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Drug-Induced Liver Injury

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Adverse Drug Reactions

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 196))

Abstract

Many drugs and environmental chemicals are capable of evoking some degree of liver injury. The liver represents a primary target for adverse drug reactions due to its central role in biotransformation and excretion of foreign compounds, its portal location within the circulation exposing it to a wide variety of substances, and its anatomic and physiologic structure. Drug-induced liver injury (DILI) remains the single most common adverse indication leading to drug candidate failure or withdrawal from the market. However, the absolute incidence of DILI is low, and this presents a challenge to mechanistic studies. DILI remains unpredictable making prevention very difficult. In this chapter, we focus on the current understanding of DILI. We begin with an overview regarding the significance and epidemiology of DILI and then examine the clinical presentation and susceptibility factors related to DILI. This is followed by a review of the current literature regarding the proposed pathogenesis of DILI, which involves the participation of a drug, or most often a reactive metabolite of the drug, that either directly affects cellular function or elicits an immune response. It is our hope that this chapter will shed light on the major problems associated with DILI in regards to the pharmaceutical industry, drug regulatory agencies, physicians and pharmacists, and patients.

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Abbreviations

DILI:

Drug-induced liver injury

US:

United States

FDA:

Food and Drug Administration

APAP:

Acetaminophen

NSAIDs:

Nonsteroidal antiinflammatory drugs

PPAR:

Peroxisome proliferator activated receptor

ALT:

Alanine aminotransferase

ULN:

Upper limit of normal

AP:

Alkaline phosphatase

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

CYP450:

Cytochrome P450

p-i:

concept Direct pharmacological interaction of drugs with immune receptors

APC:

Antigen presenting cell

SMX:

Sulfamethoxazole

SMX-NHOH:

Hydroxylamine metabolite of SMX

SMX-NO:

Nitroso-SMX

NK:

Natural killer

NKT:

NK cell with T cell receptor

DAMP:

Damage-associated molecular pattern

TNF:

Tumor necrosis factor

IL:

Interleukin

IFN:

Interferon

COX:

Cyclooxygenase

TFA:

Trifluoroacetic acid

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

polyI:C:

Polyinosinic-polycytidylic-acid

TLR:

Toll-like receptor

NKG2D:

A lectin-like stimulatory receptor originally identified on NK cells

Reference

  • Abbiati C, Vecchi M, Rossi G, Donata MF, de Franchis R (2002) Inappropriate pemoline therapy leading to acute liver failure and liver transplantation. Dig Liver Dis 34:447–451

    Article  PubMed  CAS  Google Scholar 

  • Ackerman Z, Levy M (1987) Hypersensitivity reactions to drugs in acquired immunodeficiency syndrome. Postgrad Med J 63:55–56

    Article  PubMed  CAS  Google Scholar 

  • Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39:1430–1440

    Article  PubMed  CAS  Google Scholar 

  • Al Salman J, Arjomand H, Kemp DG, Mittal M (2000) Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Int Med 132:121–124

    PubMed  CAS  Google Scholar 

  • Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmeron J, Martin-Vivaldi R (2005) Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129:512–521

    PubMed  Google Scholar 

  • Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  PubMed  CAS  Google Scholar 

  • AYD FJ Jr (1963) Chlorpromazine: ten years' experience. JAMA 184:51–54

    Article  PubMed  Google Scholar 

  • Bakke OM, Manocchia M, de Abajo F, Kaitin KI, Lasagna L (1995) Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: a regulatory perspective. Clin Pharmacol Ther 58:108–117

    Article  PubMed  CAS  Google Scholar 

  • Ballet F (1997) Hepatotoxicity in drug development: detection, significance and solutions. J Hepatol 26(Suppl 2):26–36

    Article  PubMed  CAS  Google Scholar 

  • Banks AT, Zimmerman HJ, Ishak KG, Harter JG (1995) Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 22:820–827

    Article  PubMed  CAS  Google Scholar 

  • Bernal W (2003) Changing patterns of causation and the use of transplantation in the United Kingdom. Semin Liver Dis 23:227–237

    Article  PubMed  Google Scholar 

  • Berson A, De BV, Letteron P, Robin MA, Moreau C, El Kahwaji J, Verthier N, Feldmann G, Fromenty B, Pessayre D (1998) Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 114:764–774

    Article  PubMed  CAS  Google Scholar 

  • Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029

    Article  PubMed  CAS  Google Scholar 

  • Bjornsson E, Olsson R (2005) Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 42:481–489

    Article  PubMed  CAS  Google Scholar 

  • Bjornsson E, Nordlinder H, Olsson R (2006) Clinical characteristics and prognostic markers in disulfiram-induced liver injury. J Hepatol 44:791–797

    Article  PubMed  CAS  Google Scholar 

  • Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epler GR (1975) Isoniazid-associated hepatitis in 114 patients. Gastroenterology 69:289–302

    PubMed  CAS  Google Scholar 

  • Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI (1995) Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 133:43–52

    Article  PubMed  CAS  Google Scholar 

  • Blazka ME, Elwell MR, Holladay SD, Wilson RE, Luster MI (1996) Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. Toxicol Pathol 24:181–189

    Article  PubMed  CAS  Google Scholar 

  • Boelsterli UA, Zimmerman HJ, Kretz-Rommel A (1995) Idiosyncratic liver toxicity of nonsteroidal antiinflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 25:207–235

    Article  PubMed  CAS  Google Scholar 

  • Bonierbale E, Valadon P, Pons C, Desfosses B, Dansette PM, Mansuy D (1999) Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: use of specific anti-tienilic acid-protein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compo. Chem Res Toxicol 12:286–296

    Article  PubMed  CAS  Google Scholar 

  • Bourdi M, Tinel M, Beaune PH, Pessayre D (1994) Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies. Mol Pharmacol 45:1287–1295

    PubMed  CAS  Google Scholar 

  • Bourdi M, Amouzadeh HR, Rushmore TH, Martin JL, Pohl LR (2001) Halothane-induced liver injury in outbred guinea pigs: role of trifluoroacetylated protein adducts in animal susceptibility. Chem Res Toxicol 14:362–370

    Article  PubMed  CAS  Google Scholar 

  • Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, Shah AG, Pohl LR (2002) Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 35:289–298

    Article  PubMed  CAS  Google Scholar 

  • Bryant AE III, Dreifuss FE (1996) Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology 46:465–469

    PubMed  Google Scholar 

  • Burkhart C, von Greyerz S, Depta JP, Naisbitt DJ, Britschgi M, Park KB, Pichler WJ (2001) Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells. Br J Pharmacol 132:623–630

    Article  PubMed  CAS  Google Scholar 

  • Carney FM, Van Dyke RA (1972) Halothane hepatitis: a critical review. Anesth Analg 51:135–160

    PubMed  CAS  Google Scholar 

  • Carvajal Garcia-Pando A, Garcia DP, Sanchez AS, Velasco MA, Rueda de Castro AM, Lucena MI (2002) Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 63:135–137

    Article  PubMed  Google Scholar 

  • Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD (2004) Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 126:1287–1292

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, You Q, Yin H, Holt M, Franklin C, Ju C (2009) Effect of polyI:C cotreatment on halothane-induced liver injury in mice. Hepatology 49:215–226

    Article  PubMed  CAS  Google Scholar 

  • Christen U, Quinn J, Yeaman SJ, Kenna JG, Clarke JB, Gandolfi AJ, Gut J (1994) Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis. Molecular mimicry of trifluoroacetyl-lysine by lipoic acid. Eur J Biochem 223:1035–1047

    Article  PubMed  CAS  Google Scholar 

  • Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT (2004) Medical genetics: a marker for Stevens–Johnson syndrome. Nature 428:486

    Article  PubMed  CAS  Google Scholar 

  • Claudel S, Euvrard P, Bory R, Chavaillon A, Paliard P (1979) Intra-hepatic cholestasis after taking a triacetyloleandomycin-estroprogestational combination. Nouv Presse Med 8:1182

    PubMed  CAS  Google Scholar 

  • Coopman SA, Johnson RA, Platt R, Stern RS (1993) Cutaneous disease and drug reactions in HIV infection. N Engl J Med 328:1670–1674

    Article  PubMed  CAS  Google Scholar 

  • Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, Jaeschke H (2006) Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 216:98–107

    Article  PubMed  CAS  Google Scholar 

  • Dahms M, Spahn-Langguth H (1996) Covalent binding of acidic drugs via reactive intermediates: detection of benoxaprofen and flunoxaprofen protein adducts in biological material. Pharmazie 51:874–881

    PubMed  CAS  Google Scholar 

  • de Groot H, Noll T (1983) Halothane hepatotoxicity: relation between metabolic activation, hypoxia, covalent binding, lipid peroxidation and liver cell damage. Hepatology 3:601–606

    Article  PubMed  Google Scholar 

  • De Valle MB, Av KV, Alem N, Olsson R, Bjornsson E (2006) Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 24:1187–1195

    Article  PubMed  CAS  Google Scholar 

  • den Brinker M, Wit FW, Wertheim-van Dillen PM, Jurriaans S, Weel J, van Leeuwen R, Pakker NG, Reiss P, Danner SA, Weverling GJ, Lange JM (2000) Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS 14:2895–2902

    Article  Google Scholar 

  • Deng X, Stachlewitz RF, Liguori MJ, Blomme EA, Waring JF, Luyendyk JP, Maddox JF, Ganey PE, Roth RA (2006) Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation. J Pharmacol Exp Ther 319:1191–1199

    Article  PubMed  CAS  Google Scholar 

  • Deng X, Luyendyk JP, Zou W, Lu J, Malle E, Ganey PE, Roth RA (2007) Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 322:852–861

    Article  PubMed  CAS  Google Scholar 

  • Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y (2008) In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 103:335–345

    Article  PubMed  CAS  Google Scholar 

  • Eger EI (2004) Characteristics of anesthetic agents used for induction and maintenance of general anesthesia. Am J Health Syst Pharm 61(Suppl 4):S3–S10

    PubMed  CAS  Google Scholar 

  • Fairley CK, McNeil JJ, Desmond P, Smallwood R, Young H, Forbes A, Purcell P, Boyd I (1993) Risk factors for development of flucloxacillin associated jaundice. BMJ 306:233–235

    Article  PubMed  CAS  Google Scholar 

  • Farell OC (1994) Drug-induced liver disease. Churchill Livingstone, London

    Google Scholar 

  • Fee JP, Thompson GH (1997) Comparative tolerability profiles of the inhaled anaesthetics. Drug Saf 16:157–170

    Article  PubMed  CAS  Google Scholar 

  • Fontana RJ, McCashland TM, Benner KG, Appelman HD, Gunartanam NT, Wisecarver JL, Rabkin JM, Lee WM (1999) Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. The Acute Liver Failure Study Group. Liver Transpl Surg 5:480–484

    Article  PubMed  CAS  Google Scholar 

  • Forman LM, Simmons DA, Diamond RH (2000) Hepatic failure in a patient taking rosiglitazone. Ann Int Med 132:118–121

    PubMed  CAS  Google Scholar 

  • Funk C, Ponelle C, Scheuermann G, Pantze M (2001) Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol 59:627–635

    PubMed  CAS  Google Scholar 

  • Gale EA (2001) Lessons from the glitazones: a story of drug development. Lancet 357: 1870–1875

    Article  PubMed  CAS  Google Scholar 

  • Gandolfi AJ, White RD, Sipes IG, Pohl LR (1980) Bioactivation and covalent binding of halothane in vitro: studies with [3H]- and [14C]halothane. J Pharmacol Exp Ther 214:721–725

    PubMed  CAS  Google Scholar 

  • Ganey PE, Roth RA (2001) Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents. Toxicology 169:195–208

    Article  PubMed  CAS  Google Scholar 

  • GL Brody, RB Sweet (1963) Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology 24:29–37

    Article  Google Scholar 

  • Graham DJ, Green L, Senior JR, Nourjah P (2003) Troglitazone-induced liver failure: a case study. Am J Med 114:299–306

    Article  PubMed  Google Scholar 

  • Green VJ, Pirmohamed M, Kitteringham NR, Knapp MJ, Park BK (1995) Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis. Br J Clin Pharmacol 39:411–415

    PubMed  CAS  Google Scholar 

  • Gross-Steinmeyer K, Stapleton PL, Tracy JH, Bammler TK, Lehman T, Strom SC, Eaton DL (2005) Influence of Matrigel-overlay on constitutive and inducible expression of nine genes encoding drug-metabolizing enzymes in primary human hepatocytes. Xenobiotica 35:419–438

    Article  PubMed  CAS  Google Scholar 

  • Gunawan B, Kaplowitz N (2004) Clinical perspectives on xenobiotic-induced hepatotoxicity. Drug Metab Rev 36:301–312

    Article  PubMed  CAS  Google Scholar 

  • Gut J, Christen U, Huwyler J, Burgin M, Kenna JG (1992) Molecular mimicry of trifluoroacetylated human liver protein adducts by constitutive proteins and immunochemical evidence for its impairment in halothane hepatitis. Eur J Biochem 210:569–576

    Article  PubMed  CAS  Google Scholar 

  • Hartleb M, Biernat L, Kochel A (2002) Drug-induced liver damage – a three-year study of patients from one gastroenterological department. Med Sci Monit 8:CR292–CR296

    Google Scholar 

  • He K, Woolf TF, Kindt EK, Fielder AE, Talaat RE (2001) Troglitazone quinone formation catalyzed by human and rat CYP3A: an atypical CYP oxidation reaction. Biochem Pharmacol 62:191–198

    Article  PubMed  CAS  Google Scholar 

  • Hoffmaster KA, Turncliff RZ, LeCluyse EL, Kim RB, Meier PJ, Brouwer KL (2004) P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Pharm Res 21:1294–1302

    Article  PubMed  CAS  Google Scholar 

  • Hogan V (2000) Pemoline (Cylert): market withdrawal. CMAJ 162(106):110

    Google Scholar 

  • Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD (2003) Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37:924–930

    Article  PubMed  CAS  Google Scholar 

  • Igarashi (1994) The duration of toxicity studies required to support repeated dosing in clinical investigation--A toxicologists opinion. In: Parkinson C, McAuslane N, Lumley C, Waler SR (eds) CMR Workshop: the timing of toxicological studies to support clinical trials. Kluwer, Boston, pp 67–74

    Google Scholar 

  • Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N (2002) A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J 16:1227–1236

    Article  PubMed  CAS  Google Scholar 

  • Ishida Y, Kondo T, Kimura A, Tsuneyama K, Takayasu T, Mukaida N (2006) Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol 36:1028–1038

    Article  PubMed  CAS  Google Scholar 

  • Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    Article  PubMed  CAS  Google Scholar 

  • Jee RC, Sipes IG, Gandolfi AJ, Brown BR Jr (1980) Factors influencing halothane hepatotoxicity in the rat hypoxic model. Toxicol Appl Pharmacol 52:267–277

    Article  PubMed  CAS  Google Scholar 

  • Ju C, Pohl LR (2005) Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions. Toxicology 209:109–112

    Article  PubMed  CAS  Google Scholar 

  • Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George JW, Pohl LR (2002) Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 15:1504–1513

    Article  PubMed  CAS  Google Scholar 

  • Ju C, McCoy JP, Chung CJ, Graf ML, Pohl LR (2003) Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol 16:1514–1519

    Article  PubMed  CAS  Google Scholar 

  • Kalgutkar AS, Vaz AD, Lame ME, Henne KR, Soglia J, Zhao SX, Abramov YA, Lombardo F, Collin C, Hendsch ZS, Hop CE (2005) Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 33:243–253

    Article  PubMed  CAS  Google Scholar 

  • Kaplowitz N (2001) Drug-induced liver disorders: implications for drug development and regulation. Drug Saf 24:483–490

    Article  PubMed  CAS  Google Scholar 

  • Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baillie TA (2001) Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62–70

    Article  PubMed  CAS  Google Scholar 

  • Kenna JG, Neuberger J, Mieli-Vergani G, Mowat AP, Williams R (1987) Halothane hepatitis in children. Br Med J (Clin Res Ed) 294:1209–1211

    Article  CAS  Google Scholar 

  • Kenna JG, Satoh H, Christ DD, Pohl LR (1988) Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane. J Pharmacol Exp Ther 245:1103–1109

    PubMed  CAS  Google Scholar 

  • Kharasch ED (2008) Adverse drug reactions with halogenated anesthetics. Clin Pharmacol Ther 84:158–162

    Article  PubMed  CAS  Google Scholar 

  • Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S, Gerken G, Lohse AW (1999) Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116:1428–1440

    Article  PubMed  CAS  Google Scholar 

  • Koenigs LL, Peter RM, Hunter AP, Haining RL, Rettie AE, Friedberg T, Pritchard MP, Shou M, Rushmore TH, Trager WF (1999) Electrospray ionization mass spectrometric analysis of intact cytochrome P450: identification of tienilic acid adducts to P450 2C9. Biochemistry 38:2312–2319

    Article  PubMed  CAS  Google Scholar 

  • Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, Chalasani N (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 47:2003–2009

    Article  PubMed  CAS  Google Scholar 

  • Larrey D (2000) Drug-induced liver diseases. J Hepatol 32:77–88

    Article  PubMed  CAS  Google Scholar 

  • Larrey D (2002) Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 22:145–155

    Article  PubMed  CAS  Google Scholar 

  • Laskin, Gardner CR (2003) Nonparenchymal cells, inflammatory macrophages, and hepatotoxicity. Drug-induced liver diseases. Marcel Dekker, New York, pp 183–212

    Google Scholar 

  • Laskin DL, Gardner CR, Price VF, Jollow DJ (1995) Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 21:1045–1050

    Article  PubMed  CAS  Google Scholar 

  • Lawson JA, Farhood A, Hopper RD, Bajt ML, Jaeschke H (2000) The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci 54:509–516

    Article  PubMed  CAS  Google Scholar 

  • Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279:1200–1205

    Article  PubMed  CAS  Google Scholar 

  • Lazerow SK, Abdi MS, Lewis JH (2005) Drug-induced liver disease 2004. Curr Opin Gastroenterol 21:283–292

    Article  PubMed  Google Scholar 

  • LeCluyse EL, Alexandre E, Hamilton GA, Viollon-Abadie C, Coon DJ, Jolley S, Richert L (2005) Isolation and culture of primary human hepatocytes. Methods Mol Biol 290:207–229

    PubMed  Google Scholar 

  • Lecoeur S, Andre C, Beaune PH (1996) Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol 50:326–333

    PubMed  CAS  Google Scholar 

  • Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349:474–485

    Article  PubMed  CAS  Google Scholar 

  • Lee WM, Senior JR (2005) Recognizing drug-induced liver injury: current problems, possible solutions. Toxicol Pathol 33:155–164

    Article  PubMed  CAS  Google Scholar 

  • Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, Momburg F, Arnold B, Knolle PA (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6:1348–1354

    Article  PubMed  CAS  Google Scholar 

  • Lind RC, Gandolfi AJ, Hall PD (1989a) Age and gender influence halothane-associated hepatotoxicity in strain 13 guinea pigs. Anesthesiology 71:878–884

    Article  PubMed  CAS  Google Scholar 

  • Lind RC, Gandolfi AJ, Hall PD (1989b) The role of oxidative biotransformation of halothane in the guinea pig model of halothane-associated hepatotoxicity. Anesthesiology 70:649–653

    Article  PubMed  CAS  Google Scholar 

  • Lind RC, Gandolfi AJ, Hall PD (1990) Covalent binding of oxidative biotransformation intermediates is associated with halothane hepatotoxicity in guinea pigs. Anesthesiology 73:1208–1213

    Article  PubMed  CAS  Google Scholar 

  • Lindenbaum J, Leifer E (1963) Hepatic necrosis associated with halothane anesthesia. N Engl J Med 268:525–530

    Article  PubMed  CAS  Google Scholar 

  • Liu ZX, Kaplowitz N (2002) Immune-mediated drug-induced liver disease. Clin Liver Dis 6:755–774

    Article  PubMed  Google Scholar 

  • Liu ZX, Govindarajan S, Kaplowitz N (2004) Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 127:1760–1774

    Article  PubMed  CAS  Google Scholar 

  • Liu ZX, Han D, Gunawan B, Kaplowitz N (2006) Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 43:1220–1230

    Article  PubMed  CAS  Google Scholar 

  • Loi CM, Alvey CW, Randinitis EJ, Abel R, Young MA, Koup JR (1997) Meta-analysis of steady-state pharmacokinetics of troglitazone and its metabolites. J Clin Pharmacol 37:1038–1047

    PubMed  CAS  Google Scholar 

  • Lumley (1990) Clinical toxicity: could it have been prevented? Premarketing experience. In: Lumley CE, Walker SW (eds) CMR workshop – animal toxicity studies: their relevance for man. Quay, Lancaster, UK, pp 49–56

    Google Scholar 

  • Lunam CA, Cousins MJ, Hall PD (1985) Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia. J Pharmacol Exp Ther 232:802–809

    PubMed  CAS  Google Scholar 

  • Luster MI, Simeonova PP, Gallucci RM, Bruccoleri A, Blazka ME, Yucesoy B (2001) Role of inflammation in chemical-induced hepatotoxicity. Toxicol Lett 120:317–321

    Article  PubMed  CAS  Google Scholar 

  • Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–732

    Article  PubMed  CAS  Google Scholar 

  • Masson MJ, Carpenter LD, Graf ML, Pohl LR (2008) Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide. Hepatology 48:889–897

    Article  PubMed  CAS  Google Scholar 

  • Masubuchi Y, Bourdi M, Reilly TP, Graf ML, George JW, Pohl LR (2003) Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 304:207–212

    Article  PubMed  CAS  Google Scholar 

  • May LD, Lefkowitch JH, Kram MT, Rubin DE (2002) Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy. Ann Int Med 136:449–452

    PubMed  Google Scholar 

  • McKenzie H, Parratt D, White RG (1976) IgM and IgG antibody levels to ampicillin in patients with infectious mononucleosis. Clin Exp Immunol 26:214–221

    PubMed  CAS  Google Scholar 

  • McLain GE, Sipes IG, Brown BR Jr (1979) An animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia. Anesthesiology 51:321–326

    Article  PubMed  CAS  Google Scholar 

  • Meadows M (2001) Serious liver injury. Leading reason for drug removals, restrictions. FDA Consum 35:8–9

    PubMed  CAS  Google Scholar 

  • Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA (1999) Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 30:186–195

    Article  PubMed  CAS  Google Scholar 

  • Murphy R, Swartz R, Watkins PB (1990) Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Int Med 113:799–800

    PubMed  CAS  Google Scholar 

  • Muzio M, Bosisio D, Polentarutti N, D'amico G, Stoppacciaro A, Mancinelli R, van't Veer C, Penton-Rol G, Ruco LP, Allavena P, Mantovani A (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998–6004

    Google Scholar 

  • Naisbitt DJ, Britschgi M, Wong G, Farrell J, Depta JP, Chadwick DW, Pichler WJ, Pirmohamed M, Park BK (2003a) Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol 63:732–741

    Article  PubMed  CAS  Google Scholar 

  • Naisbitt DJ, Farrell J, Wong G, Depta JP, Dodd CC, Hopkins JE, Gibney CA, Chadwick DW, Pichler WJ, Pirmohamed M, Park BK (2003b) Characterization of drug-specific T cells in lamotrigine hypersensitivity. J Allerg Clin Immunol 111:1393–1403

    Article  CAS  Google Scholar 

  • Nelson SD, Mitchell JR, Snodgrass WR, Timbrell JA (1978) Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine. J Pharmacol Exp Ther 206:574–585

    PubMed  CAS  Google Scholar 

  • Neuberger JM (1990) Halothane and hepatitis. Incidence, predisposing factors and exposure guidelines. Drug Saf 5:28–38

    Article  PubMed  CAS  Google Scholar 

  • Neuberger J, Kenna JG (1987) Halothane hepatitis: a model of immune mediated drug hepatotoxicity. Clin Sci (Lond) 72:263–270

    CAS  Google Scholar 

  • Njoku D, Laster MJ, Gong DH, Eger EI, Reed GF, Martin JL (1997) Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury. Anesth Analg 84:173–178

    PubMed  CAS  Google Scholar 

  • O'Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RN, Mills PR (2000) Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47:717–720

    Article  PubMed  Google Scholar 

  • Ostapowicz G, Lee WM (2000) Acute hepatic failure: a Western perspective. J Gastroenterol Hepatol 15:480–488

    Article  PubMed  CAS  Google Scholar 

  • Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Int Med 137:947–954

    PubMed  Google Scholar 

  • Park BK, Pirmohamed M, Kitteringham NR (1998) Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol 11:969–988

    Article  PubMed  CAS  Google Scholar 

  • Park BK, Kitteringham NR, Powell H, Pirmohamed M (2000) Advances in molecular toxicology-towards understanding idiosyncratic drug toxicity. Toxicology 153:39–60

    Article  PubMed  CAS  Google Scholar 

  • Peitsch MC, Tschopp J, Kress A, Isliker H (1988) Antibody-independent activation of the complement system by mitochondria is mediated by cardiolipin. Biochem J 249:495–500

    PubMed  CAS  Google Scholar 

  • Pessayre LD, Biour M (1999) Drug-induced liver injury. In: Bircher J, Benhamou JP, McIntyre N, Ruzzettim M, Rodes J (eds) Oxford textbook of clinical hepatology, 2nd edn. Oxford University Press, Oxford, pp 1261–1315

    Google Scholar 

  • Pichler WJ (2002) Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allerg Clin Immunol 2:301–305

    Article  Google Scholar 

  • Pichler WJ (2005) Direct T-cell stimulations by drugs–bypassing the innate immune system. Toxicology 209:95–100

    Article  PubMed  CAS  Google Scholar 

  • Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP (2004) Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol 172:1009–1017

    PubMed  CAS  Google Scholar 

  • Pohl LR, Satoh H, Christ DD, Kenna JG (1988) The immunologic and metabolic basis of drug hypersensitivities. Annu Rev Pharmacol Toxicol 28:367–387

    Article  PubMed  CAS  Google Scholar 

  • Pohl LR, Kenna JG, Satoh H, Christ D, Martin JL (1989) Neoantigens associated with halothane hepatitis. Drug Metab Rev 20:203–217

    Article  PubMed  CAS  Google Scholar 

  • Pol S, Vallet-Pichard A, Fontaine H (2002) Hepatitis C and human immune deficiency coinfection at the era of highly active antiretroviral therapy. J Viral Hepat 9:1–8

    Article  PubMed  CAS  Google Scholar 

  • Pullen H, Wright N, Murdoch JM (1967) Hypersensitivity reactions to antibacterial drugs in infectious mononucleosis. Lancet 2:1176–1178

    Article  PubMed  CAS  Google Scholar 

  • Rabkin JM, Smith MJ, Orloff SL, Corless CL, Stenzel P, Olyaei AJ (1999) Fatal fulminant hepatitis associated with bromfenac use. Ann Pharmacother 33:945–947

    Article  PubMed  CAS  Google Scholar 

  • Reilly TP, Brady JN, Marchick MR, Bourdi M, George JW, Radonovich MF, Pise-Masison CA, Pohl LR (2001) A protective role for cyclooxygenase-2 in drug-induced liver injury in mice. Chem Res Toxicol 14:1620–1628

    Article  PubMed  CAS  Google Scholar 

  • Ross WT Jr, Daggy BP, Cardell RR Jr (1979) Hepatic necrosis caused by halothane and hypoxia in phenobarbital-treated rats. Anesthesiology 51:327–333

    Article  PubMed  CAS  Google Scholar 

  • Roth RA, Luyendyk JP, Maddox JF, Ganey PE (2003) Inflammation and drug idiosyncrasy–is there a connection? J Pharmacol Exp Ther 307:1–8

    Article  PubMed  CAS  Google Scholar 

  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P (2004) Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 10:1018–1023

    Article  PubMed  Google Scholar 

  • Safer DJ, Zito JM, Gardner JE (2001) Pemoline hepatotoxicity and postmarketing surveillance. J Am Acad Child Adolesc Psychiatry 40:622–629

    Article  PubMed  CAS  Google Scholar 

  • Satoh H, Gillette JR, Davies HW, Schulick RD, Pohl LR (1985) Immunochemical evidence of trifluoroacetylated cytochrome P-450 in the liver of halothane-treated rats. Mol Pharmacol 28:468–474

    PubMed  CAS  Google Scholar 

  • Satoh H, Martin BM, Schulick AH, Christ DD, Kenna JG, Pohl LR (1989) Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase. Proc Natl Acad Sci USA 86:322–326

    Article  PubMed  CAS  Google Scholar 

  • Saxon AJ, Sloan KL, Reoux J, Haver VM (1998) Disulfiram use in patients with abnormal liver function test results. J Clin Psychiatry 59:313–316

    Article  PubMed  CAS  Google Scholar 

  • Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ (1997) Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. J Clin Invest 100:136–141

    Article  PubMed  CAS  Google Scholar 

  • Schnyder B, Burkhart C, Schnyder-Frutig K, von Greyerz S, Naisbitt DJ, Pirmohamed M, Park BK, Pichler WJ (2000) Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals. J Immunol 164:6647–6654

    PubMed  CAS  Google Scholar 

  • Seong SY, Matzinger P (2004) Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 4:469–478

    Article  PubMed  CAS  Google Scholar 

  • Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, Lenoir C, Lemoine A, Hillon P (2002) Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 36:451–455

    Article  PubMed  Google Scholar 

  • Shevell M, Schreiber R (1997) Pemoline-associated hepatic failure: a critical analysis of the literature. Pediatr Neurol 16:14–16

    Article  PubMed  CAS  Google Scholar 

  • Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516–521

    Article  PubMed  CAS  Google Scholar 

  • Smith GS, Nadig DE, Kokoska ER, Solomon H, Tiniakos DG, Miller TA (1998) Role of neutrophils in hepatotoxicity induced by oral acetaminophen administration in rats. J Surg Res 80:252–258

    Article  PubMed  CAS  Google Scholar 

  • Spracklin DK, Hankins DC, Fisher JM, Thummel KE, Kharasch ED (1997) Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. J Pharmacol Exp Ther 281:400–411

    PubMed  CAS  Google Scholar 

  • Stachnik J (2006) Inhaled anesthetic agents. Am J Health Syst Pharm 63:623–634

    Article  PubMed  CAS  Google Scholar 

  • Stewart DE (2002) Hepatic adverse reactions associated with nefazodone. Can J Psychiatry 47:375–377

    PubMed  Google Scholar 

  • Stricker (1992) Drug-induced hepatic injury. In: Dukes M (ed) Drug-induced disorders, 2nd edn. Elviser, Amsterdam, pp 210–240

    Google Scholar 

  • Sulkowski MS, Thomas DL, Chaisson RE, Moore RD (2000) Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 283:74–80

    Article  PubMed  CAS  Google Scholar 

  • Takakusa H, Masumoto H, Yukinaga H, Makino C, Nakayama S, Okazaki O, Sudo K (2008) Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos 36:1770–1779

    Google Scholar 

  • Temple RJ, Himmel MH (2002) Safety of newly approved drugs: implications for prescribing. JAMA 287:2273–2275

    Article  PubMed  Google Scholar 

  • Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195:99–111

    Article  PubMed  CAS  Google Scholar 

  • Tettey JN, Maggs JL, Rapeport WG, Pirmohamed M, Park BK (2001) Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. Chem Res Toxicol 14:965–974

    Article  PubMed  CAS  Google Scholar 

  • Tolman KG (1998) Hepatotoxicity of non-narcotic analgesics. Am J Med 105:13S–19S

    Article  PubMed  CAS  Google Scholar 

  • Uetrecht JP (1999) New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system. Chem Res Toxicol 12:387–395

    Article  PubMed  CAS  Google Scholar 

  • Vergani D, Mieli-Vergani G, Alberti A, Neuberger J, Eddleston AL, Davis M, Williams R (1980) Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N Engl J Med 303:66–71

    Article  PubMed  CAS  Google Scholar 

  • Visintin A, Mazzoni A, Spitzer JH, Wyllie DH, Dower SK, Segal DM (2001) Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol 166:249–255

    PubMed  CAS  Google Scholar 

  • Wallin RP, Lundqvist A, More SH, von Bonin A, Kiessling R, Ljunggren HG (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol 23:130–135

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Ellison CA, Gartner JG, HayGlass KT (1998) Natural killer cell depletion fails to influence initial CD4 T cell commitment in vivo in exogenous antigen-stimulated cytokine and antibody responses. J Immunol 160:1098–1105

    PubMed  CAS  Google Scholar 

  • Waring JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA (2006) Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 316:1080–1087

    Article  PubMed  CAS  Google Scholar 

  • Warner LO, Beach TP, Garvin JP, Warner EJ (1984) Halothane and children: the first quarter century. Anesth Analg 63:838–840

    PubMed  CAS  Google Scholar 

  • Watkins PB, Seeff LB (2006) Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 43:618–631

    Article  PubMed  Google Scholar 

  • Watkins PB, Whitcomb RW (1998) Hepatic dysfunction associated with troglitazone. N Engl J Med 338:916–917

    Article  PubMed  CAS  Google Scholar 

  • Wright R, Eade OE, Chisholm M, Hawksley M, Lloyd B, Moles TM, Edwards JC, GArdner MJ (1975) Controlled prospective study of the effect on liver function of multiple exposures to halothane. Lancet 1:817–820

    Article  PubMed  CAS  Google Scholar 

  • Xu JJ, Henstock PV, Dunn MC, Smith AR, Chabot JR, de Graaf D (2008) Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury. Toxicol, Sci

    Google Scholar 

  • Yee SB, Bourdi M, Masson MJ, Pohl LR (2007) Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease. Chem Res Toxicol 20:734–744

    Article  PubMed  CAS  Google Scholar 

  • You Q, Cheng L, Reilly TP, Wegmann D, Ju C (2006) Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 44:1421–1431

    Article  PubMed  CAS  Google Scholar 

  • You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48:978–990

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman (1999a) Drug-induced liver disease. In: Schiff E, Sorrell M, Maddrey W (eds) Schiff's diseases of the liver. Lippincott-Raven, Philadelphia, pp 973–1064

    Google Scholar 

  • Zimmerman HJ (1999b) Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver, 2nd edn. Lippicott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Zimmerman HJ, Lewis JH, Ishak KG, Maddrey WC (1984) Ticrynafen-associated hepatic injury: analysis of 340 cases. Hepatology 4:315–323

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmaceutical Sciences, University of Colorado Denver, C238-P15, Research Complex 2, 12700 East 19th Avenue, Room 3007, Aurora, CO, 80045, USA

    Cynthia Ju

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    Jack Uetrecht (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions) (Professor of Pharmacy and Medicine, Canada Research Chair in Adverse Drug Reactions)

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Holt, M., Ju, C. (2010). Drug-Induced Liver Injury. In: Uetrecht, J. (eds) Adverse Drug Reactions. Handbook of Experimental Pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_1

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