Enhancing effect of a bay region methyl group on tumorigenicity in newborn mice and mouse skin of enantiomeric bay region diol epoxides formed stereoselectively from methylchrysenes in mouse epidermis.
The stereochemistry of diol epoxide formation in mouse epidermis upon topical application of [3H]-1R,2R-dihydroxy-1,2-dihydro-5-methylchrysene ([3H]-5-MeC-1R,2R-diol) and [3H]-6-MeC-1R,2R-diol, and the tumorigenicity in mouse skin and in newborn mice of the R,S,S,R and S,R,R,S enantiomers of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (5-MeC-1,2-diol-3,4-epoxide), 5-MeC-7,8-diol-9,10-epoxide, and 6-MeC-1,2-diol-3,4-epoxide were examined. Analysis of tetraols and their derived tetraacetates present in mouse epidermis, 2 h after application of [3H]-5-MeC-1R,2R-diol or [3H]-6-MeC-1R,2R-diol, demonstrated greater than 90% stereoselectivity in formation of 5-MeC-1R,2S-diol-3S,4R-epoxide and 6-MeC-1R,2S-diol-3S,4R-epoxide. Taken together with previous data, these results demonstrate that there is a high degree of stereoselectivity for formation of R,S,S,R enantiomers of 5-MeC- and 6-MeC-1,2-diol-3,4-epoxides in mouse skin. The results of the tumorigenicity studies in mouse skin and in newborn mice clearly demonstrated that 5-MeC-1R,2S-diol-3S,4R-epoxide was the most tumorigenic of the diol epoxide enantiomers tested; 6-MeC-1R,2S-diol-3S,4R-epoxide was inactive. The results of this study show that the high tumorigenicity of 5-MeC compared to 6-MeC is due to the remarkable tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide which, in contrast to 6-MeC-1R,2S-diol-3S,4R-epoxide, has a methyl group in the same bay region as the epoxide ring. We propose that such methyl bay region diol epoxides of other carcinogenic methylated polynuclear aromatic hydrocarbons will also show unique tumorigenic properties.
D000818:Animals; D000831:Animals, Newborn; D002273:Carcinogens; D002911:Chrysenes; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D008745:Methylation; D051379:Mice; D010616:Phenanthrenes; D012867:Skin / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002273:Carcinogens; D002911:Chrysenes; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D010616:Phenanthrenes; C047249:6-methylchrysene; C008422:5-methylchrysene