PPARα activation potentiates AhR-induced CYP1A1 expression

CYP1A1 is an extrahepatic enzyme largely involved in the bioactivation of various procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) and arylamines. CYP1A1 expression is mainly regulated by AhR. Our laboratory has recently shown a new CYP1A1 regulation pathway involving PPARα. The aim of this study was to evaluate, in a Caco-2 cell line, the effect of a coexposure to 3-methylcholanthrene (3MC, AhR ligand) and WY-14643 (WY, PPARα ligand) on CYP1A1 expression (enzymatic activity, mRNA level and promoter activity). An additive effect on CYP1A1 expression was shown in cells coexposed with 3MC (0.1 or 1 μM) and a low WY concentration (30 μM) whereas a potentiating effect was observed after coexposure with 3MC (0.1 or 1 μM) and a high WY concentration (200 μM). Furthermore, 200 μM WY, alone or with 3MC, was able to increase the AhR protein level (two-fold). In conclusion, coexposure with 3MC and the PPARα agonist WY leads to an additive or potentiating effect on CYP1A1 inducibility, depending on the WY concentration. Furthermore, at high concentration (200 μM), WY induced AhR expression, which could explain the potentiating effect on CYP1A1 inducibility observed after addition of an AhR ligand (3MC). This phenomenon should be taken into account for risk assessment involving CYP1A1 induction.