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Effect of a 6-Fluoro Substituent on the Metabolism and Biological Activity of Benzo(a)pyrene

Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20205 [D. R. B., F. U., D. R. T., D. M. J.]; Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37803 [T. J. S.]; and Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [A. H. C., A. W. W., R. L. C., W. L.]

Cytochrome P-450-catalyzed epoxidation of (-)-(7R,8R)-dihydroxy-7,8-dihydrobenzo(a)pyrene to (+)-(7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene is now well recognized as the primary pathway by which benzo(a)pyrene is converted to an ultimate carcinogen. The present metabolism studies of 6-fluorobenzo(a)pyrene indicate (a) that the 6-fluoro substituent does not dramatically block the formation of quinones involving position 6 and (b) that substantially more (2-fold) of the 7,8-dihydrodiol is formed from 6-fluorobenzo(a)pyrene than is formed from benzo(a)pyrene. As is the case for benzo(a)pyrene, the 6-fluoro-7,8-dihydrodiol was found to be of high optical purity and has (7R,8R)absolute configuration. Electrostatic repulsion appears to cause the fluorinated 4,5- as well as 7,8-dihydrodiols to prefer the pseudodiaxial rather than the pseudodiequatorial conformation observed for these dihydrodiols when formed from benzo(a)pyrene. Comparision of the tumor-initiating activities of benzo(a)pyrene and 6-fluorobenzo(a)pyrene on the skin of female Sencar mice indicates that the fluorinated hydrocarbon is far less active in the initiation of tumors. In addition, the metabolites of the fluorinated 7,8-dihydrodiol do not display strong mutagenic activity toward Chinese hamster V79 cells. Altered conformation of the fluorinated 7,8-dihydrodiol and the resultant 7,8-diol-9,10-epoxide diastereomer in which the benzylic 7-hydroxyl group and the epoxide oxygen are trans provides a plausible explanation for the weak tumorigenicity of 6-fluorobenzo(a)pyrene on mouse skin, since all benzo-ring dihydrodiols and diol-epoxides in which the hydroxyl groups prefer the pseudodiaxial conformation are weak or inactive as carcinogens. In formulating the bay-region theory, we had pointed out that perifluorine substituents such as at position 6 in benzo(a)pyrene have a marked inhibitory effect on the tumorigenicity of the hydrocarbon. The present results provide a basis for this "perieffect."

¹ Recipient of salary support from the Environmental Health Sciences Center, Oregon State University, Corvalis, Oreg., for a 1-year sabbatical leave during the academic year 1978–1979 during which time most of the present study was completed.

² Present address: Turkish Atomic Energy Commission, Ankara, Turkey.

³ To whom requests for reprints should be addressed.

Received 6/11/82. Accepted 1/ 4/83.