Effect of a 6-fluoro substituent on the metabolism and biological activity of benzo(a)pyrene.

Cytochrome P-450-catalyzed epoxidation of (-)-(7R,8R)-d\hydroxy-7,8-dihydrobenzo(a)pyrene to (+H7fl,8S)-dihydroxy(9S,10fl)-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 quiñones 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,8fl)absolute configuration. Elec trostatic repulsion appears to cause the fluorinated 4,5as well as 7,8-dihydrodiols to prefer the pseudodiaxial rather than the pseudodiequatorial conformation observed for these dihydrodiols when formed from benzo(a)pyrene. Comparison 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-dihy drodiol do not display strong mutagenic activity toward Chinese hamster V79 cells. Altered conformation of the fluorinated 7,8dihydrodiol 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 inac tive 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."