High stereoselectivity in mouse skin metabolic activation of methylchrysenes to tumorigenic dihydrodiols.
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.
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism*; D002942:Circular Dichroism; D005260:Female; D051379:Mice; D009152:Mutagenicity Tests; D010616:Phenanthrenes / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D013237:Stereoisomerism
D002911:Chrysenes; D010616:Phenanthrenes; C017229:1,2-dihydro-1,2-dihydroxy-5-methylchrysene; C024350:7,8-dihydro-7,8-dihydroxy-5-methylchrysene; C053042:1,2-dihydroxy-6-methylchrysene; C047249:6-methylchrysene; C008422:5-methylchrysene