Inhibition of aryl hydrocarbon receptor transactivation and DNA adduct formation by CYP1 isoform-selective metabolic deactivation of benzo[a]pyrene

Benzo[a]pyrene (BaP), a polyaromatic hydrocarbon produced by the combustion of cigarettes and coke ovens, is a known procarcinogen. BaP? activates the aryl hydrocarbon receptor (AhR) and induces the expression of a battery of genes, including CYP1A1, which metabolize BaP to toxic compounds. The possible role of CYP1 enzymes in mediating BaP detoxification or metabolic activation remains to be elucidated. In this study, we assessed the effects of CYP1 enzymes (CYP1A1, CYP1A2 and CYP1B1) on BaP-induced AhR transactivation and DNA adduct formation in HEK293 cells and HepG2 cells. Transfection of CYP1A1 and CYP 1B1, but not CYP1A2, suppressed BaP-induced activation of AhR. Expression of CYP1A1 and CYP1A2, but not CYP1B1, inhibited DNA adduct formation in BaP-treated HepG2 cells. These results indicate that CYP1A1 and CYP1B1 play a role in deactivation of BaP on AhR and that CYPIAI and CYP1A2 are involved in BaP detoxification by suppressing DNA adduct formation. Bal' treatment did not induce DNA adduct formation in HEK293 cells, even after transfection of CYPI enzymes, suggesting that expression of CYPI enzymes is not sufficient for DNA adduct formation. Lower expression of epoxide hydrolase and higher expression of glutathione S-transferase P1 (GSTPI) and GSTMI/M2 were observed in HEK293 cells compared with HepG2 cells. Dynamic expression of CYPIAI, CYPIA2 and CYPI131 along with expression of other enzymes such as epoxide hydrolase and phase 11 enzymes may determine the detoxification or metabolic activation of BaP. (c) 2008 Elsevier Inc. All rights reserved.