title: Hepatocellular organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are inhibited by silibinin.
abstract: Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na(+)-taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17β-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinin-induced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. katrin.wlcek@usz.ch
authors.forename: Katrin
authors.initials: K
authors.lastname: Wlcek
authors.forename: Fabienne
authors.initials: F
authors.lastname: Koller
authors.forename: Peter
authors.initials: P
authors.lastname: Ferenci
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004958:Estradiol / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D029363:Organic Anion Transporters, Sodium-Dependent / Q000502:physiology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D027981:Symporters / Q000502:physiology; D013656:Taurocholic Acid / Q000378:metabolism
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004958:Estradiol; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D000077385:Silybin; D012838:Silymarin; D027981:Symporters; D013656:Taurocholic Acid; C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; C071908:sodium-bile acid cotransporter