A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis

Brandy       Garzel; Lei       Zhang; Shiew-Mei       Huang; Hongbing       Wang
doi:10.2174/1389200220666190709170256
Abstract

Background: Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms.
Methods: We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so.
Results: We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC.
Conclusion: Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.
Keywords: Bile Salt Export Pump (BSEP), Drug-Induced Liver Injury (DILI), Drug-Induced Cholestasis (DIC), inhibition, repression, farnesoid X receptor.
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Graphical Abstract

[1] 
Grant, D.M. Detoxification pathways in the liver. J. Inherit. Metab. Dis.,  1991, 14(4), 421-430.
[http://dx.doi.org/10.1007/BF01797915] [PMID:  1749210] 
[2] 
Zimmerman, H.J. Iatrogenic hepatic injury. Hepatotoxicity: The adverse effects of drugs and other chemicals on the liver, 2nd ed; Lippincott Williams & Wilkins: Philadelphia, PA, 1999, pp. 427-456.
[3] 
Ghabril, M.; Chalasani, N.; Björnsson, E. Drug-induced liver injury: A clinical update. Curr. Opin. Gastroenterol.,  2010, 26(3), 222-226.
[http://dx.doi.org/10.1097/MOG.0b013e3283383c7c] [PMID:  20186054] 
[4] 
Lu, R.J.; Zhang, Y.; Tang, F.L.; Zheng, Z.W.; Fan, Z.D.; Zhu, S.M.; Qian, X.F.; Liu, N.N. Clinical characteristics of drug-induced liver injury and related risk factors. Exp. Ther. Med.,  2016, 12(4), 2606-2616.
[http://dx.doi.org/10.3892/etm.2016.3627] [PMID:  27703513] 
[5] 
Chalasani, N.P.; Hayashi, P.H.; Bonkovsky, H.L.; Navarro, V.J.; Lee, W.M.; Fontana, R.J. ACG Clinical Guideline: The diagnosis and management of idiosyncratic drug-induced liver injury. Am. J. Gastroenterol.,  2014, 109(7), 950-966.
[http://dx.doi.org/10.1038/ajg.2014.131] [PMID:  24935270] 
[6] 
Kagawa, T.; Shirai, Y.; Oda, S.; Yokoi, T. Identification of specific microRNA biomarkers in early stages of hepatocellular injury, cholestasis, and steatosis in rats. Toxicol. Sci.,  2018, 166(1), 228-239.
[http://dx.doi.org/10.1093/toxsci/kfy200] [PMID:  30125006] 
[7] 
Thacker, S.E.; Nautiyal, M.; Otieno, M.A.; Watkins, P.B.; Mosedale, M. Optimized methods to explore the mechanistic and biomarker potential of hepatocyte-derived exosomes in drug-induced liver injury. Toxicol. Sci.,  2018, 163(1), 92-100.
[http://dx.doi.org/10.1093/toxsci/kfy015] [PMID:  29385596] 
[8] 
Saini, N.; Bakshi, S.; Sharma, S. In silico approach for drug induced liver injury prediction: Recent advances. Toxicol. Lett.,  2018, 295, 288-295.
[http://dx.doi.org/10.1016/j.toxlet.2018.06.1216] [PMID:  29981923] 
[9] 
Nicoletti, P.; Aithal, G.P.; Bjornsson, E.S.; Andrade, R.J.; Sawle, A.; Arrese, M.; Barnhart, H.X.; Bondon-Guitton, E.; Hayashi, P.H.; Bessone, F.; Carvajal, A.; Cascorbi, I.; Cirulli, E.T.; Chalasani, N.; Conforti, A.; Coulthard, S.A.; Daly, M.J.; Day, C.P.; Dillon, J.F.; Fontana, R.J.; Grove, J.I.; Hallberg, P.; Hernández, N.; Ibáñez, L.; Kullak-Ublick, G.A.; Laitinen, T.; Larrey, D.; Lucena, M.I.; Maitland-van der Zee, A.H.; Martin, J.H.; Molokhia, M.; Pirmohamed, M.; Powell, E.E.; Qin, S.; Serrano, J.; Stephens, C.; Stolz, A.; Wadelius, M.; Watkins, P.B.; Floratos, A.; Shen, Y.; Nelson, M.R.; Urban, T.J.; Daly, A.K. Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology,  2017, 152(5), 1078-1089.
[http://dx.doi.org/10.1053/j.gastro.2016.12.016] [PMID:  28043905] 
[10] 
Antoine, D.J.; Jenkins, R.E.; Dear, J.W.; Williams, D.P.; McGill, M.R.; Sharpe, M.R.; Craig, D.G.; Simpson, K.J.; Jaeschke, H.; Park, B.K. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J. Hepatol.,  2012, 56(5), 1070-1079.
[http://dx.doi.org/10.1016/j.jhep.2011.12.019] [PMID:  22266604] 
[11] 
Andrade, R.J.; Robles, M.; Fernández-Castañer, A.; López-Ortega, S.; López-Vega, M.C.; Lucena, M.I. Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists. World J. Gastroenterol.,  2007, 13(3), 329-340.
[http://dx.doi.org/10.3748/wjg.v13.i3.329] [PMID:  17230599] 
[12] 
FDA. Guidance for Industry Drug-Induced Liver Injury: Premarketing
Clinical Evaluation In: Center for Drug Evaluation and Research
(CDER), US., Food and Drug Administration (FDA); , 2009. 
[13] 
Kleiner, D.E.; Chalasani, N.P.; Lee, W.M.; Fontana, R.J.; Bonkovsky, H.L.; Watkins, P.B.; Hayashi, P.H.; Davern, T.J.; Navarro, V.; Reddy, R.; Talwalkar, J.A.; Stolz, A.; Gu, J.; Barnhart, H.; Hoofnagle, J.H.; Drug-Induced Liver Injury, N. Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations. Hepatology,  2014, 59(2), 661-670.
[http://dx.doi.org/10.1002/hep.26709] [PMID:  24037963] 
[14] 
Padda, M.S.; Sanchez, M.; Akhtar, A.J.; Boyer, J.L. Drug-induced cholestasis. Hepatology,  2011, 53(4), 1377-1387.
[http://dx.doi.org/10.1002/hep.24229] [PMID:  21480339] 
[15] 
de Lima Toccafondo Vieira, M.; Tagliati, C.A. Hepatobiliary transporters in drug-induced cholestasis: A perspective on the current identifying tools. Expert Opin. Drug Metab. Toxicol.,  2014, 10(4), 581-597.
[http://dx.doi.org/10.1517/17425255.2014.884069] [PMID:  24588537] 
[16] 
Myant, N.B.; Mitropoulos, K.A. Cholesterol 7 alpha-hydroxylase. J. Lipid Res.,  1977, 18(2), 135-153.
[PMID:  557521] 
[17] 
Rossi, S.S.; Converse, J.L.; Hofmann, A.F. High pressure liquid chromatographic analysis of conjugated bile acids in human bile: Simultaneous resolution of sulfated and unsulfated lithocholyl amidates and the common conjugated bile acids. J. Lipid Res.,  1987, 28(5), 589-595.
[PMID:  3598401] 
[18] 
Keely, S.J.; Walters, J.R. The farnesoid X receptor: Good for BAD. Cell. Mol. Gastroenterol. Hepatol.,  2016, 2(6), 725-732.
[http://dx.doi.org/10.1016/j.jcmgh.2016.08.004] [PMID:  28174746] 
[19] 
Chiang, J.Y. Bile acid regulation of hepatic physiology: III. Bile acids and nuclear receptors. Am. J. Physiol. Gastrointest. Liver Physiol.,  2003, 284(3), G349-G356.
[http://dx.doi.org/10.1152/ajpgi.00417.2002] [PMID:  12576301] 
[20] 
Boyer, J.L. Bile formation and secretion. Compr. Physiol.,  2013, 3(3), 1035-1078.
[PMID:  23897680] 
[21] 
St-Pierre, M.V.; Kullak-Ublick, G.A.; Hagenbuch, B.; Meier, P.J. Transport of bile acids in hepatic and non-hepatic tissues. J. Exp. Biol.,  2001, 204(Pt 10), 1673-1686.
[PMID:  11316487] 
[22] 
Perez, M.J.; Briz, O. Bile-acid-induced cell injury and protection. World J. Gastroenterol.,  2009, 15(14), 1677-1689.
[http://dx.doi.org/10.3748/wjg.15.1677] [PMID:  19360911] 
[23] 
Maillette de Buy Wenniger, L.; Beuers, U. Bile salts and cholestasis. Dig. Liver Dis.,  2010, 42(6), 409-418.
[http://dx.doi.org/10.1016/j.dld.2010.03.015] [PMID:  20434968] 
[24] 
Zwicker, B.L.; Agellon, L.B. Transport and biological activities of bile acids. Int. J. Biochem. Cell Biol.,  2013, 45(7), 1389-1398.
[http://dx.doi.org/10.1016/j.biocel.2013.04.012] [PMID:  23603607] 
[25] 
Vítek, L.; Haluzík, M. The role of bile acids in metabolic regulation. J. Endocrinol.,  2016, 228(3), R85-R96.
[http://dx.doi.org/10.1530/JOE-15-0469] [PMID:  26733603] 
[26] 
Taoka, H.; Yokoyama, Y.; Morimoto, K.; Kitamura, N.; Tanigaki, T.; Takashina, Y.; Tsubota, K.; Watanabe, M. Role of bile acids in the regulation of the metabolic pathways. World J. Diabetes,  2016, 7(13), 260-270.
[http://dx.doi.org/10.4239/wjd.v7.i13.260] [PMID:  27433295] 
[27] 
Watanabe, M.; Houten, S.M.; Wang, L.; Moschetta, A.; Mangelsdorf, D.J.; Heyman, R.A.; Moore, D.D.; Auwerx, J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest.,  2004, 113(10), 1408-1418.
[http://dx.doi.org/10.1172/JCI21025] [PMID:  15146238] 
[28] 
Huang, W.; Ma, K.; Zhang, J.; Qatanani, M.; Cuvillier, J.; Liu, J.; Dong, B.; Huang, X.; Moore, D.D. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science,  2006, 312(5771), 233-236.
[http://dx.doi.org/10.1126/science.1121435] [PMID:  16614213] 
[29] 
Chen, W.D.; Wang, Y.D.; Zhang, L.; Shiah, S.; Wang, M.; Yang, F.; Yu, D.; Forman, B.M.; Huang, W. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology,  2010, 51(3), 953-962.
[PMID:  19998409] 
[30] 
Degirolamo, C.; Modica, S.; Vacca, M.; Di Tullio, G.; Morgano, A.; D’Orazio, A.; Kannisto, K.; Parini, P.; Moschetta, A. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation. Hepatology,  2015, 61(1), 161-170.
[http://dx.doi.org/10.1002/hep.27274] [PMID:  24954587] 
[31] 
Kong, B.; Zhu, Y.; Li, G.; Williams, J.A.; Buckley, K.; Tawfik, O.; Luyendyk, J.P.; Guo, G.L. Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis. Am. J. Physiol. Gastrointest. Liver Physiol.,  2016, 310(5), G295-G302.
[http://dx.doi.org/10.1152/ajpgi.00134.2015] [PMID:  26744468] 
[32] 
Ridlon, J.M.; Kang, D.J.; Hylemon, P.B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res.,  2006, 47(2), 241-259.
[http://dx.doi.org/10.1194/jlr.R500013-JLR200] [PMID:  16299351] 
[33] 
Stellaard, F.; Sackmann, M.; Sauerbruch, T.; Paumgartner, G. Simultaneous determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates in human serum using 13C-labeled bile acids. J. Lipid Res.,  1984, 25(12), 1313-1319.
[PMID:  6530587] 
[34] 
Chiang, J.Y. Bile acids: Regulation of synthesis. J. Lipid Res.,  2009, 50(10), 1955-1966.
[http://dx.doi.org/10.1194/jlr.R900010-JLR200] [PMID:  19346330] 
[35] 
Stieger, B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab. Rev.,  2010, 42(3), 437-445.
[http://dx.doi.org/10.3109/03602530903492004] [PMID:  20028269] 
[36] 
Jansen, P.L.; Ghallab, A.; Vartak, N.; Reif, R.; Schaap, F.G.; Hampe, J.; Hengstler, J.G. The ascending pathophysiology of cholestatic liver disease. Hepatology,  2017, 65(2), 722-738.
[http://dx.doi.org/10.1002/hep.28965] [PMID:  27981592] 
[37] 
Tu, H.; Okamoto, A.Y.; Shan, B. FXR, a bile acid receptor and biological sensor. Trends Cardiovasc. Med.,  2000, 10(1), 30-35.
[http://dx.doi.org/10.1016/S1050-1738(00)00043-8] [PMID:  11150726] 
[38] 
Kok, T.; Hulzebos, C.V.; Wolters, H.; Havinga, R.; Agellon, L.B.; Stellaard, F.; Shan, B.; Schwarz, M.; Kuipers, F. Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: Efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J. Biol. Chem.,  2003, 278(43), 41930-41937.
[http://dx.doi.org/10.1074/jbc.M306309200] [PMID:  12917447] 
[39] 
Kim, I.; Ahn, S.H.; Inagaki, T.; Choi, M.; Ito, S.; Guo, G.L.; Kliewer, S.A.; Gonzalez, F.J. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J. Lipid Res.,  2007, 48(12), 2664-2672.
[http://dx.doi.org/10.1194/jlr.M700330-JLR200] [PMID:  17720959] 
[40] 
Goodwin, B.; Jones, S.A.; Price, R.R.; Watson, M.A.; McKee, D.D.; Moore, L.B.; Galardi, C.; Wilson, J.G.; Lewis, M.C.; Roth, M.E.; Maloney, P.R.; Willson, T.M.; Kliewer, S.A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell,  2000, 6(3), 517-526.
[http://dx.doi.org/10.1016/S1097-2765(00)00051-4] [PMID:  11030332] 
[41] 
Kerr, T.A.; Saeki, S.; Schneider, M.; Schaefer, K.; Berdy, S.; Redder, T.; Shan, B.; Russell, D.W.; Schwarz, M. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell,  2002, 2(6), 713-720.
[http://dx.doi.org/10.1016/S1534-5807(02)00154-5] [PMID:  12062084] 
[42] 
Copple, B.L.; Li, T. Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol. Res.,  2016, 104, 9-21.
[http://dx.doi.org/10.1016/j.phrs.2015.12.007] [PMID:  26706784] 
[43] 
Schuetz, E.G.; Strom, S.; Yasuda, K.; Lecureur, V.; Assem, M.; Brimer, C.; Lamba, J.; Kim, R.B.; Ramachandran, V.; Komoroski, B.J.; Venkataramanan, R.; Cai, H.; Sinal, C.J.; Gonzalez, F.J.; Schuetz, J.D. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J. Biol. Chem.,  2001, 276(42), 39411-39418.
[http://dx.doi.org/10.1074/jbc.M106340200] [PMID:  11509573] 
[44] 
Ananthanarayanan, M.; Balasubramanian, N.; Makishima, M.; Mangelsdorf, D.J.; Suchy, F.J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem.,  2001, 276(31), 28857-28865.
[http://dx.doi.org/10.1074/jbc.M011610200] [PMID:  11387316] 
[45] 
Plass, J.R.; Mol, O.; Heegsma, J.; Geuken, M.; Faber, K.N.; Jansen, P.L.; Müller, M. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology,  2002, 35(3), 589-596.
[http://dx.doi.org/10.1053/jhep.2002.31724] [PMID:  11870371] 
[46] 
Ferrebee, C.B.; Dawson, P.A. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm. Sin. B,  2015, 5(2), 129-134.
[http://dx.doi.org/10.1016/j.apsb.2015.01.001] [PMID:  26579438] 
[47] 
Fang, S.; Suh, J.M.; Reilly, S.M.; Yu, E.; Osborn, O.; Lackey, D.; Yoshihara, E.; Perino, A.; Jacinto, S.; Lukasheva, Y.; Atkins, A.R.; Khvat, A.; Schnabl, B.; Yu, R.T.; Brenner, D.A.; Coulter, S.; Liddle, C.; Schoonjans, K.; Olefsky, J.M.; Saltiel, A.R.; Downes, M.; Evans, R.M. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med.,  2015, 21(2), 159-165.
[http://dx.doi.org/10.1038/nm.3760] [PMID:  25559344] 
[48] 
Hagenbuch, B.; Meier, P.J. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter. J. Clin. Invest.,  1994, 93(3), 1326-1331.
[http://dx.doi.org/10.1172/JCI117091] [PMID:  8132774] 
[49] 
Kullak-Ublick, G.A.; Hagenbuch, B.; Stieger, B.; Wolkoff, A.W.; Meier, P.J. Functional characterization of the basolateral rat liver organic anion transporting polypeptide. Hepatology,  1994, 20(2), 411-416.
[PMID:  8045503] 
[50] 
Pastor, C.M.; Müllhaupt, B.; Stieger, B. The role of organic anion transporters in diagnosing liver diseases by magnetic resonance imaging. Drug Metab. Dispos.,  2014, 42(4), 675-684.
[http://dx.doi.org/10.1124/dmd.113.055707] [PMID:  24398460] 
[51] 
Cui, Y.; König, J.; Buchholz, J.K.; Spring, H.; Leier, I.; Keppler, D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol.,  1999, 55(5), 929-937.
[PMID:  10220572] 
[52] 
König, J.; Nies, A.T.; Cui, Y.; Leier, I.; Keppler, D. Conjugate export pumps of the Multidrug Resistance Protein (MRP) family: Localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta,  1999, 1461(2), 377-394.
[http://dx.doi.org/10.1016/S0005-2736(99)00169-8] [PMID:  10581368] 
[53] 
van Helvoort, A.; Smith, A.J.; Sprong, H.; Fritzsche, I.; Schinkel, A.H.; Borst, P.; Van Meer, G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell,  1996, 87(3), 507-517.
[http://dx.doi.org/10.1016/S0092-8674(00)81370-7] [PMID:  8898203] 
[54] 
Smith, A.J.; Timmermans-Hereijgers, J.L.; Roelofsen, B.; Wirtz, K.W.; Van Blitterswijk, W.J.; Smit, J.J.; Schinkel, A.H.; Borst, P. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett.,  1994, 354(3), 263-266.
[http://dx.doi.org/10.1016/0014-5793(94)01135-4] [PMID:  7957936] 
[55] 
Groen, A.; Romero, M.R.; Kunne, C.; Hoosdally, S.J.; Dixon, P.H.; Wooding, C.; Williamson, C.; Seppen, J.; Van Den Oever, K.; Mok, K.S.; Paulusma, C.C.; Linton, K.J.; Oude Elferink, R.P. Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology,  2011, 141(5), 1927-1937.
[http://dx.doi.org/10.1053/j.gastro.2011.07.042] 
[56] 
Hirohashi, T.; Suzuki, H.; Takikawa, H.; Sugiyama, Y. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J. Biol. Chem.,  2000, 275(4), 2905-2910.
[http://dx.doi.org/10.1074/jbc.275.4.2905] [PMID:  10644759] 
[57] 
Kiuchi, Y.; Suzuki, H.; Hirohashi, T.; Tyson, C.A.; Sugiyama, Y. cDNA cloning and inducible expression of human Multidrug Resistance Associated Protein 3 (MRP3). FEBS Lett.,  1998, 433(1-2), 149-152.
[http://dx.doi.org/10.1016/S0014-5793(98)00899-0] [PMID:  9738950] 
[58] 
Zelcer, N.; Saeki, T.; Bot, I.; Kuil, A.; Borst, P. Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal Na+ -dependent bile-acid transporter. Biochem. J.,  2003, 369(Pt 1), 23-30.
[http://dx.doi.org/10.1042/bj20021081] [PMID:  12220224] 
[59] 
Müller, M.; Jansen, P.L. Molecular aspects of hepatobiliary transport. Am. J. Physiol.,  1997, 272(6 Pt 1), G1285-G1303.
[PMID:  9227463] 
[60] 
Hofmann, A.F. Bile acids: The good, the bad, and the ugly. News Physiol. Sci.,  1999, 14, 24-29.
[http://dx.doi.org/10.1152/physiologyonline.1999.14.1.24] [PMID:  11390813] 
[61] 
Dawson, P.A.; Haywood, J.; Craddock, A.L.; Wilson, M.; Tietjen, M.; Kluckman, K.; Maeda, N.; Parks, J.S. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J. Biol. Chem.,  2003, 278(36), 33920-33927.
[http://dx.doi.org/10.1074/jbc.M306370200] [PMID:  12819193] 
[62] 
Dawson, P.A.; Hubbert, M.; Haywood, J.; Craddock, A.L.; Zerangue, N.; Christian, W.V.; Ballatori, N. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J. Biol. Chem.,  2005, 280(8), 6960-6968.
[http://dx.doi.org/10.1074/jbc.M412752200] [PMID:  15563450] 
[63] 
Ballatori, N.; Christian, W.V.; Lee, J.Y.; Dawson, P.A.; Soroka, C.J.; Boyer, J.L.; Madejczyk, M.S.; Li, N. OSTalpha-OSTbeta: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology,  2005, 42(6), 1270-1279.
[http://dx.doi.org/10.1002/hep.20961] [PMID:  16317684] 
[64] 
Anwer, M.S.; Hegner, D. Effect of Na on bile acid uptake by isolated rat hepatocytes. Evidence for a heterogeneous system. Hoppe Seylers Z. Physiol. Chem.,  1978, 359(2), 181-192.
[PMID:  649053] 
[65] 
Anwer, M.S.; Stieger, B. Sodium-dependent bile salt transporters of the SLC10A transporter family: More than solute transporters. Pflugers Arch.,  2014, 466(1), 77-89.
[http://dx.doi.org/10.1007/s00424-013-1367-0] [PMID:  24196564] 
[66] 
Dong, Z.; Ekins, S.; Polli, J.E. Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP). Mol. Pharm.,  2013, 10(3), 1008-1019.
[http://dx.doi.org/10.1021/mp300453k] [PMID:  23339484] 
[67] 
Wolf, K.K.; Vora, S.; Webster, L.O.; Generaux, G.T.; Polli, J.W.; Brouwer, K.L. Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport. Toxicol. In Vitro,  2010, 24(1), 297-309.
[http://dx.doi.org/10.1016/j.tiv.2009.08.009] [PMID:  19706322] 
[68] 
Dong, Z.; Ekins, S.; Polli, J.E. Quantitative NTCP pharmacophore and lack of association between DILI and NTCP Inhibition. Eur. J. Pharm. Sci.,  2015, 66, 1-9.
[http://dx.doi.org/10.1016/j.ejps.2014.09.005] [PMID:  25220493] 
[69] 
Gerloff, T.; Stieger, B.; Hagenbuch, B.; Madon, J.; Landmann, L.; Roth, J.; Hofmann, A.F.; Meier, P.J. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem.,  1998, 273(16), 10046-10050.
[http://dx.doi.org/10.1074/jbc.273.16.10046] [PMID:  9545351] 
[70] 
Alrefai, W.A.; Gill, R.K. Bile acid transporters: Structure, function, regulation and pathophysiological implications. Pharm. Res.,  2007, 24(10), 1803-1823.
[http://dx.doi.org/10.1007/s11095-007-9289-1] [PMID:  17404808] 
[71] 
Trauner, M.; Boyer, J.L. Bile salt transporters: Molecular characterization, function, and regulation. Physiol. Rev.,  2003, 83(2), 633-671.
[http://dx.doi.org/10.1152/physrev.00027.2002] [PMID:  12663868] 
[72] 
Kostrubsky, V.E.; Strom, S.C.; Hanson, J.; Urda, E.; Rose, K.; Burliegh, J.; Zocharski, P.; Cai, H.; Sinclair, J.F.; Sahi, J. Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats. Toxicol. Sci.,  2003, 76(1), 220-228.
[http://dx.doi.org/10.1093/toxsci/kfg217] [PMID:  12944587] 
[73] 
Kostrubsky, S.E.; Strom, S.C.; Kalgutkar, A.S.; Kulkarni, S.; Atherton, J.; Mireles, R.; Feng, B.; Kubik, R.; Hanson, J.; Urda, E.; Mutlib, A.E. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci.,  2006, 90(2), 451-459.
[http://dx.doi.org/10.1093/toxsci/kfj095] [PMID:  16410371] 
[74] 
Morgan, R.E.; Trauner, M.; van Staden, C.J.; Lee, P.H.; Ramachandran, B.; Eschenberg, M.; Afshari, C.A.; Qualls, C.W., Jr; Lightfoot-Dunn, R.; Hamadeh, H.K. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol. Sci.,  2010, 118(2), 485-500.
[http://dx.doi.org/10.1093/toxsci/kfq269] [PMID:  20829430] 
[75] 
Ogimura, E.; Sekine, S.; Horie, T. Bile salt export pump inhibitors are associated with bile acid-dependent drug-induced toxicity in sandwich-cultured hepatocytes. Biochem. Biophys. Res. Commun.,  2011, 416(3-4), 313-317.
[http://dx.doi.org/10.1016/j.bbrc.2011.11.032] [PMID:  22108051] 
[76] 
Strautnieks, S.S.; Bull, L.N.; Knisely, A.S.; Kocoshis, S.A.; Dahl, N.; Arnell, H.; Sokal, E.; Dahan, K.; Childs, S.; Ling, V.; Tanner, M.S.; Kagalwalla, A.F.; Németh, A.; Pawlowska, J.; Baker, A.; Mieli-Vergani, G.; Freimer, N.B.; Gardiner, R.M.; Thompson, R.J. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet.,  1998, 20(3), 233-238.
[http://dx.doi.org/10.1038/3034] [PMID:  9806540] 
[77] 
Dröge, C.; Schaal, H.; Engelmann, G.; Wenning, D.; Häussinger, D.; Kubitz, R. Exon-skipping and mRNA decay in human liver tissue: Molecular consequences of pathogenic bile salt export pump mutations. Sci. Rep.,  2016, 6, 24827.
[http://dx.doi.org/10.1038/srep24827] [PMID:  27114171] 
[78] 
Lang, C.; Meier, Y.; Stieger, B.; Beuers, U.; Lang, T.; Kerb, R.; Kullak-Ublick, G.A.; Meier, P.J.; Pauli-Magnus, C. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet. Genomics,  2007, 17(1), 47-60.
[http://dx.doi.org/10.1097/01.fpc.0000230418.28091.76] [PMID:  17264802] 
[79] 
Meier, Y.; Pauli-Magnus, C.; Zanger, U.M.; Klein, K.; Schaeffeler, E.; Nussler, A.K.; Nussler, N.; Eichelbaum, M.; Meier, P.J.; Stieger, B. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology,  2006, 44(1), 62-74.
[http://dx.doi.org/10.1002/hep.21214] [PMID:  16799996] 
[80] 
Song, X.; Kaimal, R.; Yan, B.; Deng, R. Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression. J. Lipid Res.,  2008, 49(5), 973-984.
[http://dx.doi.org/10.1194/jlr.M700417-JLR200] [PMID:  18270374] 
[81] 
Weerachayaphorn, J.; Cai, S.Y.; Soroka, C.J.; Boyer, J.L. Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression. Hepatology,  2009, 50(5), 1588-1596.
[http://dx.doi.org/10.1002/hep.23151] [PMID:  19821532] 
[82] 
Wagner, M.; Fickert, P.; Zollner, G.; Fuchsbichler, A.; Silbert, D.; Tsybrovskyy, O.; Zatloukal, K.; Guo, G.L.; Schuetz, J.D.; Gonzalez, F.J.; Marschall, H.U.; Denk, H.; Trauner, M. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology,  2003, 125(3), 825-838.
[http://dx.doi.org/10.1016/S0016-5085(03)01068-0] [PMID:  12949728] 
[83] 
Yang, S.; Wei, L.; Xia, R.; Liu, L.; Chen, Y.; Zhang, W.; Li, Q.; Feng, K.; Yu, M.; Zhang, W.; Qu, J.; Xu, S.; Mao, J.; Fan, G.; Ma, C. Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα. Biochem. Biophys. Res. Commun.,  2019, 512(4), 770-778.
[http://dx.doi.org/10.1016/j.bbrc.2019.03.131] [PMID:  30928103] 
[84] 
Zeng, H.; Li, D.; Qin, X.; Chen, P.; Tan, H.; Zeng, X.; Li, X.; Fan, X.; Jiang, Y.; Zhou, Y.; Chen, Y.; Wang, Y.; Huang, M.; Bi, H. Hepatoprotective effects of Schisandra sphenanthera extract against lithocholic acid-induced cholestasis in male mice are associated with activation of the pregnane X receptor pathway and promotion of liver regeneration. Drug Metab. Dispos.,  2016, 44(3), 337-342.
[http://dx.doi.org/10.1124/dmd.115.066969] [PMID:  26658429] 
[85] 
Yu, J.; Lo, J.L.; Huang, L.; Zhao, A.; Metzger, E.; Adams, A.; Meinke, P.T.; Wright, S.D.; Cui, J. Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J. Biol. Chem.,  2002, 277(35), 31441-31447.
[http://dx.doi.org/10.1074/jbc.M200474200] [PMID:  12052824] 
[86] 
Kemper, J.K.; Xiao, Z.; Ponugoti, B.; Miao, J.; Fang, S.; Kanamaluru, D.; Tsang, S.; Wu, S.Y.; Chiang, C.M.; Veenstra, T.D. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab.,  2009, 10(5), 392-404.
[http://dx.doi.org/10.1016/j.cmet.2009.09.009] [PMID:  19883617] 
[87] 
Kulkarni, S.R.; Soroka, C.J.; Hagey, L.R.; Boyer, J.L. Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis. Hepatology,  2016, 64(6), 2151-2164.
[http://dx.doi.org/10.1002/hep.28826] [PMID:  27639250] 
[88] 
Yang, J.; Sun, L.; Wang, L.; Hassan, H.M.; Wang, X.; Hylemon, P.B.; Wang, T.; Zhou, H.; Zhang, L.; Jiang, Z. Activation of Sirt1/FXR signaling pathway attenuates triptolide-induced hepatotoxicity in rats. Front. Pharmacol.,  2017, 8, 260.
[http://dx.doi.org/10.3389/fphar.2017.00260] [PMID:  28536529] 
[89] 
Qu, X.; Zhang, Y.; Zhang, S.; Zhai, J.; Gao, H.; Tao, L.; Song, Y. Dysregulation of BSEP and MRP2 may play an important role in isoniazid-induced liver injury via the SIRT1/FXR pathway in rats and HepG2 cells. Biol. Pharm. Bull.,  2018, 41(8), 1211-1218.
[http://dx.doi.org/10.1248/bpb.b18-00028] [PMID:  30068870] 
[90] 
Purushotham, A.; Xu, Q.; Lu, J.; Foley, J.F.; Yan, X.; Kim, D.H.; Kemper, J.K.; Li, X. Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1α/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice. Mol. Cell. Biol.,  2012, 32(7), 1226-1236.
[http://dx.doi.org/10.1128/MCB.05988-11] [PMID:  22290433] 
[91] 
Zhao, Q.; Liu, F.; Cheng, Y.; Xiao, X.R.; Hu, D.D.; Tang, Y.M.; Bao, W.M.; Yang, J.H.; Jiang, T.; Hu, J.P.; Gonzalez, F.J.; Li, F. Celastrol protects from cholestatic liver injury through modulation of SIRT1-FXR signaling. Mol. Cell. Proteomics,  2019, 18(3), 520-533.
[http://dx.doi.org/10.1074/mcp.RA118.000817] [PMID:  30617157] 
[92] 
Blokker, B.A.; Maijo, M.; Echeandia, M.; Galduroz, M.; Patterson, A.M.; Ten, A.; Philo, M.; Schungel, R.; Gutierrez-de Juan, V.; Halilbasic, E.; Fuchs, C.; Le Gall, G.; Milkiewicz, M.; Milkiewicz, P.; Banales, J.M.; Rushbrook, S.M.; Mato, J.M.; Trauner, M.; Müller, M.; Martínez-Chantar, M.L.; Varela-Rey, M.; Beraza, N. Fine-tuning of sirtuin 1 expression is essential to protect the liver from cholestatic liver disease. Hepatology,  2019, 69(2), 699-716.
[http://dx.doi.org/10.1002/hep.30275] [PMID:  30229970] 
[93] 
Garzel, B.; Yang, H.; Zhang, L.; Huang, S.M.; Polli, J.E.; Wang, H. The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity. Drug Metab. Dispos.,  2014, 42(3), 318-322.
[http://dx.doi.org/10.1124/dmd.113.054189] [PMID:  24335466] 
[94] 
Zollner, G.; Thueringer, A.; Lackner, C.; Fickert, P.; Trauner, M. Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury. Digestion,  2014, 90(2), 81-88.
[http://dx.doi.org/10.1159/000365003] [PMID:  25196354] 
[95] 
Köck, K.; Ferslew, B.C.; Netterberg, I.; Yang, K.; Urban, T.J.; Swaan, P.W.; Stewart, P.W.; Brouwer, K.L. Risk factors for development of cholestatic drug-induced liver injury: Inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab. Dispos.,  2014, 42(4), 665-674.
[http://dx.doi.org/10.1124/dmd.113.054304] [PMID:  24154606] 
[96] 
Dawson, S.; Stahl, S.; Paul, N.; Barber, J.; Kenna, J.G. In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab. Dispos.,  2012, 40(1), 130-138.
[http://dx.doi.org/10.1124/dmd.111.040758] [PMID:  21965623] 
[97] 
Pérez, L.M.; Milkiewicz, P.; Elias, E.; Coleman, R.; Sánchez Pozzi, E.J.; Roma, M.G. Oxidative stress induces internalization of the bile salt export pump, Bsep, and bile salt secretory failure in isolated rat hepatocyte couplets: A role for protein kinase C and prevention by protein kinase A. Toxicol. Sci.,  2006, 91(1), 150-158.
[http://dx.doi.org/10.1093/toxsci/kfj113] [PMID:  16452108] 
[98] 
Misra, S.; Varticovski, L.; Arias, I.M. Mechanisms by which cAMP increases bile acid secretion in rat liver and canalicular membrane vesicles. Am. J. Physiol. Gastrointest. Liver Physiol.,  2003, 285(2), G316-G324.
[http://dx.doi.org/10.1152/ajpgi.00048.2003] [PMID:  12702492] 
[99] 
Kubitz, R.; Sütfels, G.; Kühlkamp, T.; Kölling, R.; Häussinger, D. Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase. Gastroenterology,  2004, 126(2), 541-553.
[http://dx.doi.org/10.1053/j.gastro.2003.11.003] [PMID:  14762791] 
[100] 
Román, I.D.; Fernández-Moreno, M.D.; Fueyo, J.A.; Roma, M.G.; Coleman, R. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol. Sci.,  2003, 71(2), 276-281.
[http://dx.doi.org/10.1093/toxsci/71.2.276] [PMID:  12563113] 
[101] 
Crocenzi, F.A.; Mottino, A.D.; Cao, J.; Veggi, L.M.; Pozzi, E.J.; Vore, M.; Coleman, R.; Roma, M.G. Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats. Am. J. Physiol. Gastrointest. Liver Physiol.,  2003, 285(2), G449-G459.
[http://dx.doi.org/10.1152/ajpgi.00508.2002] [PMID:  12702498] 
[102] 
Boaglio, A.C.; Zucchetti, A.E.; Sánchez Pozzi, E.J.; Pellegrino, J.M.; Ochoa, J.E.; Mottino, A.D.; Vore, M.; Crocenzi, F.A.; Roma, M.G. Phosphoinositide 3-kinase/protein kinase B signaling pathway is involved in estradiol 17β-D-glucuronide-induced cholestasis: Complementarity with classical protein kinase C. Hepatology,  2010, 52(4), 1465-1476.
[http://dx.doi.org/10.1002/hep.23846] [PMID:  20815017] 
[103] 
Crocenzi, F.A.; Sánchez Pozzi, E.J.; Ruiz, M.L.; Zucchetti, A.E.; Roma, M.G.; Mottino, A.D.; Vore, M. Ca(2+)-dependent protein kinase C isoforms are critical to estradiol 17beta-D-glucuronide-induced cholestasis in the rat. Hepatology,  2008, 48(6), 1885-1895.
[http://dx.doi.org/10.1002/hep.22532] [PMID:  18972403] 
[104] 
Hayashi, H.; Inamura, K.; Aida, K.; Naoi, S.; Horikawa, R.; Nagasaka, H.; Takatani, T.; Fukushima, T.; Hattori, A.; Yabuki, T.; Horii, I.; Sugiyama, Y. AP2 adaptor complex mediates bile salt export pump internalization and modulates its hepatocanalicular expression and transport function. Hepatology,  2012, 55(6), 1889-1900.
[http://dx.doi.org/10.1002/hep.25591] [PMID:  22262466] 
[105] 
Ortiz, D.F.; Moseley, J.; Calderon, G.; Swift, A.L.; Li, S.; Arias, I.M. Identification of HAX-1 as a protein that binds bile salt export protein and regulates its abundance in the apical membrane of Madin-Darby canine kidney cells. J. Biol. Chem.,  2004, 279(31), 32761-32770.
[http://dx.doi.org/10.1074/jbc.M404337200] [PMID:  15159385] 
[106] 
Cheng, Y.; Woolf, T.F.; Gan, J.; He, K. In vitro model systems to investigate Bile Salt Export Pump (BSEP) activity and drug interactions: A review. Chem. Biol. Interact.,  2016, 255, 23-30.
[http://dx.doi.org/10.1016/j.cbi.2015.11.029] [PMID:  26683212] 
[107] 
Barber, J.A.; Stahl, S.H.; Summers, C.; Barrett, G.; Park, B.K.; Foster, J.R.; Kenna, J.G. Quantification of drug-induced inhibition of canalicular cholyl-l-lysyl-fluorescein excretion from hepatocytes by high content cell imaging. Toxicol. Sci.,  2015, 148(1), 48-59.
[http://dx.doi.org/10.1093/toxsci/kfv159] [PMID:  26220638] 
[108] 
Morgan, R.E.; Van Staden, C.J.; Chen, Y.; Kalyanaraman, N.; Kalanzi, J.; Dunn, R.T., II; Afshari, C.A.; Hamadeh, H.K. A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol. Sci.,  2013, 136(1), 216-241.
[http://dx.doi.org/10.1093/toxsci/kft176] [PMID:  23956101] 
[109] 
Ali, I.; Welch, M.A.; Lu, Y.; Swaan, P.W.; Brouwer, K.L.R. Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay. Eur. J. Pharm. Sci.,  2017, 103, 52-59.
[http://dx.doi.org/10.1016/j.ejps.2017.02.011] [PMID:  28238947] 
[110] 
Aleo, M.D.; Shah, F.; He, K.; Bonin, P.D.; Rodrigues, A.D. Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals. Chem. Res. Toxicol.,  2017, 30(5), 1219-1229.
[http://dx.doi.org/10.1021/acs.chemrestox.7b00048] [PMID:  28437613] 
[111] 
LeCluyse, E.L.; Audus, K.L.; Hochman, J.H. Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am. J. Physiol.,  1994, 266(6 Pt 1), C1764-C1774.
[http://dx.doi.org/10.1152/ajpcell.1994.266.6.C1764] [PMID:  8023906] 
[112] 
Liu, X.; Brouwer, K.L.; Gan, L.S.; Brouwer, K.R.; Stieger, B.; Meier, P.J.; Audus, K.L.; LeCluyse, E.L. Partial maintenance of taurocholate uptake by adult rat hepatocytes cultured in a collagen sandwich configuration. Pharm. Res.,  1998, 15(10), 1533-1539.
[http://dx.doi.org/10.1023/A:1011994831139] [PMID:  9794494] 
[113] 
Liu, X.; Chism, J.P.; LeCluyse, E.L.; Brouwer, K.R.; Brouwer, K.L. Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab. Dispos.,  1999, 27(6), 637-644.
[PMID:  10348791] 
[114] 
Liu, X.; LeCluyse, E.L.; Brouwer, K.R.; Gan, L.S.; Lemasters, J.J.; Stieger, B.; Meier, P.J.; Brouwer, K.L. Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am. J. Physiol.,  1999, 277(1), G12-G21.
[PMID:  10409146] 
[115] 
Swift, B.; Pfeifer, N.D.; Brouwer, K.L. Sandwich-cultured hepatocytes: An in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab. Rev.,  2010, 42(3), 446-471.
[http://dx.doi.org/10.3109/03602530903491881] [PMID:  20109035] 
[116] 
Bachour-El Azzi, P.; Sharanek, A.; Burban, A.; Li, R.; Guével, R.L.; Abdel-Razzak, Z.; Stieger, B.; Guguen-Guillouzo, C.; Guillouzo, A. Comparative localization and functional activity of the main hepatobiliary transporters in HepaRG cells and primary human hepatocytes. Toxicol. Sci.,  2015, 145(1), 157-168.
[http://dx.doi.org/10.1093/toxsci/kfv041] [PMID:  25690737] 
[117] 
Schaefer, M.; Morinaga, G.; Matsui, A.; Schänzle, G.; Bischoff, D.; Süssmuth, R.D. Quantitative expression of hepatobiliary transporters and functional uptake of substrates in hepatic two-dimensional sandwich cultures: A comparative evaluation of upcyte and primary human hepatocytes. Drug Metab. Dispos.,  2018, 46(2), 166-177.
[http://dx.doi.org/10.1124/dmd.117.078238] [PMID:  29212823] 
[118] 
Parent, R.; Marion, M.J.; Furio, L.; Trépo, C.; Petit, M.A. Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology,  2004, 126(4), 1147-1156.
[http://dx.doi.org/10.1053/j.gastro.2004.01.002] [PMID:  15057753] 
[119] 
Cerec, V.; Glaise, D.; Garnier, D.; Morosan, S.; Turlin, B.; Drenou, B.; Gripon, P.; Kremsdorf, D.; Guguen-Guillouzo, C.; Corlu, A. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor. Hepatology,  2007, 45(4), 957-967.
[http://dx.doi.org/10.1002/hep.21536] [PMID:  17393521] 
[120] 
Qiu, X.; Zhang, Y.; Liu, T.; Shen, H.; Xiao, Y.; Bourner, M.J.; Pratt, J.R.; Thompson, D.C.; Marathe, P.; Humphreys, W.G.; Lai, Y. Disruption of BSEP function in HepaRG Cells alters bile acid disposition and is a susceptive factor to drug-induced cholestatic injury. Mol. Pharm.,  2016, 13(4), 1206-1216.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00659] [PMID:  26910619] 
[121] 
Mills, J.B.; Rose, K.A.; Sadagopan, N.; Sahi, J.; de Morais, S.M. Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J. Pharmacol. Exp. Ther.,  2004, 309(1), 303-309.
[http://dx.doi.org/10.1124/jpet.103.061713] [PMID:  14722322] 
[122] 
Zuo, R.; Li, F.; Parikh, S.; Cao, L.; Cooper, K.L.; Hong, Y.; Liu, J.; Faris, R.A.; Li, D.; Wang, H. Evaluation of a novel renewable hepatic cell model for prediction of clinical CYP3A4 induction using a correlation-based relative induction score approach. Drug Metab. Dispos.,  2017, 45(2), 198-207.
[http://dx.doi.org/10.1124/dmd.116.072124] [PMID:  28062541] 
[123] 
Kenny, J.R.; Chen, L.; McGinnity, D.F.; Grime, K.; Shakesheff, K.M.; Thomson, B.; Riley, R. Efficient assessment of the utility of immortalized Fa2N-4 cells for Cytochrome P450 (CYP) induction studies using multiplex Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) and substrate cassette methodologies. Xenobiotica,  2008, 38(12), 1500-1517.
[http://dx.doi.org/10.1080/00498250802495846] [PMID:  18989830] 
[124] 
McGinnity, D.F.; Zhang, G.; Kenny, J.R.; Hamilton, G.A.; Otmani, S.; Stams, K.R.; Haney, S.; Brassil, P.; Stresser, D.M.; Riley, R.J. Evaluation of multiple in vitro systems for assessment of CYP3A4 induction in drug discovery: Human hepatocytes, pregnane X receptor reporter gene, and Fa2N-4 and HepaRG cells. Drug Metab. Dispos.,  2009, 37(6), 1259-1268.
[http://dx.doi.org/10.1124/dmd.109.026526] [PMID:  19307295] 
[125] 
Ni, X.; Gao, Y.; Wu, Z.; Ma, L.; Chen, C.; Wang, L.; Lin, Y.; Hui, L.; Pan, G. Functional Human Induced Hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model. Sci. Rep.,  2016, 6, 38694.
[http://dx.doi.org/10.1038/srep38694] [PMID:  27934920] 
[126] 
Nakamori, D.; Akamine, H.; Takayama, K.; Sakurai, F.; Mizuguchi, H. Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction. Sci. Rep.,  2017, 7(1), 16675.
[http://dx.doi.org/10.1038/s41598-017-16856-7] [PMID:  29192290] 
[127] 
Du, Y.; Wang, J.; Jia, J.; Song, N.; Xiang, C.; Xu, J.; Hou, Z.; Su, X.; Liu, B.; Jiang, T.; Zhao, D.; Sun, Y.; Shu, J.; Guo, Q.; Yin, M.; Sun, D.; Lu, S.; Shi, Y.; Deng, H. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell,  2014, 14(3), 394-403.
[http://dx.doi.org/10.1016/j.stem.2014.01.008] [PMID:  24582926] 
[128] 
Huang, P.; Zhang, L.; Gao, Y.; He, Z.; Yao, D.; Wu, Z.; Cen, J.; Chen, X.; Liu, C.; Hu, Y.; Lai, D.; Hu, Z.; Chen, L.; Zhang, Y.; Cheng, X.; Ma, X.; Pan, G.; Wang, X.; Hui, L. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell,  2014, 14(3), 370-384.
[http://dx.doi.org/10.1016/j.stem.2014.01.003] [PMID:  24582927] 
[129] 
Burkard, A.; Dähn, C.; Heinz, S.; Zutavern, A.; Sonntag-Buck, V.; Maltman, D.; Przyborski, S.; Hewitt, N.J.; Braspenning, J. Generation of proliferating human hepatocytes using Upcyte® technology: Characterisation and applications in induction and cytotoxicity assays. Xenobiotica,  2012, 42(10), 939-956.
[http://dx.doi.org/10.3109/00498254.2012.675093] [PMID:  22524704] 
[130] 
Ramachandran, S.D.; Vivarès, A.; Klieber, S.; Hewitt, N.J.; Muenst, B.; Heinz, S.; Walles, H.; Braspenning, J. Applicability of second-generation upcyte® human hepatocytes for use in CYP inhibition and induction studies. Pharmacol. Res. Perspect.,  2015, 3(5)e00161
[http://dx.doi.org/10.1002/prp2.161] [PMID:  26516577] 
[131] 
Jansen, P.L.; Strautnieks, S.S.; Jacquemin, E.; Hadchouel, M.; Sokal, E.M.; Hooiveld, G.J.; Koning, J.H.; De Jager-Krikken, A.; Kuipers, F.; Stellaard, F.; Bijleveld, C.M.; Gouw, A.; Van Goor, H.; Thompson, R.J.; Müller, M. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology,  1999, 117(6), 1370-1379.
[http://dx.doi.org/10.1016/S0016-5085(99)70287-8] [PMID:  10579978] 
[132] 
Eloranta, M.L.; Häkli, T.; Hiltunen, M.; Helisalmi, S.; Punnonen, K.; Heinonen, S. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy. Scand. J. Gastroenterol.,  2003, 38(6), 648-652.
[http://dx.doi.org/10.1080/00365520310000807] [PMID:  12825874] 
[133] 
Xu, J.J.; Henstock, P.V.; Dunn, M.C.; Smith, A.R.; Chabot, J.R.; De Graaf, D. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci.,  2008, 105(1), 97-105.
[http://dx.doi.org/10.1093/toxsci/kfn109] [PMID:  18524759] 
[134] 
Lee, H.; Chae, S.; Kim, J.Y.; Han, W.; Kim, J.; Choi, Y.; Cho, D.W. Cell-printed 3D liver-on-a-chip possessing a liver microenvironment and biliary system. Biofabrication,  2019, 11(2)025001
[http://dx.doi.org/10.1088/1758-5090/aaf9fa] [PMID:  30566930] 
[135] 
Vernetti, L.A.; Senutovitch, N.; Boltz, R.; DeBiasio, R.; Shun, T.Y.; Gough, A.; Taylor, D.L. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Exp. Biol. Med. (Maywood),  2016, 241(1), 101-114.
[http://dx.doi.org/10.1177/1535370215592121] [PMID:  26202373] 
[136] 
Bhise, N.S.; Manoharan, V.; Massa, S.; Tamayol, A.; Ghaderi, M.; Miscuglio, M.; Lang, Q.; Shrike Zhang, Y.; Shin, S.R.; Calzone, G.; Annabi, N.; Shupe, T.D.; Bishop, C.E.; Atala, A.; Dokmeci, M.R.; Khademhosseini, A. A liver-on-a-chip platform with bioprinted hepatic spheroids. Biofabrication,  2016, 8(1)014101
[http://dx.doi.org/10.1088/1758-5090/8/1/014101] [PMID:  26756674] 
[137] 
Bhushan, A.; Senutovitch, N.; Bale, S.S.; McCarty, W.J.; Hegde, M.; Jindal, R.; Golberg, I.; Berk Usta, O.; Yarmush, M.L.; Vernetti, L.; Gough, A.; Bakan, A.; Shun, T.Y.; DeBiasio, R.; Lansing Taylor, D. Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans. Stem Cell Res. Ther.,  2013, 4(Suppl. 1), S16.
[http://dx.doi.org/10.1186/scrt377] [PMID:  24565476] 
[138] 
Ramaiahgari, S.C.; Den Braver, M.W.; Herpers, B.; Terpstra, V.; Commandeur, J.N.; Van De Water, B.; Price, L.S. A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies. Arch. Toxicol.,  2014, 88(5), 1083-1095.
[http://dx.doi.org/10.1007/s00204-014-1215-9] [PMID:  24599296] 
[139] 
Bell, C.C.; Hendriks, D.F.; Moro, S.M.; Ellis, E.; Walsh, J.; Renblom, A.; Fredriksson Puigvert, L.; Dankers, A.C.; Jacobs, F.; Snoeys, J.; Sison-Young, R.L.; Jenkins, R.E.; Nordling, Å.; Mkrtchian, S.; Park, B.K.; Kitteringham, N.R.; Goldring, C.E.; Lauschke, V.M.; Ingelman-Sundberg, M. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci. Rep.,  2016, 6, 25187.
[http://dx.doi.org/10.1038/srep25187] [PMID:  27143246] 
[140] 
Proctor, W.R.; Foster, A.J.; Vogt, J.; Summers, C.; Middleton, B.; Pilling, M.A.; Shienson, D.; Kijanska, M.; Ströbel, S.; Kelm, J.M.; Morgan, P.; Messner, S.; Williams, D. Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury. Arch. Toxicol.,  2017, 91(8), 2849-2863.
[http://dx.doi.org/10.1007/s00204-017-2002-1] [PMID:  28612260] 
[141] 
Hendriks, D.F.; Fredriksson Puigvert, L.; Messner, S.; Mortiz, W.; Ingelman-Sundberg, M. Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability. Sci. Rep.,  2016, 6, 35434.
[http://dx.doi.org/10.1038/srep35434] [PMID:  27759057] 
[142] 
Vorrink, S.U.; Zhou, Y.; Ingelman-Sundberg, M.; Lauschke, V.M. Prediction of drug-induced hepatotoxicity using long-term stable primary hepatic 3D spheroid cultures in chemically defined conditions. Toxicol. Sci.,  2018, 163(2), 655-665.
[http://dx.doi.org/10.1093/toxsci/kfy058] [PMID:  29590495] 
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DOI https://dx.doi.org/10.2174/1389200220666190709170256	Print ISSN 1389-2002
Publisher Name Bentham Science Publisher	Online ISSN 1875-5453
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