DNA Modification Induced After Metabolic Activation of the Potent Carcinogen Dibenzo[a, l]pyrene in V79 Chinese Hamster Cells Stably Expressing Single Cytochromes P450

Abstract

The polycyclic aromatic hydrocarbon (PAH) dibenzo[a, l]pyrene (DB[a, l]P) has been found to be an environmental pollutant and, considering the available data from rodent bioassays, it represents the most carcinogenic member compound of the class of PAH yet discovered. To sort out the contribution of individual cytochromes P450 (P450) in the metabolic activation of this PAH, V79 cells stably expressing a single P450 isoform were treated with DB[a, l]P or enantiomeric DB[a, l]P-11,12-dihydrodiols (diols). Subsequent analysis of the DNA adducts formed revealed substantial differences in the adduct pattern and the total DNA binding depending on the cell line used. Human P450 1B1 effectively activated 0.1 μM DB[a, l]P (350 pmol adducts/mg DNA) and 0.05 μM (-)-(R,R)-diol (1010 pmol/mg DNA). Human P450 1A1 and rat P450 1A1 were less effective than human 1B1 in activating 0.1 μM DB[a, l]P (27 and 28 pmol/mg DNA, respectively), but significantly more active than human 3A4, human 2A6, and rat 1A2 (0.1, 0.2, and 17 pmol adducts/mg DNA after treatment with 1.0 μM PAH, respectively). Although the activation of the (+)-(S,S)-diol was low in all cases, it could be responsible for a substantial fraction of total DNA binding with P450 isoforms that had only a limited ability to activate DB[a, l]P (e.g. human 2A6, rat 1A2, or rat 2B1).