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Exceptionally High Tumor-initiating Activity of Benzo(c)phenanthrene Bay-Region Diol-Epoxides on Mouse Skin

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

Benzo(c)phenanthrene [B(c)Ph], its three metabolically possible trans-dihydrodiols, and the diastereomeric bay-region diol-epoxides derived from trans-3,4-dihydroxy-3,4-dihydrobenzo(c)phenanthrene were tested for tumor-initiating activity on mouse skin. A single topical application of 0.4 or 2.0 µmol of compound was followed seven days later by twice-weekly applications of the tumor promotor 12-O-tetradecanoylphorbol-13-acetate for 20 weeks. B(c)Ph was found to be a weak tumor initiator on mouse skin, producing a 17 to 38% tumor incidence and 0.17 to 0.59 papilloma/mouse at the 0.4- and 2.0-µmol doses, respectively. Of the three metabolically possible trans-dihydrodiols of B(c)Ph, only trans-3,4-dihydroxy-3,4-dihydrobenzo(c)phenanthrene had significant tumor-initiating activity at the doses tested. This compound produced a 28 to 47% tumor incidence and 0.41 to 1.07 tumors/mouse at the 0.4- and 2.0-µmol doses, respectively. Comparisons of the number of papillomas observed per mouse indicated that both diastereomeric 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrenes in which the epoxide oxygen is either cis (diol-epoxide 1) or trans (diol-epoxide 2) to the benzylic 4-hydroxyl group were at least 40-fold more tumorigenic than was the parent hydrocarbon. The bay-region diol-epoxides of B(c)Ph produced 6.5 to 7.0 papillomas/mouse at the 0.4-µmol dose, and the first appearance of tumors was observed as early as six weeks after the beginning of promotion. This is the first example of high tumorigenic activity for a bay-region diol-epoxide 1 diastereomer of a polycyclic aromatic hydrocarbon, and both diastereomeric bay-region diol-epoxides of B(c)Ph are more potent tumor initiators than are the bay-region diol-epoxides derived from benzo(a)pyrene and benzo(a)anthracene. Two model compounds, 1,2-dihydrobenzo(c)phenanthrene and trans-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene, which cannot be metabolized to bay-region diol-epoxides of B(c)Ph, were found to be inactive as tumor initiators on mouse skin. These results support the concept that a bay-region diol-epoxide is a prime candidate for an ultimate carcinogenic metabolite of B(c)Ph.

¹ To whom requests for reprints should be addressed.

Received 5/23/80. Accepted 7/17/80.

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