Stereoselective metabolism of the (+)- and (-)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene by rat liver microsomes and by a purified and reconstituted cytochrome P-450 system.

Metabolism of the (+)-(3S,4S)and (-)-(3R,4R)-enantiomers of trnns-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene has been examined with liver microsomes from control rats, as well as rats treated with 3-methylcholanthrene or phenobarbital and by a highly purified and reconstituted system containing cytochrome P-450, and epoxide hydrolase. In contrast to the metabolism of the related (-)-benzo[a]pyrene 7,8-, (-)-phenanthrene 1,2-, and (-)-chrysene 1,2-dihydrodiols from which >65% of the total metabolites constitute bayregion diol epoxides, very little ( 4 6 % of total metabolites) formation of bay-region diol epoxides was detected from (-)-benzanthracene 3,4-dihydrodiol. For benz[a]anthracene, the (-)-(3R,4R)-enantiomer formed predominantly the (+)-3,4-diol-1,2-epoxide-2 diastereomer in which the benzylic hydroxyl group and epoxide oxygen are trans, the diastereomer which displays high tumorigenic activity. Studies on the (+)-(3S,4S)enantiomer failed to provide evidence for the formation of bay-region diol epoxides and thus provide the first example where liver microsomes form very little, if any, diol epoxide from a dihydrodiol whose hydroxyl groups are predominantly pseudodiequatorial. Major metabolites of both enantiomers consisted of bis-dihydrodiols formed via the action of epoxide hydrolase on dihydrodiol-arene oxide precursors. A novel microsomal metabolite, benz[a]anthracene 3,4-quinone, was also identified. Antibody experiments established that the quinone is formed predominantly by the NADPHsupported cytochrome P-450-dependent monooxygenase system in liver microsomes from 3-methylcholanthrene-treated rats, presumably via a mechanism involving molecular oxygen. In addition, evidence for an NAD-supported pathway which does not involve cytochrome P-450, was also detected.