Abstract

Liver microsomal metabolism of the weak carcinogen chrysene and the noncarcinogen phenanthrene are compared. In general, chrysene is a rather poor substrate whereas phenanthrene is a relatively good substrate for the cytochrome P-450-dependent monooxygenase system. With microsomes from 3-methylcholanthrene-treated rats, phenanthrene was metabolized at a rate of 7.6 nmoles/min/nmole of cytochrome P-450 as compared with a rate of only 1.5 with chrysene as substrate. Dihydrodiols were major metabolites for both substrates, accounting for 92%-96% of the metabolism of phenanthrene and 65%-76% of the metabolism of chrysene with microsomes from control and treated rats. The K-region 9,10-dihydrodiol is the major metabolite of phenanthrene, whereas the benzo-ring 1,2- and 3,4-dihydrodiols dominate the metabolism of chrysene from which very little K-region dihydrodiol was formed. For both hydrocarbons, microsomes from 3-methylcholanthrene-treated rats produced the (-)-[1R,2R]-dihydrodiol, which has a bay-region double bond, with ≥80% enantiomeric purity. With microsomes from phenobarbital-treated rats, the chrysene 1,2-dihydrodiol was only 10% enantiomerically pure. The (-)-[3R,4R]-dihydrodiols were the major enantiomers of phenanthrene and chrysene, whereas the (-)-[9S,1OS]-dihydriol predominated at the K-region of phenanthrene. Metabolism of the metabolically formed (-)-[1R,2R]-dihydrodiols of phenanthrene and chrysene by microsomes from 3-methylcholanthrene-treated rats resulted in the predominant formation in each case of a bay-region 1,2-diol-3,4-epoxide in which the benzylic hydroxyl group and oxirane oxygen are trans to each other (isomer-2). The respective 1,2-dihydrodiols were metabolized at the same rate as was chrysene. Thus, as had previously been observed for the metabolism of benzo[a]pyrene and benzo[a]anthracene, liver microsomal enzymes display high stereoselectivity in their formation of predominantly one of four possible stereoisomers of their respective bay-region diol epoxides. These diol epoxides from the four hydrocarbons are superimposable when their bay-regions are aligned.