safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2023-11-2-204-214safetyrisk-365Research ArticleГЛАВНАЯ ТЕМА: ОТ ИССЛЕДОВАНИЙ IN VITRO К IN VIVO И КЛИНИЧЕСКИМ ИССЛЕДОВАНИЯМMAIN TOPIC: FROM IN VITRO EXPERIMENTS TO IN VIVO AND CLINICAL STUDIESИдиосинкратическая лекарственная гепатотоксичность — от патогенеза к снижению рискаIdiosyncratic Drug-Induced Liver Injury: From Pathogenesis to Risk Reductionhttps://orcid.org/0000-0002-3733-6822МазеркинаИ. А.MazerkinaI. A.

Ирина Анатольевна Мазеркина, канд. мед. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Irina A. Mazerkina, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

mazerkina@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202319062023112204214Copyright © Мазеркина И.А., 20232023Мазеркина И.А.Mazerkina I.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.risksafety.ru/jour/article/view/365

Идиосинкратическая лекарственная гепатотоксичность (иЛГТ) — редкое и труднопрогнозируемое осложнение лекарственной терапии, в тяжелых случаях приводящее к смерти пациента или вызывающее необходимость пересадки печени.

Цель работы — обзор современных представлений об иммунном патогенезе иЛГТ и возможностях прогнозирования и предупреждения риска его развития.

Печень обладает высокой иммунотолерантностью, что обеспечивается комплексом механизмов с участием различных клеток (антигенпрезентирующих клеток, Т-лимфоцитов), цитокинов и других молекул, препятствующих развитию иммунных ответных реакций при попадании в организм ксенобиотиков. Показано, что идиосинкратическое лекарственное повреждение печени развивается при комбинации нескольких взаимоусиливающих неблагоприятных факторов, нарушающих иммунотолерантность печени на разных уровнях. К ним относят химические свойства лекарственных средств, определяющие их гепатотоксичность, и индивидуальные особенности организма, в том числе генетически обусловленное строение и функционирование компонентов адаптивной иммунной системы. Многофакторность и разноуровневость патогенеза иЛГТ не позволяет определить биомаркер риска для конкретного лекарственного средства. Анализ данных литературы показал, что на доклиническом этапе снизить риск гепатотоксичности препарата-кандидата и/или метаболита может оценка его способности вызывать повреждение митохондрий, образовывать нековалентные связи, активные формы кислорода, участвовать в высвобождении молекулярных паттернов, ассоциированных с повреждением (DAMPs). Ассоциации иЛГТ при применении некоторых лекарственных средств с полиморфизмами генов у пациентов благодаря высокой отрицательной прогностической ценности могут использоваться в клинической практике для исключения иЛГТ или выявления гепатотоксичного лекарственного средства при полипрагмазии. Перспективным представляется выявление комбинаций нескольких аллелей, ассоциированных с повышенным риском развития иЛГТ, что повысит прогностическую ценность генных исследований и может быть использовано в персонализированной медицине.

Idiosyncratic drug-induced liver injury (iDILI) is a rare and poorly predictable adverse drug reaction that may lead to death or liver transplantation in severe cases.

The aim of the study was to review contemporary concepts of the immune-mediated pathogenesis of iDILI and possible ways to predict and prevent the risk of developing this condition.

The liver is characterised by high immune tolerance due to a complex of mechanisms involving various cells (antigen-presenting cells, T-cells), cytokines, and other molecules, which prevents severe immune responses to xenobiotics entering the body. Previous research has shown that iDILI results from a combination of multiple synergistic unfavourable factors that impair liver immune tolerance at different levels. These factors include the hepatotoxicity-associated chemical properties of medicines and the individual characteristics of the patient, including the genetically determined structure and function of the adaptive immune system components. Since iDILI has a multilevel and multifactor pathogenesis, it is difficult to determine a risk biomarker for a particular medicine. According to the literature review, the risk of hepatotoxicity of a drug candidate and/or a metabolite can be reduced at the preclinical level by assessing the ability to cause mitochondrial damage, form non-covalent bonds, produce reactive oxygen species, and release damage-associated molecular patterns (DAMPs). The association of iDILI with gene polymorphisms in patients receiving certain medicines has a high negative predictive value and can be used in clinical practice to rule out iDILI or identify hepatotoxic medicinal products in polypharmacy. The identification of the allele combinations associated with an increased risk of iDILI seems promising for enhancing the predictive value of genetic studies and may be used in personalised medicine.

идиосинкразиялекарственное повреждение печенипатогенез лекарственной гепатотоксичностииммунотолерантностьТ-клеткисигнальные пути активациигенетические факторы рискачеловеческий лейкоцитарный антигенidiosyncrasydrug-induced hepatotoxicityiDILIpathogenesis of idiosyncratic drug-induced hepatotoxicityimmune toleranceT-cellssignalling pathway activationgenetic risk factorshuman leukocyte antigenHLAРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00052-23-00 на проведение прикладных научных исследований (номер государственного учета НИР 121022400082-4).The study reported in this publication was carried out as part of publicly funded research project No. 056-00052-23-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121022400082-4).ReferencesKwon J, Kim S, Yoo H, Lee E. Nimesulide-induced hepatotoxicity: a systematic review and meta-analysis. PLoS One. 2019;14(1):e0209264. https://doi.org/10.1371/journal.pone.0209264Kwon J, Kim S, Yoo H, Lee E. Nimesulide-induced hepatotoxicity: a systematic review and meta-analysis. PLoS One. 2019;14(1):e0209264. https://doi.org/10.1371/journal.pone.0209264McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014; 4(1):e004221. https://doi.org/10.1136/bmjopen-2013-004221McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014; 4(1):e004221. https://doi.org/10.1136/bmjopen-2013-004221Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Med. 2016;14:10. https://doi.org/10.1186/s12916-016-0553-2Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Med. 2016;14:10. https://doi.org/10.1186/s12916-016-0553-2Chen M, Will Y. Drug-induced liver toxicity. New York: Humana New York; 2018. https://doi.org/10.1007/978-1-4939-7677-5Chen M, Will Y. Drug-induced liver toxicity. New York: Humana New York; 2018. https://doi.org/10.1007/978-1-4939-7677-5de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58(1):71–80. https://doi.org/10.1111/j.1365-2125.2004.02133.xde Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58(1):71–80. https://doi.org/10.1111/j.1365-2125.2004.02133.xRobles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Cáliz I, González-Jimenez A, et al. Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147(1):109–18.e5. https://doi.org/10.1053/j.gastro.2014.03.050Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Cáliz I, González-Jimenez A, et al. Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147(1):109–18.e5. https://doi.org/10.1053/j.gastro.2014.03.050Hoofnagle JH, Björnsson ES. Drug-induced liver injury — types and phenotypes. N Engl J Med. 2019;381(3):264–73. https://doi.org/.1056/NEJMra1816149Hoofnagle JH, Björnsson ES. Drug-induced liver injury — types and phenotypes. N Engl J Med. 2019;381(3):264–73. https://doi.org/.1056/NEJMra1816149Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146(4):914–28. https://doi.org/10.1053/j.gastro.2013.12.032Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology. 2014;146(4):914–28. https://doi.org/10.1053/j.gastro.2013.12.032Jee A, Sernoskie SC, Uetrecht J. Idiosyncratic drug-induced liver injury: mechanistic and clinical challenges. Int J Mol Sci. 2021;22(6):2954. https://doi.org/10.3390/ijms22062954Jee A, Sernoskie SC, Uetrecht J. Idiosyncratic drug-induced liver injury: mechanistic and clinical challenges. Int J Mol Sci. 2021;22(6):2954. https://doi.org/10.3390/ijms22062954Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47(6):2003–9. https://doi.org/10.1002/hep.22272Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology. 2008;47(6):2003–9. https://doi.org/10.1002/hep.22272Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6. https://doi.org/10.1056/NEJMc1302338Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6. https://doi.org/10.1056/NEJMc1302338Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Drug Metab Rev. 2012;44(1):116–26. https://doi.org/10.3109/03602532.2011.605790Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Drug Metab Rev. 2012;44(1):116–26. https://doi.org/10.3109/03602532.2011.605790Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl 1):S54–62. https://doi.org/10.1002/hep.21060Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2 Suppl 1):S54–62. https://doi.org/10.1002/hep.21060Doherty DG. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J Autoimmun. 2016;66:60–75. https://doi.org/10.1016/j.jaut.2015.08.020Doherty DG. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J Autoimmun. 2016;66:60–75. https://doi.org/10.1016/j.jaut.2015.08.020Zheng M, Tian Z. Liver-mediated adaptive immune tolerance. Front Immunol. 2019;10:2525. https://doi.org/10.3389/fimmu.2019.02525Zheng M, Tian Z. Liver-mediated adaptive immune tolerance. Front Immunol. 2019;10:2525. https://doi.org/10.3389/fimmu.2019.02525Foureau DM, Walling TL, Maddukuri V, Anderson W, Culbreath K, Kleiner DE, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol. 2015;180(1):40–51. https://doi.org/10.1111/cei.12558Foureau DM, Walling TL, Maddukuri V, Anderson W, Culbreath K, Kleiner DE, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol. 2015;180(1):40–51. https://doi.org/10.1111/cei.12558Pirmohamed M, Naisbitt DJ, Gordon F, Park BK. The danger hypothesis — potential role in idiosyncratic drug reactions. Toxicology. 2002;181–182:55–63. https://doi.org/10.1016/s0300-483x(02)00255-xPirmohamed M, Naisbitt DJ, Gordon F, Park BK. The danger hypothesis — potential role in idiosyncratic drug reactions. Toxicology. 2002;181–182:55–63. https://doi.org/10.1016/s0300-483x(02)00255-xZindel J, Kubes P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu Rev Pathol. 2020;15:493–518. https://doi.org/10.1146/annurev-pathmechdis-012419-032847Zindel J, Kubes P. DAMPs, PAMPs, and LAMPs in immunity and sterile inflammation. Annu Rev Pathol. 2020;15:493–518. https://doi.org/10.1146/annurev-pathmechdis-012419-032847Fleshner M, Crane CR. Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol. 2017;38(10):768–76. https://doi.org/10.1016/j.it.2017.08.002Fleshner M, Crane CR. Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol. 2017;38(10):768–76. https://doi.org/10.1016/j.it.2017.08.002Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. 2002;2(4):301–5. https://doi.org/10.1097/00130832-200208000-00003Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol. 2002;2(4):301–5. https://doi.org/10.1097/00130832-200208000-00003Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol. 2010;(196):407–18. https://doi.org/10.1007/978-3-642-00663-0_13Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol. 2010;(196):407–18. https://doi.org/10.1007/978-3-642-00663-0_13Ko TM, Chung WH, Wei CY, Shih HY, Chen JK, Lin CH, Chen YT, Hung SI. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol. 2011;128(6):1266–76.e11. https://doi.org/10.1016/j.jaci.2011.08.013Ko TM, Chung WH, Wei CY, Shih HY, Chen JK, Lin CH, Chen YT, Hung SI. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol. 2011;128(6):1266–76.e11. https://doi.org/10.1016/j.jaci.2011.08.013Segovia-Zafra A, Di Zeo-Sánchez DE, López-Gómez C, Pérez-Valdés Z, García-Fuentes E, Andrade RJ, et al. Preclinical models of idiosyncratic drug-induced liver injury (iDILI): moving towards prediction. Acta Pharm Sin B. 2021;11(12):3685–726. https://doi.org/10.1016/j.apsb.2021.11.013Segovia-Zafra A, Di Zeo-Sánchez DE, López-Gómez C, Pérez-Valdés Z, García-Fuentes E, Andrade RJ, et al. Preclinical models of idiosyncratic drug-induced liver injury (iDILI): moving towards prediction. Acta Pharm Sin B. 2021;11(12):3685–726. https://doi.org/10.1016/j.apsb.2021.11.013Ogese MO, Jenkins RE, Adair K, Tailor A, Meng X, Faulkner L, et al. Exosomal transport of hepatocyte-derived drug-modified proteins to the immune system. Hepatology. 2019;70(5):1732–49. https://doi.org/10.1002/hep.30701Ogese MO, Jenkins RE, Adair K, Tailor A, Meng X, Faulkner L, et al. Exosomal transport of hepatocyte-derived drug-modified proteins to the immune system. Hepatology. 2019;70(5):1732–49. https://doi.org/10.1002/hep.30701Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS, et al. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol. 2009;237(3):317–30. https://doi.org/10.1016/j.taap.2009.04.002Cosgrove BD, King BM, Hasan MA, Alexopoulos LG, Farazi PA, Hendriks BS, et al. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity. Toxicol Appl Pharmacol. 2009;237(3):317–30. https://doi.org/10.1016/j.taap.2009.04.002Oda 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. https://doi.org/10.1016/j.toxlet.2015.10.029Oda 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. https://doi.org/10.1016/j.toxlet.2015.10.029Lowe R, Shirley N, Bleackley M, Dolan S, Shafee T. Transcriptomics technologies. PLoS Comput Biol. 2017;13(5):1005457. https://doi.org/10.1371/journal.pcbi.1005457Lowe R, Shirley N, Bleackley M, Dolan S, Shafee T. Transcriptomics technologies. PLoS Comput Biol. 2017;13(5):1005457. https://doi.org/10.1371/journal.pcbi.1005457De Abrew KN, Overmann GJ, Adams RL, Tiesman JP, Dunavent J, Shan YK, et al. A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action. Toxicology. 2015;328:29–39. https://doi.org/10.1016/j.tox.2014.11.008De Abrew KN, Overmann GJ, Adams RL, Tiesman JP, Dunavent J, Shan YK, et al. A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action. Toxicology. 2015;328:29–39. https://doi.org/10.1016/j.tox.2014.11.008Ölander M, Wiśniewski JR, Artursson P. Cell-type-resolved proteomic analysis of the human liver. Liver Int. 2020;40(7):1770–80. https://doi.org/10.1111/liv.14452Ölander M, Wiśniewski JR, Artursson P. Cell-type-resolved proteomic analysis of the human liver. Liver Int. 2020;40(7):1770–80. https://doi.org/10.1111/liv.14452Cuykx M, Rodrigues RM, Laukens K, Vanhaecke T, Covaci A. In vitro assessment of hepatotoxicity by metabolomics: a review. Arch Toxicol. 2018;92(10):3007–29. https://doi.org/10.1007/s00204-018-2286-9Cuykx M, Rodrigues RM, Laukens K, Vanhaecke T, Covaci A. In vitro assessment of hepatotoxicity by metabolomics: a review. Arch Toxicol. 2018;92(10):3007–29. https://doi.org/10.1007/s00204-018-2286-9Sakai C, Iwano S, Yamazaki Y, Ando A, Nakane F, Kouno M, et al. Species differences in the pharmacokinetic parameters of cytochrome P450 probe substrates between experimental animals, such as mice, rats, dogs, monkeys, and microminipigs, and humans. J Drug Metab Toxicol. 2014;5:6. https://doi.org/10.4172/2157-7609.1000173Sakai C, Iwano S, Yamazaki Y, Ando A, Nakane F, Kouno M, et al. Species differences in the pharmacokinetic parameters of cytochrome P450 probe substrates between experimental animals, such as mice, rats, dogs, monkeys, and microminipigs, and humans. J Drug Metab Toxicol. 2014;5:6. https://doi.org/10.4172/2157-7609.1000173Metushi IG, Hayes MA, Uetrecht J. Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology. 2015;61(4):1332–42. https://doi.org/10.1002/hep.27549Metushi IG, Hayes MA, Uetrecht J. Treatment of PD-1(-/-) mice with amodiaquine and anti-CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients. Hepatology. 2015;61(4):1332–42. https://doi.org/10.1002/hep.27549Chakraborty M, Fullerton AM, Semple K, Chea LS, Proctor WR, Bourdi M, et al. Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment. Hepatology. 2015;62(2):546–57. https://doi.org/10.1002/hep.27764Chakraborty M, Fullerton AM, Semple K, Chea LS, Proctor WR, Bourdi M, et al. Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment. Hepatology. 2015;62(2):546–57. https://doi.org/10.1002/hep.27764Kakuni M, Morita M, Matsuo K, Katoh Y, Nakajima M, Tateno C, Yokoi T. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury. Toxicol Lett. 2012;214(1):9–18. https://doi.org/10.1016/j.toxlet.2012.08.001Kakuni M, Morita M, Matsuo K, Katoh Y, Nakajima M, Tateno C, Yokoi T. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury. Toxicol Lett. 2012;214(1):9–18. https://doi.org/10.1016/j.toxlet.2012.08.001Ekdahl A, Weidolf L, Baginski M, Morikawa Y, Thompson RA, Wilson ID. The metabolic fate of fenclozic acid in chimeric mice with a humanized liver. Arch Toxicol. 2018;92(9):2819–28. https://doi.org/10.1007/s00204-018-2274-0Ekdahl A, Weidolf L, Baginski M, Morikawa Y, Thompson RA, Wilson ID. The metabolic fate of fenclozic acid in chimeric mice with a humanized liver. Arch Toxicol. 2018;92(9):2819–28. https://doi.org/10.1007/s00204-018-2274-0Song B, Aoki S, Liu C, Susukida T, Ito K. An animal model of abacavir-induced HLA-mediated liver injury. Toxicol Sci. 2018;162(2):713–23. https://doi.org/10.1093/toxsci/kfy001Song B, Aoki S, Liu C, Susukida T, Ito K. An animal model of abacavir-induced HLA-mediated liver injury. Toxicol Sci. 2018;162(2):713–23. https://doi.org/10.1093/toxsci/kfy001McGill MR, Jaeschke H. Animal models of drug-induced liver injury. Biochim Biophys Acta Mol Basis Dis. 2019;1865(5):1031–9. https://doi.org/10.1016/j.bbadis.2018.08.037McGill MR, Jaeschke H. Animal models of drug-induced liver injury. Biochim Biophys Acta Mol Basis Dis. 2019;1865(5):1031–9. https://doi.org/10.1016/j.bbadis.2018.08.037Stephens C, Lucena MI, Andrade RJ. Genetic risk factors in the development of idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2021;17(2):153–69. https://doi.org/10.1080/17425255.2021.1854726Stephens C, Lucena MI, Andrade RJ. Genetic risk factors in the development of idiosyncratic drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2021;17(2):153–69. https://doi.org/10.1080/17425255.2021.1854726Pachkoria K, Lucena MI, Ruiz-Cabello F, Crespo E, Cabello MR, Andrade RJ. Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI). Br J Pharmacol. 2007;150(6):808–15. https://doi.org/10.1038/sj.bjp.0707122Pachkoria K, Lucena MI, Ruiz-Cabello F, Crespo E, Cabello MR, Andrade RJ. Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI). Br J Pharmacol. 2007;150(6):808–15. https://doi.org/10.1038/sj.bjp.0707122Zhao M, Zhang T, Li G, Qiu F, Sun Y, Zhao L. Associations of CYP2C9 and CYP2A6 polymorphisms with the concentrations of valproate and its hepatotoxin metabolites and valproate-induced hepatotoxicity. Basic Clin Pharmacol Toxicol. 2017;121(2):138–43. https://doi.org/10.1111/bcpt.12776Zhao M, Zhang T, Li G, Qiu F, Sun Y, Zhao L. Associations of CYP2C9 and CYP2A6 polymorphisms with the concentrations of valproate and its hepatotoxin metabolites and valproate-induced hepatotoxicity. Basic Clin Pharmacol Toxicol. 2017;121(2):138–43. https://doi.org/10.1111/bcpt.12776Yimer G, Amogne W, Habtewold A, Makonnen E, Ueda N, Suda A, et al. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J. 2012;12(6):499–506. https://doi.org/10.1038/tpj.2011.34Yimer G, Amogne W, Habtewold A, Makonnen E, Ueda N, Suda A, et al. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J. 2012;12(6):499–506. https://doi.org/10.1038/tpj.2011.34Hu X, Zhang M, Bai H, Wu L, Chen Y, Ding L, et al. Antituberculosis drug-induced adverse events in the liver, kidneys, and blood: clinical profiles and pharmacogenetic predictors. Clin Pharmacol Ther. 2018;104(2):326–34. https://doi.org/10.1002/cpt.924Hu X, Zhang M, Bai H, Wu L, Chen Y, Ding L, et al. Antituberculosis drug-induced adverse events in the liver, kidneys, and blood: clinical profiles and pharmacogenetic predictors. Clin Pharmacol Ther. 2018;104(2):326–34. https://doi.org/10.1002/cpt.924Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132(1):272–81. https://doi.org/10.1053/j.gastro.2006.11.023Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132(1):272–81. https://doi.org/10.1053/j.gastro.2006.11.023Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, et al. NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis. 2016;20(10):1364–9. https://doi.org/10.5588/ijtld.15.0310Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, et al. NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis. 2016;20(10):1364–9. https://doi.org/10.5588/ijtld.15.0310Sharma SK, Jha BK, Sharma A, Sreenivas V, Upadhyay V, Jaisinghani C, et al. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity. Indian J Med Res. 2016;144(6):924–8. https://doi.org/10.4103/ijmr.IJMR_684_14Sharma SK, Jha BK, Sharma A, Sreenivas V, Upadhyay V, Jaisinghani C, et al. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity. Indian J Med Res. 2016;144(6):924–8. https://doi.org/10.4103/ijmr.IJMR_684_14Du H, Chen X, Fang Y, Yan O, Xu H, Li L, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep. 2013;40(5):3591–6. https://doi.org/10.1007/s11033-012-2433-yDu H, Chen X, Fang Y, Yan O, Xu H, Li L, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep. 2013;40(5):3591–6. https://doi.org/10.1007/s11033-012-2433-ySuvichapanich S, Fukunaga K, Zahroh H, Mushiroda T, Mahasirimongkol S, Toyo-Oka L, et al. NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis. Pharmacogenet Genomics. 2018;28(7):167–76. https://doi.org/10.1097/FPC.0000000000000339Suvichapanich S, Fukunaga K, Zahroh H, Mushiroda T, Mahasirimongkol S, Toyo-Oka L, et al. NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis. Pharmacogenet Genomics. 2018;28(7):167–76. https://doi.org/10.1097/FPC.0000000000000339Zhang M, Wang S, Wilffert B, Tong R, van Soolingen D, van den Hof S, Alffenaar JW. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Br J Clin Pharmacol. 2018;84(12):2747–60. https://doi.org/10.1111/bcp.13722Zhang M, Wang S, Wilffert B, Tong R, van Soolingen D, van den Hof S, Alffenaar JW. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Br J Clin Pharmacol. 2018;84(12):2747–60. https://doi.org/10.1111/bcp.13722Li YJ, Phillips EJ, Dellinger A, Nicoletti P, Schutte R, Li D, et al. Human leukocyte antigen B*14:01 and B*35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury. Hepatology. 2021;73(1):268–81. https://doi.org/10.1002/hep.31258Li YJ, Phillips EJ, Dellinger A, Nicoletti P, Schutte R, Li D, et al. Human leukocyte antigen B*14:01 and B*35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury. Hepatology. 2021;73(1):268–81. https://doi.org/10.1002/hep.31258Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J. 2008;8(1):29–33. https://doi.org/10.1038/sj.tpj.6500442Hirata K, Takagi H, Yamamoto M, Matsumoto T, Nishiya T, Mori K, et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study. Pharmacogenomics J. 2008;8(1):29–33. https://doi.org/10.1038/sj.tpj.6500442Li C, Rao T, Chen X, Zou Z, Wei A, Tang J, et al. HLA-B*35:01 allele is a potential biomarker for predicting Polygonum multiflorum-induced liver injury in humans. Hepatology. 2019;70(1):346–57. https://doi.org/10.1002/hep.30660Li C, Rao T, Chen X, Zou Z, Wei A, Tang J, et al. HLA-B*35:01 allele is a potential biomarker for predicting Polygonum multiflorum-induced liver injury in humans. Hepatology. 2019;70(1):346–57. https://doi.org/10.1002/hep.30660Yang WN, Pang LL, Zhou JY, Qiu YW, Miao L, Wang SY, et al. Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population. World J Gastroenterol. 2020;26(12):1329–39. https://doi.org/10.3748/wjg.v26.i12.1329Yang WN, Pang LL, Zhou JY, Qiu YW, Miao L, Wang SY, et al. Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population. World J Gastroenterol. 2020;26(12):1329–39. https://doi.org/10.3748/wjg.v26.i12.1329O’Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RN, Mills PR. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut. 2000;47(5):717–20. https://doi.org/10.1136/gut.47.5.717O’Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RN, Mills PR. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut. 2000;47(5):717–20. https://doi.org/10.1136/gut.47.5.717Aithal GP, Ramsay L, Daly AK, Sonchit N, Lea thart JB, Alexander G, et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology. 2004;39(5):1430–40. https://doi.org/10.1002/hep.20205Aithal GP, Ramsay L, Daly AK, Sonchit N, Lea thart JB, Alexander G, et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology. 2004;39(5):1430–40. https://doi.org/10.1002/hep.20205Uffelmann E, Huang QQ, Munung NS, Vries J, Okada Y, Martin AR, et al. Genome-wide association studies. Nat Rev Methods Primers. 2021;(1):59. https://doi.org/10.1038/s43586-021-00056-9Uffelmann E, Huang QQ, Munung NS, Vries J, Okada Y, Martin AR, et al. Genome-wide association studies. Nat Rev Methods Primers. 2021;(1):59. https://doi.org/10.1038/s43586-021-00056-9Suvichapanich S, Wattanapokayakit S, Mushiroda T, Yanai H, Chuchottawon C, Kantima T, et al. Genomewide association study confirming the association of NAT2 with susceptibility to antituberculosis drug-induced liver injury in Thai patients. Antimicrob Agents Chemother. 2019;63(8):e02692–18. https://doi.org/10.1128/AAC.02692-18Suvichapanich S, Wattanapokayakit S, Mushiroda T, Yanai H, Chuchottawon C, Kantima T, et al. Genomewide association study confirming the association of NAT2 with susceptibility to antituberculosis drug-induced liver injury in Thai patients. Antimicrob Agents Chemother. 2019;63(8):e02692–18. https://doi.org/10.1128/AAC.02692-18Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47. https://doi.org/10.1053/j.gastro.2011.04.001Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011;141(1):338–47. https://doi.org/10.1053/j.gastro.2011.04.001Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, et al. Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions. Clin Pharmacol Ther. 2019;106(5):1028–36. https://doi.org/10.1002/cpt.1493Nicoletti P, Barrett S, McEvoy L, Daly AK, Aithal G, Lucena MI, et al. Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions. Clin Pharmacol Ther. 2019;106(5):1028–36. https://doi.org/10.1002/cpt.1493Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. 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):1078–89. https://doi.org/10.1053/j.gastro.2016.12.016Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, et al. 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):1078–89. https://doi.org/10.1053/j.gastro.2016.12.016Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, et al. Minocycline hepatotoxicity: clinical characterization and identification of HLA-B*35:02 as a risk factor. J Hepatol. 2017;67(1):137–44. https://doi.org/10.1016/j.jhep.2017.03.010Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, et al. Minocycline hepatotoxicity: clinical characterization and identification of HLA-B*35:02 as a risk factor. J Hepatol. 2017;67(1):137–44. https://doi.org/10.1016/j.jhep.2017.03.010Bruno CD, Fremd B, Church RJ, Daly AK, Aithal GP, Björnsson ES, et al. HLA associations with infliximab-induced liver injury. Pharmacogenomics J. 2020;20(5):681–6. https://doi.org/10.1038/s41397-020-0159-0Bruno CD, Fremd B, Church RJ, Daly AK, Aithal GP, Björnsson ES, et al. HLA associations with infliximab-induced liver injury. Pharmacogenomics J. 2020;20(5):681–6. https://doi.org/10.1038/s41397-020-0159-0Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41(7):816–9. https://doi.org/10.1038/ng.379Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe’er I, Floratos A, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009;41(7):816–9. https://doi.org/10.1038/ng.379Nicoletti P, Aithal GP, Chamberlain TC, Coulthard S, Alshabeeb M, Grove JI, et al. Drug-induced liver injury due to flucloxacillin: relevance of multiple human leukocyte antigen alleles. Clin Pharmacol Ther. 2019;106(1):245–53. https://doi.org/10.1002/cpt.1375Nicoletti P, Aithal GP, Chamberlain TC, Coulthard S, Alshabeeb M, Grove JI, et al. Drug-induced liver injury due to flucloxacillin: relevance of multiple human leukocyte antigen alleles. Clin Pharmacol Ther. 2019;106(1):245–53. https://doi.org/10.1002/cpt.1375Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 2008;8(3):186–95. https://doi.org/10.1038/sj.tpj.6500458Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 2008;8(3):186–95. https://doi.org/10.1038/sj.tpj.6500458Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011;29(6):667–73. https://doi.org/10.1200/JCO.2010.31.3197Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011;29(6):667–73. https://doi.org/10.1200/JCO.2010.31.3197Parham LR, Briley LP, Li L, Shen J, Newcombe PJ, King KS, et al. Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01. Pharmacogenomics J. 2016;16(2):180–5. https://doi.org/10.1038/tpj.2015.40Parham LR, Briley LP, Li L, Shen J, Newcombe PJ, King KS, et al. Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01. Pharmacogenomics J. 2016;16(2):180–5. https://doi.org/10.1038/tpj.2015.40Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010;42(8):711–4. https://doi.org/10.1038/ng.632Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010;42(8):711–4. https://doi.org/10.1038/ng.632Nicoletti P, Werk AN, Sawle A, Shen Y, Urban TJ, Coulthard SA, et al. HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics. 2016;26(5):218–24. https://doi.org/10.1097/FPC.0000000000000209Nicoletti P, Werk AN, Sawle A, Shen Y, Urban TJ, Coulthard SA, et al. HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics. 2016;26(5):218–24. https://doi.org/10.1097/FPC.0000000000000209Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, et al. A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology. 2019;156(6):1707–1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, et al. A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology. 2019;156(6):1707–1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034Zhang X, Yu Y, Bai B, Wang T, Zhao J, Zhang N, et al. PTPN22 interacts with EB1 to regulate T-cell receptor signaling. FASEB J. 2020;34(7):8959–74. https://doi.org/10.1096/fj.201902811RRZhang X, Yu Y, Bai B, Wang T, Zhao J, Zhang N, et al. PTPN22 interacts with EB1 to regulate T-cell receptor signaling. FASEB J. 2020;34(7):8959–74. https://doi.org/10.1096/fj.201902811RRAlfirevic A, Pirmohamed M. Predictive genetic testing for drug-induced liver injury: considerations of clinical utility. Clin Pharmacol Ther. 2012;92(3):376–80. https://doi.org/10.1038/clpt.2012.107Alfirevic A, Pirmohamed M. Predictive genetic testing for drug-induced liver injury: considerations of clinical utility. Clin Pharmacol Ther. 2012;92(3):376–80. https://doi.org/10.1038/clpt.2012.107Kaliyaperumal K, Grove JI, Delahay RM, Griffiths WJH, Duckworth A, Aithal GP. Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications. J Hepatol. 2018;69(4):948–57. https://doi.org/10.1016/j.jhep.2018.05.013Kaliyaperumal K, Grove JI, Delahay RM, Griffiths WJH, Duckworth A, Aithal GP. Pharmacogenomics of drug-induced liver injury (DILI): molecular biology to clinical applications. J Hepatol. 2018;69(4):948–57. https://doi.org/10.1016/j.jhep.2018.05.013

The authors declare that there are no conflicts of interest present.