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]anthracene (7-Br-BA) to form predominantly trans-3,4-, 5,6-, 8,9-, and 10,11-dihydrodiols. The dihydrodiol metabolites were isolated by reversed-phase h.p.l.c. for structural and conformational analyses. N.m.r. spectral analysis indicated that the 3,4- and 10,11-dihydrodiols preferentially adopted quasidiequatorial conformations whereas the 5,6- and 8,9-dihydrodiols (which have a 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 that the major enantiomeric 7-Br-BA-3,4- and 10,11-dihydrodiol metabolites have R,R absolute sterochemistry. The absolute conformation of 7-Br-BA-5,6- and -8,9-dihydrodiol metabolites could not be deduced by comparing their c.d. spectra with those of BA 5R,6R- and 8R,9R-dihydrodiols. Catalytic hydrogenolysis converted the enzymatically formed 7-Br-BA trans-5,6-dihydrodiol to BA trans-5,6-dihydrodiol which had a c.d. spectrum identical to that of BA 5R,6R-dihydrodiol. Catalytic hydrogenolysis and hydrogenation converted the enzymatically formed 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-diol on a chiral h.p.l.c. column. These results indicate that the major enantiomers of trans-dihydrodiol metabolites formed in rat liver microsomal metabolism of 7-Br-BA all have R,R absolute stereo-chemistries.
D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002942:Circular Dichroism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D001551:Benz(a)Anthracenes; C038901:7-bromobenzanthracene