{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:34:20Z","timestamp":1791646460219,"version":"4.3.4"},"reference-count":108,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T00:00:00Z","timestamp":1679097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver\u2019s metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts\u2019 independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids\u2019 (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs\u2019 secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.<\/jats:p>","DOI":"10.3390\/ijms24065823","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T04:33:31Z","timestamp":1679286811000},"page":"5823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2603-8245","authenticated-orcid":false,"given":"Giovanni","family":"Vitale","sequence":"first","affiliation":[{"name":"Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0193-8944","authenticated-orcid":false,"given":"Alessandro","family":"Mattiaccio","sequence":"additional","affiliation":[{"name":"U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum\u2014University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5094-9092","authenticated-orcid":false,"given":"Amalia","family":"Conti","sequence":"additional","affiliation":[{"name":"U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Berardi","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Vero","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-3769","authenticated-orcid":false,"given":"Laura","family":"Turco","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2425-2176","authenticated-orcid":false,"given":"Marco","family":"Seri","sequence":"additional","affiliation":[{"name":"U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum\u2014University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9742-1981","authenticated-orcid":false,"given":"Maria Cristina","family":"Morelli","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"},{"name":"European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1002\/hep.23937","article-title":"Drug-induced acute liver failure: Results of a U.S. multi-center, prospective study","volume":"52","author":"Reuben","year":"2010","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Moreno-Torres, M., Quint\u00e1s, G., and Castell, J.V. (2022). The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment. Metabolites, 12.","DOI":"10.3390\/metabo12060564"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/0895-4356(93)90102-7","article-title":"Causality assessment of adverse reactions to drugs\u2013II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge","volume":"46","author":"Benichou","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/0895-4356(93)90101-6","article-title":"Causality assessment of adverse reactions to drugs\u2013I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"878","DOI":"10.14309\/ajg.0000000000001259","article-title":"Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury","volume":"116","author":"Chalasani","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2015). RUCAM in Drug and Herb Induced Liver Injury: The Update. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010014"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1053\/jhep.2002.34857","article-title":"Incidence of drug-induced hepatic injuries: A French population-based study","volume":"36","author":"Sgro","year":"2002","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/hep4.1088","article-title":"Drug-induced cholestasis","volume":"1","author":"Sundaram","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1002\/hep.26709","article-title":"Drug-Induced Liver Injury Network (DILIN). Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations","volume":"59","author":"Kleiner","year":"2014","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Berry, P., Kotha, S., Zen, Y., Papa, S., El Menabawey, T., Webster, G., Joshi, D., and Heneghan, M. (2022). Immune checkpoint inhibitor-related cholangiopathy: Novel clinicopathological de-scription of a multicentre cohort. Liver. Int., epub ahead of print.","DOI":"10.1111\/liv.15340"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1080\/14712598.2020.1762562","article-title":"Anti-programmed cell death-1 and anti-programmed cell death ligand-1 immune-related liver diseases: From clinical pivotal studies to real-life experience","volume":"20","author":"Vitale","year":"2020","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.jhep.2010.08.002","article-title":"Drug-induced liver injury: Is it time for genetics to change our clinical practice?","volume":"53","author":"Invernizzi","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0168-8278(97)82330-6","article-title":"Vanishing bile duct syndrome in drug-induced liver disease","volume":"26","author":"Desmet","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/hep.21359","article-title":"Hepatobiliary transporters and drug-induced cholestasis","volume":"44","author":"Meier","year":"2006","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.dld.2019.04.013","article-title":"Familial intrahepatic cholestasis: New and wide perspectives","volume":"51","author":"Vitale","year":"2019","journal-title":"Dig. Liver. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-0031-1272831","article-title":"Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: A review of the liver pathology findings","volume":"31","author":"Morotti","year":"2011","journal-title":"Semin. Liver. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.jhep.2017.07.004","article-title":"Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants","volume":"67","author":"Bonus","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1002\/hep4.2051","article-title":"Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1","volume":"6","author":"Nayagam","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1007\/s00535-017-1423-1","article-title":"Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing","volume":"53","author":"Vitale","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1111\/apt.16118","article-title":"Review article: Liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1","volume":"52","author":"Nayagam","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Vitale, G., Mattiaccio, A., Conti, A., Turco, L., Seri, M., Piscaglia, F., and Morelli, M.C. (2022). Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers, 14.","DOI":"10.3390\/cancers14143421"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.jhep.2020.04.036","article-title":"Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults","volume":"73","author":"Halilbasic","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1097\/01.fpc.0000236337.41799.b3","article-title":"MRP2 haplotypes confer differential susceptibility to toxic liver injury","volume":"17","author":"Choi","year":"2007","journal-title":"Pharmacogenetics Genom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1002\/1873-3468.14018","article-title":"ABCB1\/MDR1\/P-gp employs an ATP-dependent twist-and-squeeze mechanism to export hydrophobic drugs","volume":"595","author":"Kodan","year":"2021","journal-title":"FEBS Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/s41422-021-00611-9","article-title":"Structures of human bile acid exporter ABCB11 reveal a transport mechanism facilitated by two tandem substrate-binding pockets","volume":"32","author":"Wang","year":"2022","journal-title":"Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41594-019-0354-3","article-title":"Structure of the human lipid exporter ABCB4 in a lipid environment","volume":"27","author":"Olsen","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/JCMA.0000000000000470","article-title":"The association of transporter ABCC2 (MRP2) genetic variation and drug-induced hyperbilirubinemia","volume":"84","author":"Huang","year":"2021","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1365-2710.2003.00487.x","article-title":"Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors","volume":"28","author":"Wang","year":"2003","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev.pharmtox.39.1.361","article-title":"Biochemical, cellular, and pharmacological aspects of the multidrug transporter","volume":"39","author":"Ambudkar","year":"1999","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/978-3-642-14541-4_6","article-title":"P-glycoprotein: Tissue distribution, substrates, and functional consequences of genetic variations","volume":"201","author":"Cascorbi","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1086\/507097","article-title":"Adult AIDS Clinical Trials Group. Pharmacogenetics of nevirapine-associated hepatotoxicity: An Adult AIDS Clinical Trials Group collaboration","volume":"43","author":"Haas","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1086\/507101","article-title":"Drug transporter and metabolizing enzyme gene variants and nonnucleoside reverse-transcriptase inhibitor hepatotoxicity","volume":"43","author":"Ritchie","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2217\/pgs.09.142","article-title":"Nevirapine-induced hepatotoxicity and pharmacogenetics: A retrospective study in a population from Mozambique","volume":"11","author":"Ciccacci","year":"2010","journal-title":"Pharmacogenomics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.canlet.2005.05.051","article-title":"MRP2 and 3 in health and disease","volume":"234","author":"Borst","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/toxsci\/kfn268","article-title":"Bile Acid sulfation: A pathway of bile acid elimination and detoxification","volume":"108","author":"Alnouti","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s10354-006-0312-7","article-title":"Molecular mechanisms of cholestasis","volume":"156","author":"Zollner","year":"2006","journal-title":"Wien. Med. Wochenschr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00424-006-0109-y","article-title":"The apical conjugate efflux pump ABCC2 (MRP2)","volume":"453","author":"Nies","year":"2007","journal-title":"Pflugers. Arch."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.bbamcr.2006.04.014","article-title":"Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration","volume":"1773","author":"Geier","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/hep.510250635","article-title":"A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome","volume":"25","author":"Paulusma","year":"1997","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1194\/jlr.R900012-JLR200","article-title":"Bile acid transporters","volume":"50","author":"Dawson","year":"2009","journal-title":"J. Lipid. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s00424-006-0152-8","article-title":"The bile salt export pump","volume":"453","author":"Stieger","year":"2007","journal-title":"Pflugers. Arch."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1097\/MOL.0b013e32832b677c","article-title":"Recent insights into the function and regulation of the bile salt export pump (ABCB11)","volume":"20","author":"Stieger","year":"2009","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mam.2013.05.001","article-title":"Biosynthesis and trafficking of the bile salt export pump, BSEP: Therapeutic implications of BSEP mutations","volume":"37","author":"Soroka","year":"2014","journal-title":"Mol. Aspects. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.clinre.2018.07.010","article-title":"Systematic review of progressive familial intrahepatic cholestasis","volume":"43","author":"Baker","year":"2019","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jhep.2005.03.017","article-title":"Enterohepatic transport of bile salts and genetics of cholestasis","volume":"43","author":"Stieger","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.jhep.2005.05.020","article-title":"Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis","volume":"43","author":"Noe","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/toxsci\/kfq269","article-title":"Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development","volume":"118","author":"Morgan","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/toxsci\/kft176","article-title":"A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development","volume":"136","author":"Morgan","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1136\/gut.50.3.436","article-title":"Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis","volume":"50","author":"Prince","year":"2002","journal-title":"Gut"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/01.fpc.0000230418.28091.76","article-title":"Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury","volume":"17","author":"Lang","year":"2007","journal-title":"Pharm. Genom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1067\/mcp.2001.114667","article-title":"The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions","volume":"69","author":"Fattinger","year":"2001","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0300-483X(01)00460-7","article-title":"Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate","volume":"167","author":"Funk","year":"2001","journal-title":"Toxicology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/S0016-5085(00)70224-1","article-title":"Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver","volume":"118","author":"Stieger","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1101\/gr.184901","article-title":"The human ATP-binding cassette (ABC) transporter superfamily","volume":"11","author":"Dean","year":"2001","journal-title":"Genome. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1042\/bse0500043","article-title":"Structure of ABC transporters","volume":"50","author":"Zolnerciks","year":"2011","journal-title":"Essays. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"954781","DOI":"10.1155\/2014\/954781","article-title":"Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts","volume":"2014","author":"Morita","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1053\/j.gastro.2011.07.042","article-title":"Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity","volume":"141","author":"Groen","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1002\/hep4.1149","article-title":"Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset","volume":"2","author":"Schatz","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/hep.28300","article-title":"A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3","volume":"63","author":"Delaunay","year":"2016","journal-title":"Hepatology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1055\/s-0031-1273427","article-title":"Cholestatic liver diseases from child to adult: The diversity of MDR3 disease","volume":"49","author":"Kubitz","year":"2011","journal-title":"Z Gastroenterol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/ng.3247","article-title":"Large-scale whole-genome sequencing of the Icelandic population","volume":"47","author":"Gudbjartsson","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1470-2045(17)30167-5","article-title":"Common genetic variation and risk of gallbladder cancer in India: A case-control genome-wide association study","volume":"18","author":"Mhatre","year":"2017","journal-title":"Lancet. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1055\/s-0038-1667299","article-title":"ABCB4 gene aberrations in human liver disease: An evolving spectrum","volume":"38","author":"Reichert","year":"2018","journal-title":"Semin. Liver. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1159\/000365003","article-title":"Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury","volume":"90","author":"Zollner","year":"2014","journal-title":"Digestion"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1002\/path.1379","article-title":"High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease","volume":"200","author":"Ros","year":"2003","journal-title":"J. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/cyto.a.22263","article-title":"Implication of hepatic transporters (MDR1 and MRP2) in inflammation-associated idiosyncratic drug-induced hepatotoxicity investigated by microvolume cytometry","volume":"83","author":"Saab","year":"2013","journal-title":"Cytom. A"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Fukunaga, K., Nakagawa, H., Ishikawa, T., Kubo, M., and Mushiroda, T. (2016). ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population. BMC Genet., 17.","DOI":"10.1186\/s12863-016-0390-5"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.tips.2004.06.002","article-title":"Importance of P-glycoprotein at blood-tissue barriers","volume":"25","author":"Fromm","year":"2004","journal-title":"Trends. Pharmacol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1111\/j.1349-7006.2007.00538.x","article-title":"Mechanism of multidrug recognition by MDR1\/ABCB1","volume":"98","author":"Kimura","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tube.2011.09.007","article-title":"Polymorphisms in drug transporter genes (ABCB1, SLCO1B1 and ABCC2) and hepatitis induced by antituberculosis drugs","volume":"92","author":"Kim","year":"2012","journal-title":"Tuberculosis (Edinb.)"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/jcph.1533","article-title":"Association of ABCC Gene Polymorphism With Susceptibility to Antituberculosis Drug-Induced Hepatotoxicity in Western Han Patients With Tuberculosis","volume":"60","author":"Bai","year":"2020","journal-title":"J. Clin. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1097\/QAD.0b013e32834779df","article-title":"Nevirapine Toxicogenomics Study Team. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent","volume":"25","author":"Yuan","year":"2011","journal-title":"AIDS"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1002\/path.3019","article-title":"Canalicular ABC transporters and liver disease","volume":"226","author":"Nicolaou","year":"2012","journal-title":"J. Pathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1053\/j.gastro.2006.11.023","article-title":"Genetic susceptibility to diclofenac-induced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes","volume":"132","author":"Daly","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/S0168-8278(02)00107-1","article-title":"Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan","volume":"37","author":"Fouassier","year":"2002","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41401-019-0266-0","article-title":"Rifampicin induces clathrin-dependent endocytosis and ubiquitin-proteasome degradation of MRP2 via oxidative stress-activated PKC-ERK\/JNK\/p38 and PI3K signaling pathways in HepG2 cells","volume":"41","author":"Xu","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mad.2016.07.001","article-title":"Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis","volume":"157","author":"Bozaykut","year":"2016","journal-title":"Mech. Ageing Dev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.taap.2009.06.022","article-title":"Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice","volume":"240","author":"Chen","year":"2009","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/toxsci\/kfz154","article-title":"Novel Mechanisms of Valproate Hepatotoxicity: Impaired Mrp2 Trafficking and Hepatocyte Depolarization","volume":"171","author":"Fu","year":"2019","journal-title":"Toxicol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2217\/pgs.13.124","article-title":"Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: A case report","volume":"14","author":"Laurenty","year":"2013","journal-title":"Pharmacogenomics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1124\/dmd.120.000086","article-title":"A Two-Tiered In Vitro Approach to De-Risk Drug Candidates for Potential Bile Salt Export Pump Inhibition Liabilities in Drug Discovery","volume":"48","author":"Hafey","year":"2020","journal-title":"Drug. Metab. Dispos."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3109\/15376516.2015.1033074","article-title":"The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid\/rifampicin-induced hepatotoxicity","volume":"25","author":"Guo","year":"2015","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3748\/wjg.14.38","article-title":"Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump","volume":"14","author":"Meier","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1124\/dmd.114.061325","article-title":"No contribution of the ABCB11 p.444A polymorphism in Japanese patients with drug-induced cholestasis","volume":"43","author":"Kagawa","year":"2015","journal-title":"Drug. Metab. Dispos."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1111\/liv.12193","article-title":"Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury","volume":"33","author":"Ulzurrun","year":"2013","journal-title":"Liver. Int."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"27750","DOI":"10.1038\/srep27750","article-title":"Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1002\/hep.27206","article-title":"Human drug-induced liver in-jury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump","volume":"60","author":"Aleo","year":"2014","journal-title":"Hepatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3109\/03602530903492004","article-title":"Role of the bile salt export pump, BSEP, in acquired forms of cholestasis","volume":"42","author":"Stieger","year":"2010","journal-title":"Drug. Metab. Rev."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/hep.24229","article-title":"Drug-induced cholestasis","volume":"53","author":"Padda","year":"2011","journal-title":"Hepatology"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2019). Electronic address: Easloffice@easloffice.eu; Clinical Practice Guideline Panel: Chair; Panel members; EASL Governing Board representative: EASL Clinical Practice Guidelines: Drug-induced liver injury. J. Hepatol., 70, 1222\u20131261.","DOI":"10.1016\/j.jhep.2019.02.014"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e20182146","DOI":"10.1542\/peds.2018-2146","article-title":"Beyond an Obvious Cause of Cholestasis in a Toddler: Compound Heterozygosity for ABCB11 Mutations","volume":"143","author":"Fotoulaki","year":"2019","journal-title":"Pediatrics"},{"key":"ref_93","first-page":"795","article-title":"Bile salt export pump deficiency disease: Two novel, late onset, ABCB11 mutations identified by next generation sequencing","volume":"15","author":"Vitale","year":"2016","journal-title":"Ann. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"101475","DOI":"10.1016\/j.clinre.2020.06.002","article-title":"Contraceptive vaginal ring-induced cholestasis in a patient with a history of intrahepatic cholestasis of pregnancy","volume":"45","author":"Perrault","year":"2021","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1021\/acs.chemrestox.7b00048","article-title":"Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals","volume":"30","author":"Aleo","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1124\/mol.116.103390","article-title":"Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis","volume":"90","author":"Mahdi","year":"2016","journal-title":"Mol. Pharmacol."},{"key":"ref_97","first-page":"86","article-title":"Mechanisms of Hepatic Cholestatic Drug Injury","volume":"7","author":"Wu","year":"2019","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.clinre.2015.12.008","article-title":"The pathophysiology of intrahepatic cholestasis of pregnancy","volume":"40","author":"Dixon","year":"2016","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"12","DOI":"10.2174\/157488411794941313","article-title":"The pharmacological management of intrahepatic cholestasis of pregnancy","volume":"6","author":"Azzaroli","year":"2011","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.dld.2021.07.003","article-title":"The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series","volume":"54","author":"Pedroto","year":"2022","journal-title":"Dig. Liver. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1159\/000484612","article-title":"A Complex Case of Cholestasis in a Patient with ABCB4 and ABCB11 Mutations","volume":"25","author":"Cardoso","year":"2018","journal-title":"GE Port. J. Gastroenterol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1007\/s10620-022-07416-9","article-title":"ABCB4 Mutations in Adults Cause a Spectrum Cholestatic Disorder Histologically Distinct from Other Biliary Disease","volume":"67","author":"Sinha","year":"2022","journal-title":"Dig. Dis. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"23530","DOI":"10.1074\/jbc.M909002199","article-title":"MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping","volume":"275","author":"Smith","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0928-0987(00)00186-X","article-title":"Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport","volume":"12","author":"Hooiveld","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1007\/BF03402158","article-title":"Gene expression of ABC proteins in hepatocellular carcinoma, perineoplastic tissue, and liver diseases","volume":"8","author":"Bonin","year":"2002","journal-title":"Mol. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/hep.28323","article-title":"Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports","volume":"63","author":"Hoofnagle","year":"2016","journal-title":"Hepatology"},{"key":"ref_107","unstructured":"European Association for the Study of the Liver (2017). Electronic address: Easloffice@easloffice.eu; European Association for the Study of the Liver: EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J. Hepatol., 67, 145\u2013172."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1186\/s13023-022-02565-6","article-title":"A common variant in the hepatobiliary phospholipid transporter ABCB4 modulates liver injury in PBC but not in PSC: Prospective analysis in 867 patients","volume":"17","author":"Kruk","year":"2022","journal-title":"Orphanet. J. Rare Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5823\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:58:24Z","timestamp":1760122704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,18]]},"references-count":108,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065823"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065823","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,18]]}}}