Inhibition by a peri-fluorine atom of 1,2-dihydrodiol formation as a basis for the lower tumorigenicity of 12-fluoro-5-methylchrysene than of 5-methylchrysene.
12-Fluoro-5-methylchrysene, which has a fluorine atom at a peri position, is less carcinogenic toward mouse skin than is 5-methylchrysene. To determine the basis for this observation, we identified metabolites of 12-fluoro-5-methylchrysene formed by rat liver in vitro, and used these as standards to study the metabolism of [3H]-12-fluoro-5-methylchrysene in mouse liver in vitro and in mouse epidermis in vivo. Metabolites were identified by their ultraviolet, mass, and nuclear magnetic resonance spectra, by comparison to synthetic standards, and by chemical transformations. Dihydrodiols, phenols, and hydroxymethyl derivatives of 12-fluoro-5-methylchrysene were characterized. The extents of formation of 1,2-dihydro-1,2-dihydroxy-12-fluoro-5-methylchrysene and 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene in mouse liver in vitro were strongly influenced by pretreatment with 3-methylcholanthrene, but the ratio of 1,2-dihydrodiol to 7,8-dihydrodiol was lower than in the metabolism of 5-methylchrysene carried out under identical conditions. The major metabolites of [3H]-12-fluoro-5-methylchrysene formed in mouse epidermis, 0.33 to 4 hr after topical application, were 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene and 7-hydroxy-12-fluoro-5-methylchrysene. The ratio of 7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene to 1,2-dihydro-1,2-dihydroxy-12-fluoro-5-methylchrysene in mouse epidermis, 2 hr after application of [3H]-12-fluoro-5-methylchrysene, was 68:1, compared to 1:1 for the corresponding dihydrodiols of 5-methylchrysene. These results show that fluorine substitution at the 12-peri position of 5-methylchrysene inhibits formation of the 1,2-dihydrodiol in the adjacent ring. Since the 1,2-dihydrodiol is a major proximate carcinogen of 5-methylchrysene, the results provide an explanation for the relatively low carcinogenicity of 12-fluoro-5-methylchrysene.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D055598:Chemical Phenomena; D002621:Chemistry; D002911:Chrysenes / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010616:Phenanthrenes / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D014316:Tritium
D002273:Carcinogens; D002911:Chrysenes; D007202:Indicators and Reagents; D010616:Phenanthrenes; D014316:Tritium; C042379:12-fluoro-5-methylchrysene; C042381:1,2-dihydro-1,2-dihydroxy-12-fluoro-5-methylchrysene; C042380:7,8-dihydro-7,8-dihydroxy-12-fluoro-5-methylchrysene; C008422:5-methylchrysene