RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.078683
DO 10.1124/dmd.117.078683
A1 Hugues De Boussac
A1 Claire Gondeau
A1 Philippe Briolotti
A1 Cedric Duret
A1 Fridolin Treindl
A1 Michael Roemer
A1 Jean-Michel Fabre
A1 Astrid Herrero
A1 Jeanne Ramos
A1 Patrick Maurel
A1 Markus Templin
A1 Sabine Gerbal-Chaloin
A1 Martine Daujat-Chavanieu
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/12/21/dmd.117.078683.abstract
AB 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 towards a Pregnane X Receptor (PXR)-mediated mechanism.