Stereoselective metabolism of dibenz[a,h]acridine to bay-region diol epoxides by rat liver microsomes.

The carcinogen dibenz[a,h]acridine (DB[a,h]ACR is metabolized predominantly to trans-3,4-dihydroxy-3,4-dihydro-dibenz[a,h]acridine (DB[a,h]ACR-3,4-diol) and the proximate carcinogen trans-10,11-dihydroxy-10,11-dihydrodibenz[a,h]acridine (DB[a,h]ACR-10,11-diol) [Steward et al. (1987) Carcinogenesis, 8, 1043-1050]. In the present investigation, the stereoselectivity of rat liver enzymes in metabolism of DB[a,h]ACR to its 3,4-diol and 10,11-diol and of DB[a,h]ACR-10,11-diol enantiomers to their bay-region diol epoxides has been examined with liver microsomes from control and 3-methylcholanthrene-treated rats. Both microsomal preparations produced the major metabolites DB[a,h]ACR-3,4-diol and DB[a,h]ACR-10,11-diol containing predominantly R,R-enantiomers with 38-54% optical purity. Metabolism of (-)-(10R,11R)- and (+)-(10S,11S)-enantiomers of DB[a,h]ACR-10,11-diol by liver microsomes from control rats produced predominantly bay-region diol epoxides (46-59% of total metabolites), whereas very little bay-region diol epoxides (14-17% of total metabolites) were produced by liver microsomes from 3-methylcholanthrene-treated rats. The bay-region diol epoxides produced in these studies consisted of predominantly DB[a,h]ACR-10,11-trans-diol epoxide diastereomer in which the benzylic hydroxyl group and epoxide oxygen are trans. However, (-)-DB[a,h]ACR-10R,11R-diol, a major metabolite of DB[a,h]ACR, was metabolized by liver microsomes from 3-methylcholanthrene-treated rats to (+)-[8R,9S,10S,11R]-DB[a,h]ACR-10,11-trans-diol epoxide, a diastereomer which displayed high mutagenic activity in V79 cells, in an amount which was 6.5-fold greater than that of the corresponding cis-diol epoxide diastereomer. The relative amounts of trans-diol epoxide versus cis-diol epoxide in the mixture of bay-region diol epoxides produced from DB[a,h]ACR-10R,11R-diol and DB[a,h]ACR-10S,11R-diol with liver microsomes from control rats and from DB[a,h]ACR-10S,11S-diol with liver microsomes from 3-methylcholanthrene-treated rats were 1.7, 2.1 and 2.3 respectively.