title: Regulation of drug transporter expression by oncostatin M in human hepatocytes.
abstract: The cytokine oncostatin M (OSM) is a member of the interleukin (IL)-6 family, known to down-regulate expression of drug metabolizing cytochromes P-450 in human hepatocytes. The present study was designed to determine whether OSM may also impair expression of sinusoidal and canalicular drug transporters, which constitute important determinants of drug hepatic clearance. Exposure of primary human hepatocytes to OSM down-regulated mRNA levels of major sinusoidal solute carrier (SLC) influx transporters, including sodium-taurocholate co-transporting polypeptide (NTCP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter 1 and organic anion transporter 2. OSM also repressed mRNA expressions of ATP binding cassette (ABC) efflux transporters such as multidrug resistance protein (MRP) 2/ABCC2 and breast cancer resistance protein/ABCG2, without however impairing those of multidrug resistance gene 1/P-glycoprotein/ABCB1, MRP3/ABCC3, MRP4/ABCC4 and bile salt export pump/ABCB11. The cytokine concomitantly reduced NTCP, OATP1B1, OATP2B1 and ABCG2 protein expression and NTCP and OATP transport activities. OSM effects towards transporters were found to be dose-dependent and highly correlated with those of IL-6, but not with those of other inflammatory cytokines such as tumor necrosis factor-α or interferon-γ. In addition, OSM-mediated repression of some transporters such as NTCP, OATP1B1 and OATP2B1, was counteracted by knocking-down expression of the type II OSM receptor subunits through siRNA transfection. This OSM-mediated down-regulation of drug SLC transporters and ABCG2 in human hepatocytes may contribute to alterations of pharmacokinetics in patients suffering from diseases associated with increased production of OSM.
authors.affiliation: EA 4427 SeRAIC, Institut de Recherches Santé, Environnement et Travail, Université de Rennes 1, Département HITC, Hôpital Pontchaillou, CHU, 2 Avenue du Pr L. Bernard, 35043 Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Valérie
authors.initials: V
authors.lastname: Lecureur
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D053683:Oncostatin M / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D013997:Time Factors
chemical_list: C000715087:ABCC2 protein, human; D002352:Carrier Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053683:Oncostatin M; D002097:C-Reactive Protein