Yang S K
Department of Pharmacology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
Biochem Pharmacol. 1988 Jan 1;37(1):61-70. doi: 10.1016/0006-2952(88)90755-1.
Enantiomeric compositions of epoxides formed in the metabolism of planar benz[a]anthracene (BA), benzo[a]pyrene (BaP), and chrysene (CR), and nonplanar benzo[c]phenanthrene (BcPh), 12-methylbenz[a]anthracene (12-MBA) and 7,12-dimethylbenz[a]anthracene (7,12-DMBA) by liver microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats are determined either by direct chiral stationary phase HPLC analysis or by the enantiomeric compositions of metabolically formed trans-dihydrodiols. Cytochrome P-450 isozymes contained in various liver microsomal preparations have varying degrees of stereoselectivity in catalyzing the epoxidation reactions at various formal double bonds of the polycyclic aromatic hydrocarbons studied. In general, cytochrome P-450c, the major cytochrome P-450 isozyme contained in liver microsomes from 3-methylcholanthrene-treated rats, has the highest degree of stereoselectivity. Regardless of absolute configuration, non-K-region epoxides are converted to trans-dihydrodiols by epoxide hydrolase-catalyzed water attack at the allylic carbon. The S-center of K-region S,R-epoxide enantiomers derived from planar BA, BaP and CR is the major site of epoxide hydrolase-catalyzed water attack. In contrast, the R-center of K-region S,R-epoxide enantiomers derived from nonplanar BcPh, 12-MBA and 7,12-DMBA is the major site of epoxide hydrolase-catalyzed water attack. However, the K-region R,S-epoxide enantiomers of the six polycyclic aromatic hydrocarbons studied are hydrated by microsomal epoxide hydrolase with varying degrees of regioselectivity. Thus the enantiomeric composition of a metabolically formed dihydrodiol is determined by (i) the stereoselective epoxidation at a formal double bond of a parent hydrocarbon by microsomal cytochrome P-450 isozymes and (ii) the enantioselective and regioselective hydration of the metabolically formed epoxide by microsomal epoxide hydrolase.
通过直接手性固定相高效液相色谱分析或代谢形成的反式二氢二醇的对映体组成，测定了未经处理、经苯巴比妥处理和经3-甲基胆蒽处理的大鼠肝脏微粒体对平面苯并[a]蒽（BA）、苯并[a]芘（BaP）和屈（CR）以及非平面苯并[c]菲（BcPh）、12-甲基苯并[a]蒽（12-MBA）和7,12-二甲基苯并[a]蒽（7,12-DMBA）进行代谢时形成的环氧化物的对映体组成。各种肝脏微粒体制剂中所含的细胞色素P-450同工酶在催化所研究的多环芳烃各个形式双键的环氧化反应时具有不同程度的立体选择性。一般来说，细胞色素P-450c是经3-甲基胆蒽处理的大鼠肝脏微粒体中所含的主要细胞色素P-450同工酶，其立体选择性程度最高。无论绝对构型如何，非K区域环氧化物通过环氧化物水解酶催化水进攻烯丙基碳而转化为反式二氢二醇。源自平面BA、BaP和CR的K区域S,R-环氧化物对映体的S中心是环氧化物水解酶催化水进攻的主要位点。相反，源自非平面BcPh、12-MBA和7,12-DMBA的K区域S,R-环氧化物对映体的R中心是环氧化物水解酶催化水进攻的主要位点。然而，所研究的六种多环芳烃的K区域R,S-环氧化物对映体被微粒体环氧化物水解酶以不同程度的区域选择性进行水合作用。因此，代谢形成的二氢二醇的对映体组成由以下因素决定：（i）微粒体细胞色素P-450同工酶对母体烃形式双键的立体选择性环氧化作用，以及（ii）微粒体环氧化物水解酶对代谢形成的环氧化物的对映选择性和区域选择性水合作用。
