The K-region trans-8,9-diol does not significantly contribute as an intermediate in the metabolic activation of dibenzo[a,l]pyrene to DNA-binding metabolites by human cytochrome P450 1A1 or 1B1

Metabolic activation of the K-region trans-8,9-diol, of the highly carcinog enic hexacyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) by human cytochrome P-450 (P450) 1A1 and 1B1 was investigated in Chinese hamster V7 9 cell lines expressing human P450 1A1 or 1B1, P450 1A1 and 1B1 are the maj or P450s involved in metabolic activation of polycyclic aromatic hydrocarbo ns in human cells. The major DNA adducts formed by metabolism of DB[a,l]P i n cultures expressing P450 1A1 or 1B1 resulted mainly from the Ford region (-)-anti-DB[a,l]P-11,12-diol 13,14-epoxide [(-)-anti-DB[a,l]PDE] and, to a lesser extent, (+)-synDB[a,l]PDE. In V79 cells expressing human P450 1A1, h igh amounts of as yet unidentified highly polar DNA adducts are formed in a ddition to the DNA adducts derived from DB[a,l]RDEs. Human P450 1A1 has bee n found to metabolize DB[a,l]P on its K-region to the trans-8,9-diol, and i t has been proposed that the DNA binding of the parent compound in P450 1A1 -expressing tissues may he partially mediated by activation of the K-region trans-8,9-diol to form bis-diol epoxides, V79 cells expressing human P450 1A1 or 1B1 formed only low amounts of DNA adducts after treatment with high doses of the K-region trans-8,9-diol. None of the adducts formed were iden tical to the main adducts formed in the same cell lines by metabolic activa tion of DB[a,l]P or (-)-DB[a,l]P-trans-11,12-diol. These results demonstrat e that the K-region trans-g,9-diol does not significantly contribute to the genotoxicity of the very potent carcinogen DB[a,l]P in human cells or tiss ues expressing P450 1A1 or 1B1.