title: The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity.
abstract: The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of BSEP transcription would contribute to drug-induced cholestasis is largely unknown. In this study, we selected 30 drugs previously reported as BSEP inhibitors to evaluate their effects on BSEP expression, farnesoid X receptor (FXR) activation, and correlations to clinically reported liver toxicity. Our results indicate that of the 30 BSEP inhibitors, five exhibited potent repression of BSEP expression (≥60% repression), ten were moderate repressors (20-60% repression), whereas others had negligible effects (≤20% repression). Of importance, two drugs (troglitazone and benzbromarone), previously withdrawn from the market because of liver injury, are among the potent repressors. Further investigation of the five potent repressors revealed that transcriptional repression of BSEP by lopinavir and troglitazone may occur through their interaction with FXR, whereas others are via FXR-independent yet unidentified pathways. Our data suggest that in addition to functional inhibition, repression of BSEP expression may play an important role in drug-induced cholestatic liver toxicity. Thus, a combination of the two would reveal a more accurate prediction of drug-induced cholestasis than does either repression or inhibition alone.
authors: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore Maryland (B.G., H.Y., J.E.P., H.W.) and Office of Clinical Pharmacology, Office of Translational Sciences, CDER, Food and Drug Administration, Silver Spring, Maryland (L.Z., S.H.).
authors: Brandy
authors: B
authors: Garzel
authors: Hui
authors: H
authors: Yang
authors: Lei
authors: L
authors: Zhang
authors: Shiew-Mei
authors: SM
authors: Huang
authors: James E
authors: JE
authors: Polli
authors: Hongbing
authors: H
authors: Wang
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000235:genetics*; D002779:Cholestasis / Q000209:etiology / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000032:analysis; D011237:Predictive Value of Tests; D061251:Primary Cell Culture; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human