Reactivity with DNA Bases and Mutagenicity toward Salmonella typhimurium of Methylchrysene Diol Epoxide Enantiomers1

Abstract

The reactions with DNA and mutagenic activities toward Salmonella typhimurium TA 100 of the R,S,S,R and S,R,R,S enantiomers of antil,2,-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5-methylchrysene (anti5-MeC-l,2-diol-3,4-epoxide), an»i-5-MeC-7,8-diol-9,10-epoxide, and «nf/-6-MeC-l,2-diol-3,4-epoxide were compared because among these compounds only the H,S,S,K enantiomer of anri-5-MeC-l,2-diol-3,4epoxide is highly tumorigenic. The major products formed in the reaction of each run-in ic diol epoxide with DNA were two pairs of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts; one product in each pair was formed from the R.S.S.R enantiomer and the other from the S,R,R,S enantiomer of each racemic diol epoxide. Formation of products from R,S,S,R enantiomers exceeded formation of those from S,R,R,S enantio mers in each case. Among the R,S,S,R enantiomers, 5-MeC-l,2-diol-3,4epoxide, which has a methyl group in the same bay region as the epoxide ring, was most reactive toward DNA, and in particular toward dGuo. The dGuo/dAdo adduct ratios were greater for the products formed from the R,S,S,R enantiomer compared to the S,R,R,S enantiomer of each diol epoxide. The dGuo/dAdo adduct ratios were also greater for the enantio mers of anfi-5-MeC-l,2-diol-3,4-epoxide than for the enantiomers of either anfi-5-MeC-7,8-diol-9,10-epoxide or anr/-6-MeC-l,2-diol-3,4epoxide. In S. typhimurium TA 100, the R,S,S,R enantiomer of anti-5MeC-l,2-diol-3,4-epoxide was the most mutagenic compound (6700 revertants/nmol), followed by the R,S,S,R enantiomer of anii-5-MeC-7,8diol-9,10-epoxide (1500 revertants/nmol). The other diol epoxide enan tiomers were weakly active or inactive at the doses tested. The results of this study demonstrate that both the absolute configuration of a diol epoxide and the position of the methyl group have major effects on its reactivity with DNA. The greatest reactivity is seen in an R,S,S,R enantiomer with the methyl group and epoxide ring in the same bay region, e.g., the highly tumorigenic and mutagenic ^-Mr( I A'.iS-iliolSS'^A-epoxide. Comparison of the dGuo/dAdo adduct ratios of the various diol epoxides with their tumorigenic and mutagenic activities suggests that dGuo adducts are important in the expression of biological activity of methylchrysene diol epoxides.

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@inproceedings{Melikian2006ReactivityWD, title={Reactivity with DNA Bases and Mutagenicity toward Salmonella typhimurium of Methylchrysene Diol Epoxide Enantiomers1}, author={Assieh A. Melikian and Shantu G. Amin and Keith C. Huie and Stephen S Hecht and Ronald G. Harvey}, year={2006} }