Amin S, Huie K, Balanikas G, Hecht S S, Pataki J, Harvey R G
Cancer Res. 1987 Jul 15;47(14):3613-7.
The stereoselectivity of mouse skin metabolic activation to dihydrodiols of the strong carcinogen 5-methylchrysene (5-MeC) and the weak carcinogen 6-methylchrysene (6-MeC) was investigated. Synthetic 1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol), 5-MeC-7,8-diol, and 6-MeC-1,2-diol were resolved into their R,R- and S,S-enantiomers by chiral stationary phase high performance liquid chromatography. The absolute configurations of the enantiomers were assigned by their circular dichroism spectra. Using these enantiomers as standards, the metabolism of 5-MeC and 6-MeC in vitro in rat and mouse liver and in vivo in mouse epidermis was investigated. Only the R,R-enantiomers of each dihydrodiol predominated (greater than 90%). The dihydrodiol enantiomers were tested for tumor initiating activity on mouse skin. In each case, the R,R-dihydrodiol enantiomer was significantly more tumorigenic than the S,S-enantiomer. The most tumorigenic compound was 5-MeC-1R,2R-diol; it was significantly more active than either 5-MeC-7R,8R-diol or 6-MeC-1R,2R-diol. The results of this study demonstrate that there is a high degree of stereoselectivity in the metabolic activation of 5-MeC and 6-MeC to proximate tumorigenic dihydrodiols in mouse skin. The bay region methyl group has no effect on the stereoselectivity of activation to 1,2-dihydrodiol metabolites in the chrysene system.
研究了小鼠皮肤对强致癌物5-甲基屈（5-MeC）和弱致癌物6-甲基屈（6-MeC）二氢二醇的代谢活化的立体选择性。通过手性固定相高效液相色谱法将合成的1,2-二氢-1,2-二羟基-5-甲基屈（5-MeC-1,2-二醇）、5-MeC-7,8-二醇和6-MeC-1,2-二醇拆分为其R,R-和S,S-对映体。通过圆二色光谱确定对映体的绝对构型。以这些对映体为标准，研究了5-MeC和6-MeC在大鼠和小鼠肝脏中的体外代谢以及在小鼠表皮中的体内代谢。每种二氢二醇的R,R-对映体占主导地位（大于90%）。测试了二氢二醇对映体在小鼠皮肤上的肿瘤启动活性。在每种情况下，R,R-二氢二醇对映体的致瘤性均明显高于S,S-对映体。致瘤性最强的化合物是5-MeC-1R,2R-二醇；其活性明显高于5-MeC-7R,8R-二醇或6-MeC-1R,2R-二醇。本研究结果表明，在小鼠皮肤中，5-MeC和6-MeC代谢活化为近致癌物二氢二醇的过程中存在高度的立体选择性。湾区甲基对屈系统中1,2-二氢二醇代谢物活化的立体选择性没有影响。
