Comparative metabolic activation in mouse skin of the weak carcinogen 6-methylchrysene and the strong carcinogen 5-methylchrysene.
We compared the metabolic activation in mouse skin of the weak carcinogen 6-methylchrysene, which lacks a bay region methyl group, and the strong carcinogen 5-methylchrysene, which has a bay region methyl group. Metabolites of 6-methyl-chrysene were prepared using liver homogenates and were identified by their spectral properties and by comparison to synthetic standards as dihydrodiols, hydroxymethyl derivatives, and phenols; their relative levels of formation in liver homogenates from rats and mice were dependent on inducer pretreatment. In mouse skin in vivo, the major metabolite of 6-methyl-chrysene was trans-1,2-dihydro-1,2-dihydroxy-6-methylchrysene (6-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide. Its concentration was greater than that of trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed in mouse skin from 5-methylchrysene. Since 5-MeC-1,2-diol has been identified as a major proximate carcinogen of 5-methylchrysene, the further metabolism and tumorigenicity of 5-MeC-1,2-diol and 6-MeC-1,2-diol were compared. Both dihydrodiols were converted to 1,2,3,4-tetraols and to 1,2-dihydroxy metabolites to similar extents in mouse skin. However, 5-MeC-1,2-diol was significantly more active than was 6-MeC-1,2-diol as a tumor initiator on mouse skin. The formation of DNA adducts in mouse skin from 5-methylchrysene and 6-methylchrysene was compared. Both hydrocarbons gave qualitatively similar adduct patterns, but the formation of dihydrodiol epoxide type adducts was 1/20 as great from 6-methylchrysene as from 5-methylchrysene. The results of this study indicate that the weak tumorigenicity of 6-methylchrysene compared to that of 5-methylchrysene is not due to differing rates of formation or further metabolism of their 1,2-dihydrodiols but is a likely consequence of the lower activity of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene compared to 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; the unique structural feature of the latter is the presence of a methyl group and an epoxide ring in the same bay region.
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism*; D051379:Mice; D010616:Phenanthrenes / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D002911:Chrysenes; D010616:Phenanthrenes; C047249:6-methylchrysene; C008422:5-methylchrysene