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 Epidermis1

The stereochemistry of diol epoxide formation in mouse epidermis upon topical applicationof [3H]-l/f,2A-dihydroxy-l,2-dihydro-5-methylchrysene (|3H|-5-MeC-l/f,2A-diol)and |3Hl-6-MeC-lÄ,2Ä-diol, and the tumorigenicityin mouse skin and in newborn mice of the R,S,S,R and S,R,K,S enantiomers of l,2-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5methylchrysene (5-MeC-l,2-diol-3,4-epoxide), 5-MeC-7,8-diol-9,10epoxide, and 6-MeC-l,2-dioI-3,4-epoxide were examined. Analysis of tetraols and their derived tetraacetates present in mouse epidermis, 2 h after application of |3H}-5-MeC-l/f,2A-diolor (3H]-6-MeC-l/f,2/f-diol, demonstratedgreater than 90% stereoselectivityin formationof 5-MeCl/f,2S-diol-3S,4A-epoxide and 6-MeC-l/î,2S-diol-3S,4/f-epoxide. Taken together with previousdata, these results demonstrate that there is a highdegreeof stereoselectivityfor formationof R,S,S,R enantiomers of 5-MeCand 6-MeC-l,2-diol-3,4-epoxides in mouse skin. The results of the tumorigenicitystudies in mouse skin and in newbornmice clearly demonstrated that 5-MeC-l/?,25-dioI-35,4/t-epoxide was the most tumorigenic of the diol epoxide enantiomers tested; 6-MeC-lA,2S-diol35,4/l-epoxide was inactive.The results of this study show that the high tumorigenicityof 5-MeC compared to 6-MeC is due to the remarkable tumorigenicactivity of 5-MeC-lÄ,2S-diol-3S,4Ä-epoxide which, in con trast to 6-MeC-lÄ,25-diol-3S,4Ä-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 carcinogenicmethylated polynuclear aro matic hydrocarbonswill also show unique tumorigenicproperties.