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Tumorigenicity of Enantiomers of Chrysene 1,2-Dihydrodiol and of the Diastereomeric Bay-Region Chrysene 1,2-Diol-3,4-epoxides on Mouse Skin and 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.], and Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20205 [H. Y., M. T., K. P. V., D. M. J.]

The tumorigenicity of chrysene, (+)- and (-)-trans-1,2-dihydroxy-1,2-dihydrochrysene (chrysene 1,2-dihydrodiol), and the (+)- and (-)-enantiomers of the diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides was assessed in two tumor models. A single topical application of 0.4 or 1.2 µmol of the chrysene derivatives on mouse skin followed by 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate revealed that (-)-chrysene 1,2-dihydrodiol had approximately twice the tumor-initiating activity of chrysene, while the (+)-enantiomer had no significant tumorigenic activity. Of the four isomers of chrysene 1,2-diol-3,4-epoxide, only (+)-1ß,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene [(+)-diolepoxide 2], in which the benzylic hydroxyl group and epoxide oxygen are trans, had significant tumorigenic activity. The (+)-diol-epoxide 2 isomer had tumor-initiating activity that was equivalent to the activity of the parent hydrocarbon. In newborn mice, a total dose of 0.7 or 1.4 µmol of compound divided into three i.p. injections was administered on the first, eighth, and 15 days of life, and tumorigenic activity was determined when the mice were 37 to 41 weeks old. Control animals developed an average of 0.13 lung tumor/mouse, whereas animals treated with (+)-diol-epoxide 2, (-)-chrysene 1,2-dihydrodiol, or racemic chrysene 1,2-dihydrodiol had an average of 7.8, 6.5, and 2.5 lung tumors per mouse per µmol of compound administered, respectively. The parent hydrocarbon and all other derivatives tested were essentially inactive in producing lung tumors. With respect to hepatic tumors in male mice, (-)-chrysene 1,2-dihydrodiol was the most active compound tested, and produced 3-, 4-, 6-, and 10-fold more hepatic tumors per mouse per µmol of compound administered than did (+)-diol-epoxide 2, racemic chrysene 1,2-dihydrodiol, chrysene, and (+)-chrysene 1,2-dihydrodiol, respectively. Other derivatives had no significant hepatotumorigenic activity at the doses tested. The high tumorigenic activity of (-)-chrysene 1,2-dihydrodiol and (+)-diol-epoxide 2 on mouse skin and in newborn mice indicate that these compounds are, respectively, proximate and ultimate carcinogenic metabolites of chrysene. The (+)-diol-epoxide 2 isomer of chrysene has absolute configuration such that it is superimposable on the (+)-diol-epoxide 2 isomer of benzo(a)pyrene [(+)-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene], the ultimate carcinogenic metabolite of benzo(a)pyrene.

¹ To whom requests for reprints should be addressed.

Received 5/19/82. Accepted 8/31/82.

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