Stereoselective metabolism of 9-methyl-, 9-hydroxymethyl- and 9,10-dimethylanthracenes: absolute configurations and optical purities of trans-dihydrodiol metabolites.

Abstract

Stereoselective metabolism of 9-methylanthracene (9-M-A), 9-hydroxymethylanthracene (9-OHM-A) and 9,10-dimethylanthracene (9,10-DM-A) by liver microsomes from untreated rats, and from rats pretreated with either 3-methylcholanthrene or phenobarbital was studied. The metabolites were separated by h.p.l.c. and characterized by analysis of the u.v.-visible, mass and n.m.r. spectral data and compared to published spectral data. The identified trans-dihydrodiol metabolites were 9-M-A trans-1,2- and 3,4-dihydrodiols, 9-OHM-A trans-1,2- and 3,4-dihydrodiols, and 9,10-DM-A trans-1,2-dihydrodiol. The absolute configuration and optical (enantiomeric) purity of the trans-dihydrodiol metabolites were determined. In order to assist in determining the absolute configuration of these trans-dihydrodiols, metabolism of 9-bromoanthracene by liver microsomes of rats pretreated with 3-methylcholanthrene was performed and its trans-1,2- and 3,4-dihydrodiol metabolites were determined to both possess an R,R absolute configuration. Absolute configurations of the trans-dihydrodiol metabolites of 9-methylanthracene, 9-hydroxymethylanthracene and 9,10-dimethylanthracene were then determined by comparison of their CD spectra with those of anthracene 1R,2R-dihydrodiol or 9-bromoanthracene 1R,2R-dihydrodiol. The optical purities of the trans-dihydrodiol metabolites were determined by analysis of the chiral stationary phase h.p.l.c. profiles of the dihydrodiols or their corresponding tetrahydrodiol derivatives. The results indicated that the R,R enantiomers were the predominant products and that liver microsomes of rats pretreated with 3-methylcholanthrene exhibited much higher stereoselectivity than the liver microsomes of untreated rats or rats pretreated with phenobarbital in the formation of trans-dihydrodiols from anthracene, 9-methylanthracene, 9-hydroxymethylanthracene and 9,10-dimethylanthracene. The methyl and hydroxymethyl substituents slightly decreased the stereoselectivity of the trans-dihydrodiol formation.