title: Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation.
abstract: Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to induce drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor. Available data suggest rifampin entry into hepatocytes may be transporter-mediated. Accordingly, it is therefore plausible that modulation of the achievable intracellular concentration of rifampin by drug uptake transporters would influence the degree of induction. In this study, we expressed an array of known hepatic uptake transporters to show the key hepatic rifampin uptake transporters are liver-specific members of the organic anion transporting polypeptide family (OATP). Indeed, both OATP-C and OATP8 seemed capable of mediating rifampin uptake into HeLa cells. OATP-C, however, seemed to have far greater affinity and capacity for rifampin transport. In addition, several allelic variants of OATP-C known to be present among European and African Americans were found to have markedly decreased rifampin transport activity. In cell-based, transactivation assays, OATP-C expression was associated with increased cellular rifampin retention as well as potentiation of PXR reporter gene activity. This is the first demonstration of an uptake transporter such as OATP-C, in modulating PXR function, and sheds important new insight into our understanding of the molecular determinants of PXR-mediated inductive processes.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Leake
authors.forename: Allan W
authors.initials: AW
authors.lastname: Wolkoff
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000096:biosynthesis / Q000378:metabolism*; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology*; D027981:Symporters; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D000904:Antibiotics, Antitubercular; D002352:Carrier Proteins; D018076:DNA, Complementary; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027702:Organic Cation Transporter 1; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D027981:Symporters; C071908:sodium-bile acid cotransporter; D004958:Estradiol; C017199:2',3'-dialdehyde ATP; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin