title: Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes.
abstract: Sinusoidal and canalicular hepatic drug transporters constitute key factors involved in drug elimination from liver. Regulation of their expression via activation of xenosensors, such as aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and nuclear factor E2-related factor 2 (Nrf2), remains incompletely characterized. The present study was therefore designed to carefully analyze expression of major drug transporters in primary human hepatocytes exposed to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) (an AhR activator), rifampicin (RIF) (a PXR activator), phenobarbital (PB) (a CAR activator), and oltipraz (OPZ) (a Nrf2 activator), using mainly reverse transcription-real time polymerase chain reaction assays. With a threshold corresponding to a 1.5-fold factor change in mRNA levels, observed in at least three of seven independent human hepatocyte cultures, efflux transporters such as MDR1, MRP2 and BCRP were up-regulated by PB, RIF, and OPZ, whereas MRP3 was induced by OPZ and RIF. MDR1 and BCRP expression was also increased by TCDD- and RIF-augmented mRNA levels of the influx transporter OATP-C. Bile acid transporters, i.e., bile salt export pump and Na(+)-taurocholate cotransporting polypeptide, and the sinusoidal transporter, OAT2, were down-regulated by all the tested chemicals. Influx transporters such as OCT1, OATP-B, and OATP8 were repressed by PB and TCDD. PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively. Taken together, these data establish a complex pattern of transporter regulation by xenobiotics in human hepatocytes, in addition to interindividual variability in responsiveness. This may deserve further attention with respect to drug-drug interactions and adverse effects of hepatic drugs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Faculté de Pharmacie, Rennes, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jigorel
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.forename: Claire
authors.initials: C
authors.lastname: Boursier-Neyret
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012293:Rifampin / Q000494:pharmacology; D027981:Symporters / Q000235:genetics; D013871:Thiones; D013876:Thiophenes; D014157:Transcription Factors / Q000235:genetics; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000090702:Constitutive Androstane Receptor; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D009363:Neoplasm Proteins; D010634:Phenobarbital; D000072317:Polychlorinated Dibenzodioxins; D000077297:Pregnane X Receptor; D011719:Pyrazines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011955:Receptors, Drug; D011987:Receptors, Steroid; D012293:Rifampin; D027981:Symporters; D013871:Thiones; D013876:Thiophenes; D014157:Transcription Factors; D015262:Xenobiotics; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C026209:oltipraz