Stereoselectivity of cytochrome P-450 isozymes and epoxide hydrolase in the metabolism of polycyclic aromatic hydrocarbons.

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.