RT Journal Article
SR Electronic
T1 The WNT/β-catenin Pathway is a Transcriptional Regulator of CYP2E1, CYP1A2 and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.094797
DO 10.1124/mol.114.094797
A1 Sabine Gerbal-Chaloin
A1 Anne-Sophie Dume
A1 Philippe Briolotti
A1 Sylvie Klieber
A1 Edith Raulet
A1 Cedric Duret
A1 Jean-Michel Fabre
A1 Jeanne Ramos
A1 Patrick Maurel
A1 Martine Daujat-Chavanieu
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/09/16/mol.114.094797.abstract
AB The WNT/β-catenin/Adenomatous polyposis coli (CTNNB1/APC) pathway has been identified as a regulator of drug-metabolizing enzymes in rodent liver. Conversely, little is known about the role of this pathway in drug metabolism regulation in human liver. Primary human hepatocytes (PHHs) that are the most physiologically relevant culture system to study drug metabolism in vitro were used to investigate this issue. Therefore, the aim of this study was to assess the link between CYP expression and WNT/β-catenin pathway activity in PHHs by modulating its activity with recombinant mouse Wnt3a (the canonical activator), inhibitors of glycogen synthase kinase 3β, siRNAs to invalidate CTNNB1 or its repressor APC, used separately or in combination. We found that the WNT/β-catenin pathway can be activated in PHHs, as assessed by universal β-catenin target gene expression, leucine-rich repeat containing G protein-coupled receptor 5. Moreover, WNT/β-catenin pathway activation induces the expression of CYP2E1, CYP1A2 and aryl hydrocarbon receptor, but not of CYP3A4, hepatocyte nuclear factor-4α (HNF4α) and pregnane X receptor (PXR) in PHHs. Specifically, we show for the first time that CYP2E1 is transcriptionally regulated by the WNT/β-catenin pathway. Moreover, CYP2E1 induction was accompanied by an increase of its metabolic activity, as indicated by the increased production of 6-OH-chlorzoxazone and by glutathione depletion following incubation with high doses of acetaminophen. In conclusion, the WNT/β-catenin pathway is functional in PHHs and its induction in PHHs represents a powerful tool to evaluate hepatotoxicity of drugs that are metabolized by CYP2E1.