High stereoselectivity in mouse skin metabolic activation of methylchrysenes to tumorigenic dihydrodiols

Abstract

The stereoselectivity of mouse skin metabolic activation to dihydrodiols of the strong carcinogen 5-methylchrysene (5-MeC) and the weak carcinogen 6-methylchrysene (6-MeC) was investigated. Synthetic 1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol), 5-MeC-7,8-diol, and 6-MeC-1,2-diol were resolved into their R,R- and S,S-enantiomers by chiral stationary phase high performance liquid chromatography. The absolute configurations of the enantiomers were assigned by their circular dichroism spectra. Using these enantiomers as standards, the metabolism of 5-MeC and 6-MeC in vitro in rat and mouse liver and in vivo in mouse epidermis was investigated. Only the R,R-enantiomers of each dihydrodiol predominated (greater than 90%). The dihydrodiol enantiomers were tested for tumor initiating activity on mouse skin. In each case, the R,R-dihydrodiol enantiomer was significantly more tumorigenic than the S,S-enantiomer. The most tumorigenic compound was 5-MeC-1R,2R-diol; it was significantly more active than either 5-MeC-7R,8R-diol or 6-MeC-1R,2R-diol. The results of this study demonstrate that there is a high degree of stereoselectivity in the metabolic activation of 5-MeC and 6-MeC to proximate tumorigenic dihydrodiols in mouse skin. The bay region methyl group has no effect on the stereoselectivity of activation to 1,2-dihydrodiol metabolites in the chrysene system.