Drug-induced liver injury: Advances in mechanistic understanding that will inform risk management

Clinical Pharmacology and Therapeutics

Volumn 101, Issue 4, 2017, Pages 469-480

  Mosedale, M ^a,b   Watkins, P B ^a,b  

^a UNIVERSITY OF NORTH CAROLINA   (United States)

^b University of North Carolina   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIGEN; ANALGESIC AGENT; PARACETAMOL;

ADAPTIVE IMMUNITY; ARTICLE; CHOLESTASIS; GENETIC SCREENING; HUMAN; IDIOSYNCRATIC DRUG INDUCED LIVER INJURY; IMMUNOLOGICAL TOLERANCE; INNATE IMMUNITY; INTRINSIC DRUG INDUCED LIVER INJURY; LIVER CELL; LIVER CELL DAMAGE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; RISK MANAGEMENT; TOXIC HEPATITIS; ANIMAL; CHEMICAL AND DRUG INDUCED LIVER INJURY; DOSE RESPONSE; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; IMMUNOLOGY; RISK FACTOR;

ACETAMINOPHEN; ANALGESICS, NON-NARCOTIC; ANIMALS; CHEMICAL AND DRUG INDUCED LIVER INJURY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; HUMANS; RISK FACTORS; RISK MANAGEMENT;

EID: 85010375946     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1002/cpt.564     Document Type: Article

References (74)

1. Lee, W.M. Drug-induced acute liver failure. Clin Liver Dis. 17, 575–586, viii (2013).
2. Fontana, R.J. et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 147, 96–108.e104 (2014).
3. Watkins, P.B. How to diagnose and exclude drug-induced liver injury. Dig Dis (Basel). 33, 472–476 (2015).
4. Watkins, P.B. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther. 89, 788–790 (2011).
5. . Takeda Shares Drop After Scrapping Development of Diabetes Drug. Cited December 27, 2013.
6. Temple, R.R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 15, 241–243 (2006).
7. Patel, M.R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 365, 883–891 (2011).
8. Watkins, P.B. Managing the risk of drug-induced liver injury. Clin Pharmacol Ther. 94, 629–631 (2013).
9. Watkins, P.B., et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 296, 87–93 (2006).
10. Navarro, V.J. et al. Liver injury from herbals and dietary supplements in the US drug induced liver injury network. Hepatology (Baltimore) 60, 1399–1408 (2014).
11. Navarro, V.J. & Lucena, M.I. Hepatotoxicity induced by herbal and dietary supplements. Semin Liver Dis. 34, 172–193 (2014).
12. Fontana, R.J. Acute liver failure including acetaminophen overdose. Med Clin N Am. 92, 761–794 (2008).
13. Lee, W.M. Drug-induced acute liver failure. Clin Liver Dis. 17, 574–586 (2013).
14. Morgan, R.E. et al. A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 136, 216–241 (2013).
15. Gómez-Lechón, M.J., Tolosa, L. & Donato, M.T. Metabolic activation and drug-induced liver injury: in vitro approaches for the safety risk assessment of new drugs. J Appl Toxicol. 36, 752–768 (2016).
16. Aleo, M.D. et al. Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology 60, 1015–1022 (2014).
17. Will, Y. & Dykens, J. Mitochondrial toxicity assessment in industry — a decade of technology development and insight. Expert Opin Drug Metab Toxicol. 10, 1061–1067 (2014).
18. Jaeschke, H., Xie, Y. & McGill, M.R. Acetaminophen-induced liver injury: from animal models to humans. J Clin Transl Hepatol. 2, 153–161 (2014).
19. Martignoni, M., Groothuis, G.M. & de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2, 875–894 (2006).
20. Jiang, J., Wolters, J.E.J., van Breda, S.G., Kleinjans, J.C. & de Kok, T.M. Development of novel tools for the in vitro investigation of drug-induced liver injury. Expert Opin Drug Metab Toxicol. 11, 1523–1537 (2015).
21. Schadt, H.S. et al. Bile acids in drug induced liver injury: Key players and surrogate markers. Clin Res Hepatol Gastroenterol. 40, 257–266 (2016).
22. Marion, T.L., Perry, C.H., St. Claire, R.L. & Brouwer, K.L.R. Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes. Toxicol Appl Pharmacol. 261, 1–9 (2012).
23. Susukida, T., Sekine, S., Nozaki, M., Tokizono, M. & Ito, K. Prediction of the clinical risk of drug-induced cholestatic liver injury using an in vitro sandwich cultured hepatocyte assay. Drug Metab Dispos. 43, 1760–1768 (2015).
24. PSTC. PSTC BSEP Webinar Series. Current trends in BSEP inhibition and perturbation to bile acid homeostasis as mechanisms of drug-induced liver injury. (2006).
25. Jean, P.A. & Roth, R.A. Naphthylisothiocyanate disposition in bile and its relationship to liver glutathione and toxicity. Biochem Pharmacol. 50, 1469–1474 (1995).
26. Sundaram, S.S. & Sokol, R.J. The multiple facets of ABCB4 (MDR3) deficiency. Curr Treat Opt Gastroenterol. 10, 495–503 (2007).
27. He, K., Cai, L., Shi, Q., Liu, H. & Woolf, T.F. Inhibition of MDR3 activity in human hepatocytes by drugs associated with liver injury. Chem Res Toxicol. 28, 1987–1990 (2015).
28. Uetrecht, J. & Naisbitt, D.J. Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev. 65, 779–808 (2013).
29. Watkins, P. et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 38, 1103–1113 (2015).
30. Maria, V. & Victorino R. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut 41, 534–540 (1997).
31. Monshi, M.M. et al. Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury. Hepatology 57, 727–739 (2013).
32. Foureau, D.M. et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol. 180, 40–51 (2015).
33. Mennicke, M. et al. Fulminant liver failure after vancomycin in a sulfasalazine-induced DRESS syndrome: fatal recurrence after liver transplantation. Am J Transplant. 9, 2197–2202 (2009).
34. Urban, T.J., Daly, A.K. & Aithal, G.P. Genetic basis of drug-induced liver injury: present and future. Semin Liver Dis. 34, 123–133 (2014).
35. Tailor, A., Faulkner, L., Naisbitt, D. & Park, B. The chemical, genetic and immunological basis of idiosyncratic drug-induced liver injury. Hum Exp Toxicol. 34, 1310–1317 (2015).
36. Kim, S-H. et al. Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury. Hepatology 62, 887–899 (2015).
37. Nattrass, R. et al. Activation of flucloxacillin-specific CD8+ T cells with the potential to promote hepatocyte cytotoxicity in a mouse model. Toxicol Sci. 146, 146–156 (2015).
38. White, K.D., Chung, W-H., Hung, S-I., Mallal, S. & Phillips, E.J. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol. 136, 219–234 (2015).
39. Daly, A.K. et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 41, 816–819 (2009).
40. Li, J. & Uetrecht, J.P. The danger hypothesis applied to idiosyncratic drug reactions. Handb Exp Pharmacol. 196, 493–509 (2010).
41. Garside, H. et al. Evaluation of the use of imaging parameters for the detection of compound-induced hepatotoxicity in 384-well cultures of HepG2 cells and cryopreserved primary human hepatocytes. Toxicol In Vitro 28, 171–181 (2014).
42. Takemura, A., Izaki, A., Sekine, S. & Ito, K. Inhibition of bile canalicular network formation in rat sandwich cultured hepatocytes by drugs associated with risk of severe liver injury. Toxicol In Vitro 35, 121–130 (2016).
43. Martin-Murphy, B.V., Holt, M.P. & Ju, C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett. 192, 387 (2010).
44. Foell, D., Wittkowski, H. & Roth, J. Mechanisms of Disease: a ‘DAMP’ view of inflammatory arthritis. Nat Clin Pract Rheum. 3, 382–390 (2007).
45. Maiuri, A.R. et al. Cytotoxic synergy between cytokines and NSAIDs associated with idiosyncratic hepatotoxicity is driven by mitogen-activated protein kinases. Toxicol Sci. 146, 265–280 (2015).
46. Kindmark, A. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 8, 186–195 (2008).
47. Singer, J.B. et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 42, 711–714 (2010).
48. Spraggs, C.F. et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 29, 667–673 (2011).
49. Warrington, R.J., McPhilips-Feener, S. & Rutherford, W.J. The predictive value of the lymphocyte transformation test in isoniazid-associated hepatitis. Clin Allergy. 12, 217–222 (1982).
50. Chisari, F.V., Isogawa, M. & Wieland, S.F. Pathogenesis of hepatitis B virus infection. Pathol Biol. 58, 258–266 (2010).
51. Holman, N.S., Mosedale, M., Wolf, K.K., LeCluyse, E.L. & Watkins, P.B. Subtoxic alterations in hepatocyte-derived exosomes: an early step in drug-induced liver injury? Toxicol Sci. 151, 365–375 (2016).
52. Yang, Y., Han, Q., Hou, Z., Zhang, C., Tian, Z. & Zhang, J. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell Mol Immunol (2016); e-pub ahead of print.
53. Mak, A. & Uetrecht, J. The combination of anti-CTLA-4 and PD1-/- mice unmasks the potential of isoniazid and nevirapine to cause liver injury. Chem Res Toxicol. 28, 2287–2291 (2015).
54. Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 44, 51–60 (2016).
55. Rossi, R.E. et al. Anti-tumour necrosis factor agent and liver injury: Literature review, recommendations for management. World J Gastroenterol. 20, 17352–17359 (2014).
56. Mosedale, M. et al. Transient changes in hepatic physiology impacting bilirubin and bile acid transport may help explain the elevations in liver chemistries observed in clinical trials of GGF2 (Cimaglermin Alpha). Soc Toxicol Annu Meet. Submitted (2016).
57. Thomson, J.P., Moggs, J.G., Wolf, C.R. & Meehan, R.R. Epigenetic profiles as defined signatures of xenobiotic exposure. Mutat Res Genet Toxicol Environ Mutagen. 764–765, 3–9 (2014).
58. Yang, K., Woodhead, J.L., Watkins, P.B., Howell, B.A. & Brouwer, K.L. Systems pharmacology modeling predicts delayed presentation and species differences in bile Acid-mediated troglitazone hepatotoxicity. Clin Pharmacol Ther. 96, 589–598 (2014).
59. Woodhead, J.L. et al. Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. Toxicol Sci. (2016) [Epub ahead of print].
60. Lundbäck, P. et al. A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice. Hepatology (2016); e-pub ahead of print.
61. Fontana, R.J. Pathogenesis of idiosyncratic drug–induced liver injury and clinical perspectives. Gastroenterology 146, (2014).
62. Godoy, P. et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 87, 1315–1530 (2013).
63. Mosedale, M. et al. Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach. Toxicol Sci. Submitted (2016).
64. Cheng, L., Li, F., Bility, M.T., Murphy, C.M. & Su, L. Modeling hepatitis B virus infection, immunopathology and therapy in mice. Antiviral Res. 121, 1–8 (2015).
65. Laifenfeld, D. et al. Utilization of causal reasoning of hepatic gene expression in rats to identify molecular pathways of idiosyncratic drug-induced liver injury. Toxicol Sci. 137, 234–248 (2014).
66. Grove, J.I. & Aithal, G.P. Human leukocyte antigen genetic risk factors of drug-induced liver toxicology. Expert Opin Drug Metab Toxicol. 11, 395–409 (2015).
67. Nicoletti, P. et al. HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics 26, 218–224 (2016).
68. Beger, R.D. et al. Translational biomarkers of acetaminophen-induced acute liver injury. Arch Toxicol. 89, 1497–1522 (2015).
69. McGill, M.R. et al. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 122, 1574–1583 (2012).
70. Adebayo, D. et al. Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study. Liver Int. 35, 2564–2574 (2015).
71. Steuerwald, N.M. et al. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance. PLoS One 8, e81974 (2013).
72. Fannin, R.D. et al. Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 99, 432–441 (2015).
73. Antoine, D.J. et al. Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J Hepatol. 56, 1070–1079 (2012).
74. Arrese, M., Eguchi, A. & Feldstein, A.E. Circulating microRNAs: emerging biomarkers of liver disease. Semin Liver Dis. 35, 043–054 (2015).