Stereoselective metabolism of 7-bromobenz [a]anthracene by rat liver microsomes: absolute configurations of trans-dihydrodiol metabolites

Rat liver microsomes metabolized the weak carcinogen 7-bromobenz[a](7-Br-BA) to form predominantly trans-3,4-, 5,6-, 8,9-, and10,11-dihydrodiols. The dihydrodiol metabolites were isolatedby reversed-phase h.p.l.c. for structural and conformationalanalyses. N.m.r. spectral analysis indicated that the 3,4- and10,11-dihydrodiols preferentially adopted quasidiequatorialconformations whereas the 5,6- and 8,9-dihydrodiols (which havea peri bromo substituent) preferred quasidiaxial conformations.Comparison of c.d. spectra with those of quasidiequatorial benz[a]anthracene(BA) 3R,4R-dihydrodiol and 10R,11R-dihydrodiol indicated thatthe major enantiomeric 7-Br-BA- 3,4- and 10,11-dihydrodiol metaboliteshave R,R absolute stereochemistry. The absolute conformationof 7-Br-BA-5,6-and -8,9-dihydrodiol metabolites could not bededuced by comparing their c.d. spectra with those of BA 5R,6R-and 8R,9R-dihydrodiols. Catalytic hydrogenolysis converted theenzymalically formed 7-Br-BA trans-5,6-dihydrodiol to BA trans-5,6-dihydrodiolwhich had a c.d. spectrum identical to that of BA 5R,6R-dihydrodiol.Catalytic hydrogenolysis and hydrogenation converted the enzymaticallyformed 7-Br-BA trans-8,9-dihydrodiol to a BA 8,9,10,11-tetrahydro-trans-8,9-diol which had a retention time identical to that of BA 8,9,10,11-tetrahydro-8R,9R-diolon a chiral h.p.l.c. column. These results indicate that themajor enantiomers of trans-dihydrodiol metabolites formed inrat liver microsomal metabolism of 7-Br-BA all have R,R absolutestereochemistries.