Metabolic activation of dibenzo[A,L]pyrene by cytochrome P450 enzymes to stable DNA adducts occurs exclusively through the formation of the (-)-trans-(11R,12R)-Diol

At low doses, the carcinogenic hexacyclic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) forms DNA adducts in human MCF-7 cells exclusively through formation of the (-)-anti-(11R,12S)-diol (13S,14R)-epoxide (DB[a,l]PDE) via its metabolic precursor, the (-)-(11R,12R)-diol. The same result was obtained by exposure of V79 cells stably expressing human cytochrome P450 (P450) 1B1. Although several other metabolites such as the 7-phenol and a 11,12-diol phenol are formed, no other DNA adducts are detectable after exposure to 0.1 μM DB[a,l]P. Exposure to 1 μM DB[a,l]P leads to the formation of low levels of (+)-syn-DB[a,l]P-DE-DNA adducts through intermediate generation of the (+)-(11S,12S)-diol. In contrast, treatment of P450 1A1-expressing V79 cells results also in the formation of several polar DNA adducts. Incubation of the trans8,9-diol and trans-11,12-enantiomers of DB[a,l]P demonstrated that all polar DNA adducts detected in 1A1-expressing cells resulted from intermediate formation of the (-)-trans-11,12-diol. Although the K-region trans-8,9-diol is metabolically converted to several diol phenols and bis-diols, this compound does not contribute to the strong DNA binding or cytotoxicity observed after exposure of P450 1A1- and 1B1-expressing cells to the parent hydrocarbon.