Melikian A A, Amin S, Huie K, Hecht S S, Harvey R G
Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595.
Cancer Res. 1988 Apr 1;48(7):1781-7.
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 anti-1,2,-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-5-MeC-1,2-diol-3,4-epoxide), anti-5-MeC-7,8-diol-9,10-epoxide, and anti-6-MeC-1,2-diol-3,4-epoxide were compared because among these compounds only the R,S,S,R enantiomer of anti-5-MeC-1,2-diol-3,4-epoxide is highly tumorigenic. The major products formed in the reaction of each racemic 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 enantiomers in each case. Among the R,S,S,R enantiomers, 5-MeC-1,2-diol-3,4-epoxide, 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 enantiomers of anti-5-MeC-1,2-diol-3,4-epoxide than for the enantiomers of either anti-5-MeC-7,8-diol-9,10-epoxide or anti-6-MeC-1,2-diol-3,4-epoxide. In S. typhimurium TA 100, the R,S,S,R enantiomer of anti-5-MeC-1,2-diol-3,4-epoxide was the most mutagenic compound (6700 revertants/nmol), followed by the R,S,S,R enantiomer of anti-5-MeC-7,8-diol-9,10-epoxide (1500 revertants/nmol). The other diol epoxide enantiomers 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 5-MeC-1R,2S-diol-3S,4R-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.
比较了反式-1,2-二羟基-3,4-环氧-1,2,3,4-四氢-5-甲基屈（反式-5-MeC-1,2-二醇-3,4-环氧化物）、反式-5-MeC-7,8-二醇-9,10-环氧化物和反式-6-MeC-1,2-二醇-3,4-环氧化物的R,S,S,R和S,R,R,S对映体与DNA的反应以及对鼠伤寒沙门氏菌TA 100的诱变活性，因为在这些化合物中，只有反式-5-MeC-1,2-二醇-3,4-环氧化物的R,S,S,R对映体具有高度致瘤性。每个外消旋二醇环氧化物与DNA反应形成的主要产物是两对脱氧鸟苷（dGuo）和脱氧腺苷（dAdo）加合物；每对产物中的一个由每个外消旋二醇环氧化物的R,S,S,R对映体形成，另一个由S,R,R,S对映体形成。在每种情况下，由R,S,S,R对映体形成的产物的生成量超过由S,R,R,S对映体形成的产物的生成量。在R,S,S,R对映体中，与环氧环处于同一湾区的5-MeC-1,2-二醇-3,4-环氧化物对DNA，特别是对dGuo的反应性最强。与每种二醇环氧化物的S,R,R,S对映体相比，由R,S,S,R对映体形成的产物的dGuo/dAdo加合物比率更高。反式-5-MeC-1,2-二醇-3,4-环氧化物对映体的dGuo/dAdo加合物比率也高于反式-5-MeC-7,8-二醇-9,10-环氧化物或反式-6-MeC-1,2-二醇-3,4-环氧化物对映体的dGuo/dAdo加合物比率。在鼠伤寒沙门氏菌TA 100中，反式-5-MeC-1,2-二醇-3,4-环氧化物的R,S,S,R对映体是最具诱变活性的化合物（6700回复突变体/nmol），其次是反式-5-MeC-7,8-二醇-9,10-环氧化物的R,S,S,R对映体（1500回复突变体/nmol）。在测试剂量下，其他二醇环氧化物对映体活性较弱或无活性。本研究结果表明，二醇环氧化物的绝对构型和甲基的位置对其与DNA的反应性有主要影响。在甲基和环氧环处于同一湾区的R,S,S,R对映体中观察到最大的反应性，例如高度致瘤和诱变的5-MeC-1R,2S-二醇-3S,4R-环氧化物。各种二醇环氧化物的dGuo/dAdo加合物比率与其致瘤和诱变活性的比较表明，dGuo加合物在甲基屈二醇环氧化物的生物活性表达中很重要。
