Recent Progress in Prediction Systems for Drug-induced Liver Injury Using In vitro Cell Culture

Shogo       Ozawa; Toshitaka       Miura; Jun       Terashima; Wataru       Habano; Seiichi       Ishida
Abstract

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed.
Objective: In this study, recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as on the limitations of in vitro cell culture systems for DILI research, was carried out.
Methods: Information related to DILI was collected through a literature search of the PubMed database.
Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4⁺ helper T lymphocytes and recognition by CD8⁺ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILI-inducing drugs, with approximately 50% sensitivity and 90% specificity.
Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.
Keywords: Drug-induced liver injury, human hepatocytes, reactive intermediates, cytochrome P450, Kupffer cells, monocytes, co-culture, immune system.
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Graphical Abstract

[1] 
Stirnimann, G.; Kessebohm, K.; Lauterburg, B. Liver injury caused by drugs: an update. Swiss Med. Wkly.,  2010, 140, w13080.
[http://dx.doi.org/10.4414/smw.2010.13080] [PMID: 20927685] 
[2] 
Hinson, J.A. Reactive metabolites of phenacetin and acetaminophen: a review. Environ. Health Perspect.,  1983, 49, 71-79.
[http://dx.doi.org/10.1289/ehp.834971] [PMID: 6339229] 
[3] 
Larson, A.M. Drug-induced liver injury. UpToDate, 2020.www.uptodate.com/contents/drug-induced-liver-injury
[4] 
Roth, A.D.; Lee, M.Y. Idiosyncratic drug-induced liver injury (IDILI): potential mechanisms and predictive assays. BioMed Res. Int.,  2017, 2017, 9176937.
[http://dx.doi.org/10.1155/2017/9176937] [PMID: 28133614] 
[5] 
Uetrecht, J. Mechanistic studies of idiosyncratic DILI: Clinical implications. Front. Pharmacol.,  2019, 10, 837.
[http://dx.doi.org/10.3389/fphar.2019.00837] [PMID: 31402866] 
[6] 
Koch, D.G.; Speiser, J.L.; Durkalski, V.; Fontana, R.J.; Davern, T.; McGuire, B.; Stravitz, R.T.; Larson, A.M.; Liou, I.; Fix, O.; Schilsky, M.L.; McCashland, T.; Hay, J.E.; Murray, N.; Shaikh, O.S.; Ganger, D.; Zaman, A.; Han, S.B.; Chung, R.T.; Brown, R.S.; Munoz, S., Jr; Reddy, K.R.; Rossaro, L.; Satyanarayana, R.; Hanje, A.J.; Olson, J.; Subramanian, R.M.; Karvellas, C.; Hameed, B.; Sherker, A.H.; Lee, W.M.; Reuben, A. Acute Liver Failure Study Group. The Natural History of Severe Acute Liver Injury. Am. J. Gastroenterol.,  2017, 112(9), 1389-1396.
[http://dx.doi.org/10.1038/ajg.2017.98] [PMID: 28440304] 
[7] 
Davern, T.J., II; James, L.P.; Hinson, J.A.; Polson, J.; Larson, A.M.; Fontana, R.J.; Lalani, E.; Munoz, S.; Shakil, A.O.; Lee, W.M. Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology,  2006, 130(3), 687-694.
[http://dx.doi.org/10.1053/j.gastro.2006.01.033] [PMID: 16530510] 
[8] 
Bartolone, J.B.; Birge, R.B.; Sparks, K.; Cohen, S.D.; Khairallah, E.A. Immunochemical analysis of acetaminophen covalent binding to proteins. Partial characterization of the major acetaminophen-binding liver proteins. Biochem. Pharmacol.,  1988, 37(24), 4763-4774.
[http://dx.doi.org/10.1016/0006-2952(88)90350-4] [PMID: 3060126] 
[9] 
Homberg, J.C.; Andre, C.; Abuaf, N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin. Exp. Immunol.,  1984, 55(3), 561-570.
[PMID: 6368059] 
[10] 
Pirmohamed, M.; Kitteringham, N.R.; Breckenridge, A.M.; Park, B.K. Detection of an autoantibody directed against human liver microsomal protein in a patient with carbamazepine hypersensitivity. Br. J. Clin. Pharmacol.,  1992, 33(2), 183-186.
[http://dx.doi.org/10.1111/j.1365-2125.1992.tb04022.x] [PMID: 1550698] 
[11] 
O’Connor, N.; Dargan, P.I.; Jones, A.L. Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM,  2003, 96(11), 787-791.
[http://dx.doi.org/10.1093/qjmed/hcg138] [PMID: 14566034] 
[12] 
Scully, L.J.; Clarke, D.; Barr, R.J. Diclofenac induced hepatitis. 3 cases with features of autoimmune chronic active hepatitis. Dig. Dis. Sci.,  1993, 38(4), 744-751.
[http://dx.doi.org/10.1007/BF01316809] [PMID: 8462374] 
[13] 
Lecoeur, S.; André, C.; Beaune, P.H. Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol. Pharmacol.,  1996, 50(2), 326-333.
[PMID: 8700140] 
[14] 
Belloc, C.; Gauffre, A.; André, C.; Beaune, P.H. Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis. Pharmacogenetics,  1997, 7(3), 181-186.
[http://dx.doi.org/10.1097/00008571-199706000-00002] [PMID: 9241657] 
[15] 
Walton, B.; Simpson, B.R.; Strunin, L.; Doniach, D.; Perrin, J.; Appleyard, A.J. Unexplained hepatitis following halothane. BMJ,  1976, 1(6019), 1171-1176.
[http://dx.doi.org/10.1136/bmj.1.6019.1171] [PMID: 1268612] 
[16] 
McKenzie, R.; Fried, M.W.; Sallie, R.; Conjeevaram, H.; Di Bisceglie, A.M.; Park, Y.; Savarese, B.; Kleiner, D.; Tsokos, M.; Luciano, C. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N. Engl. J. Med.,  1995, 333(17), 1099-1105.
[http://dx.doi.org/10.1056/NEJM199510263331702] [PMID: 7565947] 
[17] 
Ware, B.R.; Brown, G.E.; Soldatow, V.Y.; LeCluyse, E.L.; Khetani, S.R. Long-term engineered cultures of primary mouse hepatocytes for strain and species comparison studies during drug development. Gene Expr.,  2019, 19(3), 199-214.
[http://dx.doi.org/10.3727/105221619X15638857793317] [PMID: 31340881] 
[18] 
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] 
[19] 
Rendic, S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev.,  2002, 34(1-2), 83-448.
[http://dx.doi.org/10.1081/DMR-120001392] [PMID: 11996015] 
[20] 
Kharasch, E.D.; Regina, K.J.; Blood, J.; Friedel, C. Methadone pharmacogenetics: CYP2B6 polymorphisms determine plasma concentrations, clearance and metabolism. Anesthesiology,  2015, 123(5), 1142-1153.
[http://dx.doi.org/10.1097/ALN.0000000000000867] [PMID: 26389554] 
[21] 
Shu, W.; Guan, S.; Yang, X.; Liang, L.; Li, J.; Chen, Z.; Zhang, Y.; Chen, L.; Wang, X.; Huang, M. Genetic markers in CYP2C19 and CYP2B6 for prediction of cyclophosphamide’s 4-hydroxylation, efficacy and side effects in Chinese patients with systemic lupus erythematosus. Br. J. Clin. Pharmacol.,  2016, 81(2), 327-340.
[http://dx.doi.org/10.1111/bcp.12800] [PMID: 26456622] 
[22] 
Mhandire, D.; Lacerda, M.; Castel, S.; Mhandire, K.; Zhou, D.; Swart, M.; Shamu, T. Smith, P.; Musingwini, T.; Wiesner, L.; Stray-Pedersen, B.; Dandara, C. Effects of CYP2B6 and CYP1A2 Genetic Variation on Nevirapine Plasma Concentration and harmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients. OMICS,  2015, 19, 553-562.
[http://dx.doi.org/10.1089/omi.2015.0104] [PMID: 26348712] 
[23] 
Yamazaki, H.; Shibata, A.; Suzuki, M.; Nakajima, M.; Shimada, N.; Guengerich, F.P.; Yokoi, T. Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab. Dispos.,  1999, 27(11), 1260-1266.
[PMID: 10534310] 
[24] 
Zeman, M.V.; Hirschfield, G.M. Autoantibodies and liver disease: uses and abuses. Can. J. Gastroenterol.,  2010, 24(4), 225-231.
[http://dx.doi.org/10.1155/2010/431913] [PMID: 20431809] 
[25] 
Tsouris, Z.; Liaskos, C.; Dardiotis, E.; Scheper, T.; Tsimourtou, V.; Meyer, W.; Hadjigeorgiou, G.; Bogdanos, D.P. A comprehensive analysis of antigen-specific autoimmune liver disease related autoantibodies in patients with multiple sclerosis. Auto Immun. Highlights,  2020, 11(1), 7.
[http://dx.doi.org/10.1186/s13317-020-00130-4] [PMID: 32308974] 
[26] 
Obermayer-Straub, P.; Strassburg, C.P.; Manns, M.P. Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases. Can. J. Gastroenterol.,  2000, 14(5), 429-439.
[http://dx.doi.org/10.1155/2000/910107] [PMID: 10851284] 
[27] 
Rowland, K.; Yeo, W.W.; Ellis, S.W.; Chadwick, I.G.; Haq, I.; Lennard, M.S.; Jackson, P.R.; Ramsay, L.E.; Tucker, G.T. Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4-hydroxy propranolol. Br. J. Clin. Pharmacol.,  1994, 38(1), 9-14.
[http://dx.doi.org/10.1111/j.1365-2125.1994.tb04315.x] [PMID: 7946944] 
[28] 
Goetz, M.P.; Kamal, A.; Ames, M.M. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin. Pharmacol. Ther.,  2008, 83(1), 160-166.
[http://dx.doi.org/10.1038/sj.clpt.6100367] [PMID: 17882159] 
[29] 
Sutti, S.; Rigamonti, C.; Vidali, M.; Albano, E. CYP2E1 autoantibodies in liver diseases. Redox Biol.,  2014, 3, 72-78.
[http://dx.doi.org/10.1016/j.redox.2014.11.004] [PMID: 25462068] 
[30] 
Patten, C.J.; Ishizaki, H.; Aoyama, T.; Lee, M.; Ning, S.M.; Huang, W.; Gonzalez, F.J.; Yang, C.S. Catalytic properties of the human cytochrome P450 2E1 produced by cDNA expression in mammalian cells. Arch. Biochem. Biophys.,  1992, 299(1), 163-171.
[http://dx.doi.org/10.1016/0003-9861(92)90258-X] [PMID: 1444447] 
[31] 
Brodie, M.J.; Forrest, G.; Rapeport, W.G. Carbamazepine 10, 11 epoxide concentrations in epileptics on carbamazepine alone and in combination with other anticonvulsants. Br. J. Clin. Pharmacol.,  1983, 16(6), 747-749.
[http://dx.doi.org/10.1111/j.1365-2125.1983.tb02257.x] [PMID: 6661364] 
[32] 
De Berardinis, V.; Moulis, C.; Maurice, M.; Beaune, P.; Pessayre, D.; Pompon, D.; Loeper, J. Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. Mol. Pharmacol.,  2000, 58(3), 542-551.
[http://dx.doi.org/10.1124/mol.58.3.542] [PMID: 10953047] 
[33] 
Riley, R.J.; Kitteringham, N.R.; Park, B.K. Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro. Br. J. Clin. Pharmacol.,  1989, 28(4), 482-487.
[http://dx.doi.org/10.1111/j.1365-2125.1989.tb03530.x] [PMID: 2590607] 
[34] 
Wolf, K.K.; Wood, S.G.; Allard, J.L.; Hunt, J.A.; Gorman, N.; Walton-Strong, B.W.; Szakacs, J.G.; Duan, S.X.; Hao, Q.; Court, M.H.; von Moltke, L.L.; Greenblatt, D.J.; Kostrubsky, V.; Jeffery, E.H.; Wrighton, S.A.; Gonzalez, F.J.; Sinclair, P.R.; Sinclair, J.F. Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: comparison of wild-type and Cyp2e1(-/-) mice. Drug Metab. Dispos.,  2007, 35(7), 1223-1231.
[http://dx.doi.org/10.1124/dmd.107.014738] [PMID: 17392391] 
[35] 
Thummel, K.E.; Lee, C.A.; Kunze, K.L.; Nelson, S.D.; Slattery, J.T. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem. Pharmacol.,  1993, 45(8), 1563-1569.
[http://dx.doi.org/10.1016/0006-2952(93)90295-8] [PMID: 8387297] 
[36] 
Kullak-Ublick, G.A.; Andrade, R.J.; Merz, M.; End, P.; Benesic, A.; Gerbes, A.L.; Aithal, G.P. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut,  2017, 66(6), 1154-1164.
[http://dx.doi.org/10.1136/gutjnl-2016-313369] [PMID: 28341748] 
[37] 
Zhang, X.; Liu, F.; Chen, X.; Zhu, X.; Uetrecht, J. Involvement of the immune system in idiosyncratic drug reactions. Drug Metab. Pharmacokinet.,  2011, 26(1), 47-59.
[http://dx.doi.org/10.2133/dmpk.DMPK-10-RV-085] [PMID: 21084762] 
[38] 
Ikeda, T. Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. Drug Metab. Pharmacokinet.,  2011, 26(1), 60-70.
[http://dx.doi.org/10.2133/dmpk.DMPK-10-RV-090] [PMID: 21178300] 
[39] 
Mauri-Hellweg, D.; Bettens, F.; Mauri, D.; Brander, C.; Hunziker, T.; Pichler, W.J. Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J. Immunol.,  1995, 155(1), 462-472.
[PMID: 7602118] 
[40] 
Yaseen, F.S.; Saide, K.; Kim, S.H.; Monshi, M.; Tailor, A.; Wood, S.; Meng, X.; Jenkins, R.; Faulkner, L.; Daly, A.K.; Pirmohamed, M.; Park, B.K.; Naisbitt, D.J. Promiscuous T-cell responses to drugs and drug-haptens. J. Allergy Clin. Immunol.,  2015, 136(2), 474-6.e8.
[http://dx.doi.org/10.1016/j.jaci.2015.02.036] [PMID: 25910715] 
[41] 
Daly, A.K.; Donaldson, P.T.; Bhatnagar, P.; Shen, Y.; Pe’er, I.; Floratos, A.; Daly, M.J.; Goldstein, D.B.; John, S.; Nelson, M.R.; Graham, J.; Park, B.K.; Dillon, J.F.; Bernal, W.; Cordell, H.J.; Pirmohamed, M.; Aithal, G.P.; Day, C.P. DILIGEN Study; International SAE Consortium. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet.,  2009, 41(7), 816-819.
[http://dx.doi.org/10.1038/ng.379] [PMID: 19483685] 
[42] 
Guillouzo, A. Liver cell models in in vitro toxicology. Environ. Health Perspect.,  1998, 106(Suppl. 2), 511-532.
[PMID: 9599700] 
[43] 
Ozawa, S.; Ohta, K.; Miyajima, A.; Kurebayashi, H.; Sunouchi, M.; Shimizu, M.; Murayama, N.; Matsumoto, Y.; Fukuoka, M.; Ohno, Y. Metabolic activation of o-phenylphenol to a major cytotoxic metabolite, phenylhydroquinone: role of human CYP1A2 and rat CYP2C11/CYP2E1. Xenobiotica,  2000, 30(10), 1005-1017.
[http://dx.doi.org/10.1080/00498250050200159] [PMID: 11315102] 
[44] 
Donato, M.T.; Jiménez, N.; Castell, J.V.; Gómez-Lechón, M.J. Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes. Drug Metab. Dispos.,  2004, 32(7), 699-706.
[http://dx.doi.org/10.1124/dmd.32.7.699] [PMID: 15205384] 
[45] 
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] 
[46] 
Yang, K.; Guo, C.; Woodhead, J.L.; St Claire, R.L., III; Watkins, P.B.; Siler, S.Q.; Howell, B.A.; Brouwer, K.L.R. Sandwich-cultured hepatocytes as a tool to study drug disposition and drug-induced liver injury. J. Pharm. Sci.,  2016, 105(2), 443-459.
[http://dx.doi.org/10.1016/j.xphs.2015.11.008] [PMID: 26869411] 
[47] 
Treijtel, N.; Barendregt, A.; Freidig, A.P.; Blaauboer, B.J.; van Eijkeren, J.C. Modeling the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide determined in sandwich-cultured rat hepatocytes. Drug Metab. Dispos.,  2004, 32(8), 884-891.
[http://dx.doi.org/10.1124/dmd.32.8.884] [PMID: 15258115] 
[48] 
Treijtel, N.; van Helvoort, H.; Barendregt, A.; Blaauboer, B.J.; van Eijkeren, J.C. The use of sandwich-cultured rat hepatocytes to determine the intrinsic clearance of compounds with different extraction ratios: 7-ethoxycoumarin and warfarin. Drug Metab. Dispos.,  2005, 33(9), 1325-1332.
[http://dx.doi.org/10.1124/dmd.105.004390] [PMID: 15951450] 
[49] 
Khetani, S.R.; Bhatia, S.N. Microscale culture of human liver cells for drug development. Nat. Biotechnol.,  2008, 26(1), 120-126.
[http://dx.doi.org/10.1038/nbt1361] [PMID: 18026090] 
[50] 
Wang, W.W.; Khetani, S.R.; Krzyzewski, S.; Duignan, D.B.; Obach, R.S. Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites. Drug Metab. Dispos.,  2010, 38(10), 1900-1905.
[http://dx.doi.org/10.1124/dmd.110.034876] [PMID: 20595376] 
[51] 
Ware, B.R.; Berger, D.R.; Khetani, S.R. Prediction of drug-induced liver injury in micropatterned co-cultures containing iPSC-derived human hepatocytes. Toxicol. Sci.,  2015, 145(2), 252-262.
[http://dx.doi.org/10.1093/toxsci/kfv048] [PMID: 25716675] 
[52] 
Chen, M.; Zhang, J.; Wang, Y.; Liu, Z.; Kelly, R.; Zhou, G.; Fang, H.; Borlak, J.; Tong, W. The liver toxicity knowledge base: a systems approach to a complex end point. Clin. Pharmacol. Ther.,  2013, 93(5), 409-412.
[http://dx.doi.org/10.1038/clpt.2013.16] [PMID: 23486446] 
[53] 
Granitzny, A.; Knebel, J.; Müller, M.; Braun, A.; Steinberg, P.; Dasenbrock, C.; Hansen, T. Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study. Toxicol. Rep.,  2017, 4, 89-103.
[http://dx.doi.org/10.1016/j.toxrep.2017.02.001] [PMID: 28959630] 
[54] 
Ozawa, S.; Tamura, H.; Omura, R.; Sato, H.; Suzuki, R.; Ono, L.; Yoshida, K.; Kikuchi, T.; Namba, T.; Ishida, S.; Terashima, J.; Habano, W. A Hepatocellular co-culture system for the investigation of cellular-based mechanisms of troglitazone-induced liver injury. Jap. J. Gastroenterol. Hepatol,  2020, 4, 1-5.
[55] 
Nguyen, T.V.; Ukairo, O.; Khetani, S.R.; McVay, M.; Kanchagar, C.; Seghezzi, W.; Ayanoglu, G.; Irrechukwu, O.; Evers, R. Establishment of a hepatocyte-kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters. Drug Metab. Dispos.,  2015, 43(5), 774-785.
[http://dx.doi.org/10.1124/dmd.114.061317] [PMID: 25739975] 
[56] 
Nakai, K.; Tanaka, H.; Hanada, K.; Ogata, H.; Suzuki, F.; Kumada, H.; Miyajima, A.; Ishida, S.; Sunouchi, M.; Habano, W.; Kamikawa, Y.; Kubota, K.; Kita, J.; Ozawa, S.; Ohno, Y. Decreased expression of cytochromes P450 1A2, 2E1, and 3A4 and drug transporters Na+-taurocholate-cotransporting polypeptide, organic cation transporter 1, and organic anion-transporting peptide-C correlates with the progression of liver fibrosis in chronic hepatitis C patients. Drug Metab. Dispos.,  2008, 36(9), 1786-1793.
[http://dx.doi.org/10.1124/dmd.107.020073] [PMID: 18515332] 
[57] 
Hanada, K.; Nakai, K.; Tanaka, H.; Suzuki, F.; Kumada, H.; Ohno, Y.; Ozawa, S.; Ogata, H. Effect of nuclear receptor downregulation on hepatic expression of cytochrome P450 and transporters in chronic hepatitis C in association with fibrosis development. Drug Metab. Pharmacokinet.,  2012, 27(3), 301-306.
[http://dx.doi.org/10.2133/dmpk.DMPK-11-RG-077] [PMID: 22166890] 
[58] 
Kostadinova, R.; Boess, F.; Applegate, D.; Suter, L.; Weiser, T.; Singer, T.; Naughton, B.; Roth, A. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity. Toxicol. Appl. Pharmacol.,  2013, 268(1), 1-16.
[http://dx.doi.org/10.1016/j.taap.2013.01.012] [PMID: 23352505] 
[59] 
Rose, K.A.; Holman, N.S.; Green, A.M.; Andersen, M.E.; LeCluyse, E.L. Co-culture of hepatocytes and Kupffer cells as an in vitro model of inflammation and drug-induced hepatotoxicity. J. Pharm. Sci.,  2016, 105(2), 950-964.
[http://dx.doi.org/10.1016/S0022-3549(15)00192-6] [PMID: 26869439] 
[60] 
Baze, A.; Parmentier, C.; Hendriks, D.F.G.; Hurrell, T.; Heyd, B.; Bachellier, P.; Schuster, C.; Ingelman-Sundberg, M.; Richert, L. Three-dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Eng. Part C Methods,  2018, 24(9), 534-545.
[http://dx.doi.org/10.1089/ten.tec.2018.0134] [PMID: 30101670] 
[61] 
Oda, S.; Matsuo, K.; Nakajima, A.; Yokoi, T. A novel cell-based assay for the evaluation of immune- and inflammatory-related gene expression as biomarkers for the risk assessment of drug-induced liver injury. Toxicol. Lett.,  2016, 241, 60-70.
[http://dx.doi.org/10.1016/j.toxlet.2015.10.029] [PMID: 26546780] 
[62] 
Woolbright, B.L.; Jaeschke, H. Mechanisms of inflammatory liver injury and drug-induced hepatotoxicity. Curr. Pharmacol. Rep.,  2018, 4(5), 346-357.
[http://dx.doi.org/10.1007/s40495-018-0147-0] [PMID: 30560047] 
[63] 
Warrington, R.J.; Tse, K.S. Lymphocyte transformation studies in drug hypersensitivity. Can. Med. Assoc. J.,  1979, 120(9), 1089-1094.
[PMID: 445303] 
[64] 
Maria, V.A.; Victorino, R.M. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut,  1997, 41(4), 534-540.
[http://dx.doi.org/10.1136/gut.41.4.534] [PMID: 9391255] 
[65] 
Kaplowitz, N. Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discov.,  2005, 4(6), 489-499.
[http://dx.doi.org/10.1038/nrd1750] [PMID: 15931258] 
[66] 
Kano, Y.; Hirahara, K.; Mitsuyama, Y.; Takahashi, R.; Shiohara, T. Utility of the lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy,  2007, 62(12), 1439-1444.
[http://dx.doi.org/10.1111/j.1398-9995.2007.01553.x] [PMID: 17983378] 
[67] 
Whritenour, J.; Ko, M.; Zong, Q.; Wang, J.; Tartaro, K.; Schneider, P.; Olson, E.; Van Volkenburg, M.; Serrano, J.; Hayashi, P.; Fontana, R.; Chalasani, N.; Bonkovsky, H.L. Development of a modified lymphocyte transformation test for diagnosing drug-induced liver injury associated with an adaptive immune response. J. Immunotoxicol.,  2017, 14(1), 31-38.
[http://dx.doi.org/10.1080/1547691X.2016.1254305] [PMID: 28121193] 
[68] 
Fontana, R.J.; Watkins, P.B.; Bonkovsky, H.L.; Chalasani, N.; Davern, T.; Serrano, J.; Rochon, J. DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf.,  2009, 32(1), 55-68.
[http://dx.doi.org/10.2165/00002018-200932010-00005] [PMID: 19132805] 
[69] 
Taghibakhshi, A.; Barisam, M.; Saidi, M.S.; Kashaninejad, N.; Nguyen, N.T. Three-Dimensional Modeling of Avascular Tumor Growth in Both Static and Dynamic Culture Platforms. Micromachines (Basel),  2019, 10(9), 580.
[http://dx.doi.org/10.3390/mi10090580] [PMID: 31480431] 
[70] 
Khetani, S.R.; Kanchagar, C.; Ukairo, O.; Krzyzewski, S.; Moore, A.; Shi, J.; Aoyama, S.; Aleo, M.; Will, Y. Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. Toxicol. Sci.,  2013, 132(1), 107-117.
[http://dx.doi.org/10.1093/toxsci/kfs326] [PMID: 23152190] 
[71] 
Hendriks, D.F.G.; Hurrell, T.; Riede, J.; van der Horst, M.; Tuovinen, S.; Ingelman-Sundberg, M. Mechanisms of chronic fialuridine hepatotoxicity as revealed in primary human hepatocyte spheroids. Toxicol. Sci.,  2019, 171, 385-395.
[http://dx.doi.org/10.1093/toxsci/kfz195] [PMID: 31505000] 
[72] 
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] 
[73] 
Hayashi, T.; Takahashi, T.; Minami, T.; Akaike, J.; Kasahara, K.; Adachi, M.; Hinoda, Y.; Takahashi, S.; Hirayama, T.; Imai, K. Fatal acute hepatic failure induced by danazol in a patient with endometriosis and aplastic anemia. J. Gastroenterol.,  2001, 36(11), 783-786.
[http://dx.doi.org/10.1007/s005350170022] [PMID: 11757752] 
[74] 
Heikkinen, J.; Rönnberg, L.; Kirkinen, P.; Sotaniemi, E. Serum bile acid concentrations as an indicator of liver dysfunction induced during danazol therapy. Fertil. Steril.,  1988, 50(5), 761-765.
[http://dx.doi.org/10.1016/S0015-0282(16)60312-6] [PMID: 3181486] 
[75] 
de Abajo, F.J.; Montero, D.; Madurga, M.; García Rodríguez, L.A. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br. J. Clin. Pharmacol.,  2004, 58(1), 71-80.
[http://dx.doi.org/10.1111/j.1365-2125.2004.02133.x] [PMID: 15206996] 
[76] 
Mattes, W.B.; Kamp, H.G.; Fabian, E.; Herold, M.; Krennrich, G.; Looser, R.; Mellert, W.; Prokoudine, A.; Strauss, V.; van Ravenzwaay, B.; Walk, T.; Naraoka, H.; Omura, K.; Schuppe-Koistinen, I.; Nadanaciva, S.; Bush, E.D.; Moeller, N.; Ruiz-Noppinger, P.; Piccoli, S.P. Prediction of clinically relevant safety signals of nephrotoxicity through plasma metabolite profiling. Biomed. Res. Int, 2013.  2013, 202497
[http://dx.doi.org/10.1155/2013/202497] 
[77] 
Helliwell, T.R.; Yeung, J.H.K.; Park, B.K. Hepatic necrosis and glutathione depletion in captopril-treated mice. Br. J. Exp. Pathol.,  1985, 66(1), 67-78.
[PMID: 3882119] 
[78] 
Vatakuti, S.; Pennings, J.L.A.; Gore, E.; Olinga, P.; Groothuis, G.M.M. Classification of cholestatic and necrotic hepatotoxicants using transcriptomics on human precision-cut liver slices. Chem. Res. Toxicol.,  2016, 29(3), 342-351.
[http://dx.doi.org/10.1021/acs.chemrestox.5b00491] [PMID: 26881866] 
[79] 
Vallejo, M.; Briz, O.; Serrano, M.A.; Monte, M.J.; Marin, J.J.G. Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy. J. Hepatol.,  2006, 44(6), 1150-1157.
[http://dx.doi.org/10.1016/j.jhep.2005.09.017] [PMID: 16458994] 
[80] 
Yang, J.; Zhang, J.; Xu, Q.; Sheng, G-p.; Weng, W-w.; Dong, M-j. Unusual synchronous methimazole-induced agranulocytosis and severe hepatotoxicity in patient with hyperthyroidism: A case report and review of the literature. Int. J. Endocrinol, 2015. Article ID/34/26
[81] 
Gomez-Peralta, F.; Velasco-Martinez, P.; Abreu, C.; Cepeda, M.; Fernández-Puente, M. Hepatotoxicity in hyperthyroid patient after consecutive methimazole and propylthiouracil therapies. Endocrinol. Diabetes Metabol., 2018. Jan 5, 2018: 17-0173.
[82] 
Heidari, R.; Babaei, H.; Roshangar, L.; Eghbal, M.A. Effects of enzyme induction and/or glutathione depletion on methimazole-induced hepatotoxicity in mice and the protective role of N-acetylcysteine. Adv. Pharm. Bull.,  2014, 4(1), 21-28.
[PMID: 24409405] 
[83] 
Yoshikawa, Y.; Hosomi, H.; Fukami, T.; Nakajima, M.; Yokoi, T. Establishment of knockdown of superoxide dismutase 2 and expression of CYP3A4 cell system to evaluate drug-induced cytotoxicity. Toxicol. In Vitro,  2009, 23(6), 1179-1187.
[http://dx.doi.org/10.1016/j.tiv.2009.05.024] [PMID: 19501153] 
[84] 
Ahmad, M.E.; Shadab, G.G.; Azfer, M.A.; Afzal, M. Evaluation of genotoxic potential of synthetic progestins-norethindrone and norgestrel in human lymphocytes in vitro. Mutat. Res.,  2001, 494(1-2), 13-20.
[http://dx.doi.org/10.1016/S1383-5718(01)00164-4] [PMID: 11423341] 
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DOI https://dx.doi.org/10.2174/1872312814666201202112610	Print ISSN 1872-3128
Publisher Name Bentham Science Publisher	Online ISSN 1874-0758
Drug Metabolism Letters

Recent Progress in Prediction Systems for Drug-induced Liver Injury Using In vitro Cell Culture

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