Webster mice received a total dose of 0.7 µmol of compound divided into three i.p. injections of 0.1, 0.2, and 0.4 µmol on the first, eighth, and 15th days of life, respectively. 9,10-Epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene was highly toxic to the newborn mice, and the first injection of 0.1 µmol of this benzo(e)pyrene derivative killed all the mice within two weeks. The total dose of 9,10-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene was therefore reduced to 0.07 µmol in divided doses of 0.01, 0.02, and 0.04 µmol. When the animals were killed at 39 to 43 weeks of age, one of the diastereomeric bayregion diol-epoxides, (±)-9ß, 10-dihydroxy-11ß, 12ß-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene, produced a small but significant increase in pulmonary tumors in male mice but had no significant hepatotumorigenic activity. The diastereomerically related diol-epoxide, (±)-9ß,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydrobenzo(e)pyrene, produced a significant incidence of hepatic tumors but had no effect on the formation of pulmonary tumors. Benzo(e)pyrene and the other benzo(e)pyrene derivatives were all nontumorigenic at the doses tested.

¹ Recipient of National Cancer Institute Grant 5-R01-CA-22985 in partial support of this work.

Received 9/29/80. Accepted 12/ 1/80.