Chiu P L, Fu P P, Yang S K
Cancer Res. 1984 Feb;44(2):562-70.
7-Fluorobenz(a)anthracene (7-FBA) was metabolized by rat liver microsomes predominantly to 4-hydroxy-7-FBA and 7-FBA trans-3,4-, 5,6-, 8,9-, and 10,11-dihydrodiols. Proton nuclear magnetic resonance spectral analyses indicated that the fluoro substituent causes 7-FBA trans-5,6- and 8,9-dihydrodiols to adopt preferentially quasidiaxial conformations (Chiu, P.-L., Fu, P. P., and Yang, S. K. Biochem. Biophys. Res. Commun., 106: 1405-1411, 1982). The major enantiomers of the quasidiaxial trans-5,6- and trans-8,9-dihydrodiols have been determined by the exciton chirality method to have R,R absolute stereochemistries. By comparing with the circular dichroism spectra of BA 3R,4R- and 10R,11R-dihydrodiols, the major enantiomers of the quasidiequatorial 7-FBA trans-3,4- and trans-10,11-dihydrodiols were also found to have R,R absolute configurations. All four 7-FBA trans-dihydrodiol metabolites obtained from incubations of 7-FBA with liver microsomes prepared from untreated and 3-methylcholanthrene-, phenobarbital-, and polychlorinated biphenyl-treated male Sprague-Dawley rats were enriched in R,R enantiomers, differing only in optical purities. Pretreatment of rats with phenobarbital, 3-methylcholanthrene, and polychlorinated biphenyls changed the rate of 7-FBA metabolism by 0.47-, 1.14-, and 1.70-fold, respectively. Pretreatment of rats with enzyme inducers also altered the quantitative distribution of metabolites formed. The relative mutagenic activities of metabolites toward Salmonella typhimurium TA 100 were: 7-FBA trans-3,4-dihydrodiol greater than 7-FBA trans-10,11-dihydrodiol greater than 7-methyl-BA approximately equal to 7-FBA greater than 7-FBA trans-8,9-dihydrodiol approximately equal to 7-methyl-BA trans-10,11-dihydrodiol greater than 7-FBA trans-5,6-dihydrodiol approximately equal to 4-hydroxy-7-FBA. The relatively high mutagenic activities of 7-FBA trans-3,4- and trans-10,11-dihydrodiols suggest that both 7-FBA trans-3,4-dihydrodiol 1,2-epoxide(s) and 7-FBA trans-10,11-dihydrodiol 8,9-epoxide(s) may be the major metabolites which contribute to the carcinogenic properties of 7-FBA.
7-氟苯并[a]蒽（7-FBA）在大鼠肝微粒体中主要代谢为4-羟基-7-FBA以及7-FBA反式-3,4-、5,6-、8,9-和10,11-二氢二醇。质子核磁共振光谱分析表明，氟取代基致使7-FBA反式-5,6-和8,9-二氢二醇优先采取准双轴构象（Chiu, P.-L., Fu, P. P., and Yang, S. K. Biochem. Biophys. Res. Commun., 106: 1405 - 1411, 1982）。通过激子手性方法已确定准双轴反式-5,6-和反式-8,9-二氢二醇的主要对映体具有R,R绝对立体化学结构。通过与苯并[a]蒽3R,4R-和10R,11R-二氢二醇的圆二色光谱进行比较，还发现准双平伏键7-FBA反式-3,4-和反式-10,11-二氢二醇的主要对映体具有R,R绝对构型。从7-FBA与未处理的以及经3-甲基胆蒽、苯巴比妥和多氯联苯处理的雄性斯普拉格-道利大鼠制备的肝微粒体孵育中获得的所有四种7-FBA反式二氢二醇代谢物均富含R,R对映体，仅光学纯度有所不同。用苯巴比妥、3-甲基胆蒽和多氯联苯对大鼠进行预处理分别使7-FBA的代谢速率改变了0.47倍、1.14倍和1.70倍。用酶诱导剂对大鼠进行预处理也改变了所形成代谢物的定量分布。代谢物对鼠伤寒沙门氏菌TA 100的相对诱变活性为：7-FBA反式-3,4-二氢二醇大于7-FBA反式-10,11-二氢二醇大于7-甲基-苯并[a]蒽约等于7-FBA大于7-FBA反式-8,9-二氢二醇约等于7-甲基-苯并[a]蒽反式-10,11-二氢二醇大于7-FBA反式-5,6-二氢二醇约等于4-羟基-7-FBA。7-FBA反式-3,4-和反式-10,11-二氢二醇相对较高的诱变活性表明，7-FBA反式-3,4-二氢二醇1,2-环氧化物和7-FBA反式-10,11-二氢二醇8,9-环氧化物可能都是促成7-FBA致癌特性的主要代谢物。
