TY - JOUR T1 - Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 223 LP - 236 DO - 10.1124/dmd.117.078683 VL - 46 IS - 3 AU - Hugues de Boussac AU - Claire Gondeau AU - Philippe Briolotti AU - Cédric Duret AU - Fridolin Treindl AU - Michael Römer AU - Jean-Michel Fabre AU - Astrid Herrero AU - Jeanne Ramos AU - Patrick Maurel AU - Markus Templin AU - Sabine Gerbal-Chaloin AU - Martine Daujat-Chavanieu Y1 - 2018/03/01 UR - http://dmd.aspetjournals.org/content/46/3/223.abstract N2 - Growth factors have key roles in liver physiology and pathology, particularly by promoting cell proliferation and growth. Recently, it has been shown that in mouse hepatocytes, epidermal growth factor receptor (EGFR) plays a crucial role in the activation of the xenosensor constitutive androstane receptor (CAR) by the antiepileptic drug phenobarbital. Due to the species selectivity of CAR signaling, here we investigated epidermal growth factor (EGF) role in CAR signaling in primary human hepatocytes. Primary human hepatocytes were incubated with CITCO, a human CAR agonist, or with phenobarbital, an indirect CAR activator, in the presence or absence of EGF. CAR-dependent gene expression modulation and PXR involvement in these responses were assessed upon siRNA-based silencing of the genes that encode CAR and PXR. EGF significantly reduced CAR expression and prevented gene induction by CITCO and, to a lower extent, by phenobarbital. In the absence of EGF, phenobarbital and CITCO modulated the expression of 144 and 111 genes, respectively, in primary human hepatocytes. Among these genes, only 15 were regulated by CITCO and one by phenobarbital in a CAR-dependent manner. Conversely, in the presence of EGF, CITCO and phenobarbital modulated gene expression only in a CAR-independent and PXR-dependent manner. Overall, our findings suggest that in primary human hepatocytes, EGF suppresses specifically CAR signaling mainly through transcriptional regulation and drives the xenobiotic response toward a pregnane X receptor (PXR)-mediated mechanism. ER -