title: Protein kinase C-dependent regulation of human hepatic drug transporter expression.
abstract: Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-β1 or the HNF4α inhibitor BI6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Mayati
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Moreau
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Bucher
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital, 8091 Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Denizot
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire, 2 Rue Henri Le Guilloux, 35033 Rennes, France. Electronic address: olivier.fardel@univ-rennes1.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D000328:Adult; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology
chemical_list: D026901:Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C
keywords: Drug transporter; Hepatocyte; Phorbol ester; Protein kinase C; Regulation