Stereoselective metabolism of 7-methylbenz[ a]anthracene: Absolute configuration of five dihydrodiol metabolites and the effect of dihydrodiol conformation on circular dichroism spectra

Abstract

7-Methylbenz[ a]anthracene (7-MBA) was metabolized stereoselectively by rat liver microsomes to form five optically active dihydrodiols as the predominant metabolites. The dihydrodiols were purified by a combination of reversed-phase and normal-phase high performance liquid chromatography (HPLC). By comparison of their circular dichroism (CD) spectra with the corresponding benz[ a]anthracene (BA) dihydrodiols of known absolute stereochemistry, the major dihydrodiol enantiomers of 7-MBA have been determined to have 1 R,2 R-, 3 R,4 R- and 10 R,11 R- absolute configurations, respectively. Due to their quasi-diaxial conformations, the absolute configuration of trans-5,6- and trans-8,9-dihydrodiols, the two most abundant metabolites of 7-MBA, could not be determined by simple comparisons of their circular dichroism spectra with those of the quasidiequatorial BA 5 R,6 R- and 8 R,9 R-dihydrodiols. The major enantiomers of the quasi-diaxial trans-5,6- and trans-8,9-dihydrodiol metabolites of 7-MBA were determined by comparison to the CD spectrum of 7-bromo-BA 5 R,6 R-dihydrodiol and by the exciton chirality method to have R, R absolute stereochemistry. This study also revealed that the circular dichroism Cotton effects of an enantiomeric dihydrodiol of polycyclic aromatic hydrocarbons can be drastically altered if the conformation (quasi-diaxial vs. quasi-diequatorial) of the dihydrodiol is changed.