In Vitro Metabolism of Dibenzo[a,l]pyrene, 2-Chlorodibenzo [a,l]pyrene and 10-Chlorodibenzo[a,l]pyrene - Effects of Chloro Substitution

Stereoselective metabolism of dibenzo[a,l]pyrene (DB[a,l]P), 2chlorodibenzo[a,l]pyrene (2-Cl-DB[a,l]P) and 10-chlorodibenzo[a,l]pyrene (10-ClDB[a,l]P) by rat liver microsomes was studied and effects of the chloro substituent on the metabolism were determined. All three compounds produced trans-8,9-dihydrodiol, trans11,12-dihydrodiol, and the 7-hydroxyl derivative as major metabolic products and several other phenolic derivatives as minor metabolites. The trans-8,9and 11,12-dihydrodiols of DB[a,l]P and 2-Cl-DB[a,l]P preferentially adopted a quasidiequatorial conformation, whereas 10-Cl-DB[a,l]P trans-8,9and 11,12-dihydrodiols preferentially adopted a quasidiaxial conformation. The yields of the trans-11,12-dihydrodiol metabolites are: DB[a,l]P trans-11,12-dihydrodiol > 2-Cl-DB[a,l]P trans-11,12-dihydrodiol >> 10-ClDB[a,l]P trans-11,12-dihydrodiol. Circular dichroism (CD) spectral analysis indicates that the trans-8,9-dihydrodiol and trans-11,12-dihydrodiol metabolites from DB[a,l]P, 2-ClDB[a,l]P, and 10-Cl-DB[a,l]P are optically active. Furthermore, the major enantiomeric DB[a,l]P trans-11,12-dihydrodiol and 2-Cl-DB[a,l]P trans-11,12-dihydrodiol had R,R absolute configuration. Based on the fact that DB[a,l]P trans-11,12-dihydrodiol is the proximate tumorigenic metabolite of DB[a,l]P, our results suggest that DB[a,l]P exhibits the highest tumorigenic potency followed by 2-Cl-DB[a,l]P, and 10-Cl-DB[a,l]P exhibits the lowest tumorigenicity.