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Comparative Tumor-initiating Activity of Methylated Benzo(a)pyrene Derivatives in Mouse Skin¹

The University of Tennessee-Oak Ridge Graduate School of Biomedical Sciences [R. P. I.], and Biology Division, Oak Ridge National Laboratory [T. J. S.], Oak Ridge, Tennessee 37830; Department of Chemistry, Ohio State University, Columbus, Ohio 43210 [J. W. L., J. A. S.]; and Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131 [G. H. D.]

The abilities of various mono and dimethyl derivatives of benzo(a)pyrene (BP) to initiate skin tumors in mice were determined by using a two-stage system of tumorigenesis. 11-Methylbenzo(a)pyrene was found to be approximately 3 times more active as a tumor initiator than was the parent hydrocarbon; 1-methyl benzo(a)pyrene was about twice as active as was BP. Substitution of a methyl group in positions 7, 8, 9, or 10 of BP, which would be involved in a bay-region diol-epoxide, completely counteracts the tumor-initiating ability of BP. 3-, 4-, and 12-methyl-benzo(a)pyrenes had activity equivalent to that of BP, whereas 2-, 5-, and 6-methylbenzo(a)pyrenes, as well as 1,2-, 4,5-, 1,6-, and 3,6-dimethylbenzo(a)pyrenes, were all less active than BP. The concepts of steric inhibition of metabolic activation and stereospecific activation are suggested to explain the tumor-initiating activities of various methylated derivatives.

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

² Postdoctoral Investigator supported by Subcontract 3322 from the Biology Division of Oak Ridge National Laboratory to the University of Tennessee. Present address: Department of Chemistry, Johns Hopkins University, Baltimore, Md. 21218.

³ To whom requests for reprints should be addressed, at Biology Division, Oak Ridge National Laboratory, P. O. Box Y, Oak Ridge, Tenn. 37830.

Received 10/25/79. Accepted 1/ 2/80.