Wood A W, Chang R L, Levin W, Yagi H, Thakker D R, van Bladeren P J, Jerina D M, Conney A H
Cancer Res. 1983 Dec;43(12 Pt 1):5821-5.
Enantiomers of the diastereomeric pair of bay-region benz(a)anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity in two histidine-dependent strains of Salmonella typhimurium, as well as in an 8-azaguanine-sensitive Chinese hamster cell line. In strain TA 98 of S. typhimurium, the diol-epoxide with (1S,2R,3R,4S) absolute configuration [(-)-diol-epoxide 2] was the most active isomer, although there was less than a 3-fold difference in the mutagenicity of the four diol-epoxides. However, in strain TA 100 of S. typhimurium, the enantiomeric diol-epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol-epoxide 2] was the most active diol-epoxide, and the two isomers with (3S,4R) absolute configuration [(-)-diol-epoxide 1 and (+)-diol-epoxide 2] were three to eight times more active than were the two isomers with (3R,4S) configuration. The highest degree of sensitivity to absolute configuration was observed in Chinese hamster V79 cells, in which the (1R,2S,3S,4R) isomer [(+)-diol-epoxide 2] was from three to 20 times more mutagenic than were the other three isomers. This metabolically predominant (+)-diol-epoxide 2 isomer, which has high activity in strain TA 100 of S. typhimurium and the Chinese hamster V79 cells, has the same absolute configuration as do the bay-region diol-epoxide isomers of benzo(a)pyrene and chrysene that have been shown previously to be exceptionally mutagenic to mammalian cells and highly tumorigenic in mice. Analysis of the mutagenic activity of the (+)- and (-)-isomers of the 1,2- and 3,4-tetrahydroepoxides of benz(a)anthracene revealed only small enantiomeric differences in strain TA 98 of S. typhimurium (2.5 fold) and little, if any, differences (less than 1.5-fold) in the other two mutagenicity systems. However, the extent to which the four tetrahydroepoxides were converted to nonmutagenic products by homogeneous microsomal epoxide hydrolase (EC 3.3.2.3) indicated marked differences in the stereoselectivity of the enzyme. (-)-(3R,4S)-Epoxy-1,2,3,4-tetrahydrobenz(a)anthracene appears to be an exceptionally good substrate for epoxide hydrolase.
在海湾区域苯并(a)蒽3,4 -二醇 - 1,2 - 环氧化物的非对映异构体对中，苄基4 - 羟基和环氧基氧处于顺式（异构体1）或反式（异构体2）的对映体，在两种组氨酸依赖型鼠伤寒沙门氏菌菌株以及一种对8 - 氮杂鸟嘌呤敏感的中国仓鼠细胞系中评估了其致突变活性。在鼠伤寒沙门氏菌TA 98菌株中，具有(1S,2R,3R,4S)绝对构型的二醇环氧化物[(-)-二醇环氧化物2]是活性最高的异构体，尽管这四种二醇环氧化物的致突变性差异小于3倍。然而，在鼠伤寒沙门氏菌TA 100菌株中，具有(1R,2S,3S,4R)绝对构型[(+)-二醇环氧化物2]的对映体二醇环氧化物是活性最高的二醇环氧化物，并且具有(3S,4R)绝对构型的两种异构体[(-)-二醇环氧化物1和(+)-二醇环氧化物2]的活性比具有(3R,4S)构型的两种异构体高三至八倍。在中国仓鼠V79细胞中观察到对绝对构型的最高敏感度，其中(1R,2S,3S,4R)异构体[(+)-二醇环氧化物2]的致突变性比其他三种异构体高三至二十倍。这种代谢上占主导的(+)-二醇环氧化物2异构体，在鼠伤寒沙门氏菌TA 100菌株和中国仓鼠V79细胞中具有高活性，其绝对构型与先前已证明对哺乳动物细胞具有异常致突变性且在小鼠中具有高度致癌性的苯并(a)芘和屈的海湾区域二醇环氧化物异构体相同。对苯并(a)蒽的1,2 - 和3,4 - 四氢环氧化物的(+)-和(-)-异构体的致突变活性分析表明，在鼠伤寒沙门氏菌TA 98菌株中对映体差异较小（2.5倍），在其他两个致突变性系统中差异很小（如果有的话）（小于1.5倍）。然而，四种四氢环氧化物被均一化微粒体环氧化物水解酶（EC 3.3.2.3）转化为非致突变产物的程度表明该酶的立体选择性存在显著差异。(-)-(3R,4S)-环氧 - 1,2,3,4 - 四氢苯并(a)蒽似乎是环氧化物水解酶的一种异常好的底物。
