ArticleDrug metabolism and disposition: the biological fate of chemicals2014
The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 71 citations in OpenAlex.
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- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- Advances in drug-induced liver injury research: in vitro models, mechanisms, omics and gene modulation techniques.Cell & bioscience · 2024Review
- Hepatic Bile Acid Transporters and Drug-induced Hepatotoxicity.Toxicologic pathology · 2023Review
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- Polygoni Multiflori Radix interferes with bile acid metabolism homeostasis by inhibitingFrontiers in pharmacology · 2023Article
- Role of Hepatocyte Transporters in Drug-Induced Liver Injury (DILI)-In Vitro Testing.Pharmaceutics · 2022Review
- Construction of a culture protocol for functional bile canaliculi formation to apply human iPS cell-derived hepatocytes for cholestasis evaluation.Scientific reports · 2022Article
- Mouse precision-cut liver slices as an ex vivo model to study drug-induced cholestasis.Archives of toxicology · 2022Article
- Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction.Acta pharmaceutica Sinica. B · 2021Review
- Analytical and Omics-Based Advances in the Study of Drug-Induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2021Review
- The association of transporter ABCC2 (MRP2) genetic variation and drug-induced hyperbilirubinemia.Journal of the Chinese Medical Association : JCMA · 2021Article
- The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies.International journal of molecular sciences · 2021Review
- COVID-19: Therapeutics and Their Toxicities.Journal of medical toxicology : official journal of the American College of Medical Toxicology · 2020Review
- Metformin Disrupts Bile Acid Efflux by Repressing Bile Salt Export Pump Expression.Pharmaceutical research · 2020Article
- A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis.Current drug metabolism · 2019Review
- Update on FXR Biology: Promising Therapeutic Target?International journal of molecular sciences · 2018Review
- Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures.Archives of toxicology · 2018Article
- Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis.Drug design, development and therapy · 2018Article
- Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach.Archives of toxicology · 2017Article
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6 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.