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Review

Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science

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Pages 1415-1427 | Published online: 25 Oct 2008

Bibliography

  • Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279(15):1200-5
  • Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients [see comment]. BMJ 2004;329(7456):15-9
  • Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3(8):711-5
  • Park BK, Kitteringham NR, Maggs JL, et al. The role of metabolic activation in drug-induced hepatotoxicity. Ann Rev Pharmacol Toxicol 2005;45:177-202
  • Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discov Today 2003;8(18):832-7
  • Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137(12):947-54
  • Dossing M, Sonne J. Drug-induced hepatic disorders. Incidence, management and avoidance. Drug Saf 1993;9(6):441-9. Erratum appears in: Drug Saf 1994;103:269
  • Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004;17(1):3-16. Eerratum appears in: Chem Res Toxicol 2005;18(11):1777
  • Lee WM. Drug-induced hepatotoxicity [see comment]. N Engl J Med 2003;349(5):474-85
  • Navarro VJ, Senior JR. Drug-related hepatotoxicity [see comment]. N Engl J Med 2006;354(7):731-9
  • Ozer J, Ratner M, Shaw M, et al. The current state of serum biomarkers of hepatotoxicity. Toxicology 2008;245(3):194-205
  • Hinson JA, Pohl LR, Monks TJ, et al. Acetaminophen-induced hepatotoxicity. Life Sci 1981;29(2):107-16
  • Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 1974;11(3):151-69
  • Recknagel RO, Glende EA Jr, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacol Ther 1989;43(1):139-54
  • Williams DP, Antoine DJ, Butler PJ, et al. The metabolism and toxicity of furosemide in the Wistar rat and CD-1 mouse: a chemical and biochemical definition of the toxicophore. J Pharm Exp Ther 2007;322(3):1208-20
  • Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4(6):489-99
  • Kalgutkar AS, Gardner I, Obach RS, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 2005;6(3):161-225
  • Williams DP. Toxicophores: investigations in drug safety. Toxicology 2006;226(1):1-11
  • Iwanaga T, Nakakariya M, Yabuuchi H, et al. Involvement of bile salt export pump in flutamide-induced cholestatic hepatitis. Biol Pharm Bull 2007;30(4):739-44
  • Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004;17(1):3-16
  • Smith DA, Schmid EF. Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel 2006;9(1):38-46
  • Lopez-Garcia MP. Endogenous nitric oxide is responsible for the early loss of P450 in cultured rat hepatocytes. FEBS Lett 1998;438(3):145-9
  • Richert L, Binda D, Hamilton G, et al. Evaluation of the effect of culture configuration on morphology, survival time, antioxidant status and metabolic capacities of cultured rat hepatocytes. Toxicol In Vitro 2002;16(1):89-99
  • Copple I, Goldring CE, Jenkins RE, et al. The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defence system. Hepatology 2008; In press [Epub 19th June 2008]
  • Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Phamracol Exp Ther 1973;187(1):195-202
  • Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 1973;187(1):185-94
  • Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973;187(1):211-7
  • Potter WZ, Davis DC, Mitchell JR, et al. Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 1973;187(1):203-10
  • Dahlin DC, Miwa GT, Lu AY, Nelson SD. N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 1984;81(5):1327-31
  • Lee SS, Buters JT, Pineau T, et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996;271(20):12063-7
  • Massey TE, Racz WJ. Effects of N-acetylcysteine on metabolism, covalent binding, and toxicity of acetaminophen in isolated mouse hepatocytes. Toxicol Appl Pharmacol 1981;60(2):220-8
  • Reid AB, Kurten RC, McCullough SS, et al. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther 2005;312(2):509-16
  • Davies DS, Tee LB, Hampden C, Boobis AR. Acetaminophen toxicity in isolated hepatocytes. Adv Exp Med Biol 1986;197:993-1003
  • Moore M, Thor H, Moore G, et al. The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J Biol Chem 1985;260(24):13035-40
  • Tee LB, Boobis AR, Huggett AC, Davies DS. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol 1986;83(2):294-314
  • Raucy JL, Lasker JM, Lieber CS, Black M. Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch Biochem Biophys 1989;271(2):270-83
  • Davis DC, Potter WZ, Jollow DJ, Mitchell JR. Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci 1974;14(11):2099-109
  • Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 2007;27(9):1219-30
  • Krahenbuhl S, Brauchli Y, Kummer O, et al. Acute liver failure in two patients with regular alcohol consumption ingesting paracetamol at therapeutic dosage. Digestion 2007;75(4):232-7
  • Moling O, Cairon E, Rimenti G, et al. Severe hepatotoxicity after therapeutic doses of acetaminophen. Clin Ther 2006;28(5):755-60
  • Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000;49(4):291-301
  • Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology 2002;35(4):876-82
  • Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use [see comment]. JAMA 1994;272(23):1845-50
  • Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;223:767-73. Erratum appears in: Hepatology 1995;22(6):1898
  • Ju C, Reilly TP, Bourdi M, et al. Protective role of Kupffer cells in acetaminophen-induced hepatic injury in mice. Chem Res Toxicol 2002;15(12):1504-13
  • Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004;127(6):1760-74
  • Liu ZX, Han D, Gunawan B, Kaplowitz N. Neutrophil depletion protects against murine acetaminophen hepatotoxicity [see comment]. Hepatology 2006;43(6):1220-30
  • Goldring CE, Kitteringham NR, Elsby R, et al. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 2004;39(5):1267-76
  • Kitteringham NR, Powell H, Clement YN, et al. Hepatocellular response to chemical stress in CD-1 mice: induction of early genes and gamma-glutamylcysteine synthetase. Hepatology 2000;32(2):321-33
  • Okawa H, Motohashi H, Kobayashi A, et al. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem Biophys Res Commun 2006;339(1):79-88
  • Goldin RD, Ratnayaka ID, Breach CS, et al. Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol 1996;179(4):432-5
  • Ishida Y, Kondo T, Ohshima T, et al. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J 2002;16(10):1227-36
  • Bourdi M, Masubuchi Y, Reilly TP, et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase. Hepatology 2002;352:289-98
  • Masubuchi Y, Bourdi M, Reilly TP, et al. Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 2003;304(1):207-12
  • Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002;418(6894):191-5
  • Ishida Y, Kondo T, Kimura A, et al. Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol 2006;36(4):1028-38
  • You Q, Cheng L, Reilly TP, et al. Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 2006;44(6):1421-31
  • Jaeschke H. How relevant are neutrophils for acetaminophen hepatotoxicity? [comment]. Hepatology 2006;43(6):1191-4
  • Masson MJ, Carpenter LD, Graf ML, Pohl LR. Pathogenic role of NKT and NK cells in acetaminophen-induced liver injury is dependent on the presence of DMSO. Hepatology 2008;48(3):889-97
  • Kenna JG. Immunoallergic drug-induced hepatitis: lessons from halothane. J Hepatol 1997;26(Suppl 1):5-12
  • Vergani D, Mieli-Vergani G, Alberti A, et al. Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N Engl J Med 1980;303(2):66-71
  • Bourdi M, Chen W, Peter RM, et al. Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 1996;9(7):1159-66
  • Martin DC, Dennison RL, Introna RP, Aronstam RS. Influence of halothane on the interactions of serotonin1A and adenosine A1 receptors with G proteins in rat brain membranes. Biochem Pharmacol 1991;42(6):1313-6
  • Martin JL, Pumford NR, LaRosa AC, et al. A metabolite of halothane covalently binds to an endoplasmic reticulum protein that is highly homologous to phosphatidylinositol-specific phospholipase C-alpha but has no activity. Biochem Biophys Res Commun 1991;178(2):679-85
  • Pohl LR, Thomassen D, Pumford NR, et al. Hapten carrier conjugates associated with halothane hepatitis. Adv Exp Med Biol 1991;283:111-20
  • Lohse AW, Brunner S, Kyriatsoulis A, et al. Autoantibodies in experimental autoimmune hepatitis. J Hepatol 1992;14(1):48-53
  • Lohse AW, Manns M, Dienes HP, et al. Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity [see comment]. Hepatology 1990;11(1):24-30
  • Ju C, McCoy JP, Chung CJ, et al. Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol 2003;16(12):1514-9
  • Biswas P, Wilton LV, Shakir SA. Troglitazone and liver function abnormalities: lessons from a prescription event monitoring study and spontaneous reporting. Drug Saf 2001;24(2):149-54
  • Kohlroser J, Mathai J, Reichheld J, et al. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol 2000;95(1):272-6
  • Halegoua-De Marzio D, Navarro VJ. Drug-induced hepatotoxicity in humans. Curr Opin Drug Discov Devel 2008;11(1):53-9
  • Dixit R, Boelsterli UA. Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discov Today 2007;12(7-8):336-42
  • Strubelt O, Dost-Kempf E, Siegers CP, et al. The influence of fasting on the susceptibility of mice to hepatotoxic injury. Toxicol Appl Pharmacol 1981;60(1):66-77
  • Katoh M, Matsui T, Nakajima M, et al. Expression of human cytochromes P450 in chimeric mice with humanized liver. Drug Metab Dispos 2004;32(12):1402-10
  • Muruganandan S, Sinal CJ. Mice as clinically relevant models for the study of cytochrome P450-dependent metabolism. Clin Pharmacol Ther 2008;83(6):818-28
  • Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007;100(1):259-66
  • Cummings J, Ward TH, Greystoke A, et al. Biomarker method validation in anticancer drug development. Br J Pharmacol 2008;153(4):646-56
  • Soga T, Baran R, Suematsu M, et al. Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. J Biol Chem 2006;281(24):16768-76
  • Moll R, Franke WW, Schiller DL, et al. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982;31(1):11-24
  • Schutte B, Henfling M, Kolgen W, et al. Keratin 8/18 breakdown and reorganization during apoptosis. Exp Cell Res 2004;297(1):11-26
  • Ku NO, Omary MB. Effect of mutation and phosphorylation of type I keratins on their caspase-mediated degradation. J Biol Chem 2001;276(29):26792-8
  • Cummings J, Ranson M, Butt F, et al. Qualification of M30 and M65 ELISAs as surrogate biomarkers of cell death: long term antigen stability in cancer patient plasma. Cancer Chemother Pharmacol 2007;60(6):921-4
  • Cummings J, Ranson M, Lacasse E, et al. Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 2006;95(1):42-8
  • Cummings J, Ward TH, LaCasse E, et al. Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 2005;923:532-8
  • Wieckowska A, Zein NN, Yerian LM, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 2006;44(1):27-33
  • Dumitriu IE, Baruah P, Bianchi ME, et al. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol 2005;35(7):2184-90
  • Dumitriu IE, Baruah P, Manfredi AA, et al. HMGB1: guiding immunity from within. Trends Immunol 2005;267:381-7
  • Hardman CH, Broadhurst RW, Raine AR, et al. Structure of the A-domain of HMG1 and its interaction with DNA as studied by heteronuclear three- and four-dimensional NMR spectroscopy. Biochemistry 1995;34(51):16596-607
  • Read CM, Cary PD, Crane-Robinson C, et al. Solution structure of a DNA-binding domain from HMG1. Nucleic Acids Res 1993;21(15):3427-36
  • Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 2003;22(20):5551-60
  • Palumbo R, Galvez BG, Pusterla T, et al. Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation. J Cell Biol 2007;179(1):33-40
  • Yu M, Wang H, Ding A, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 2006;26(2):174-9
  • Stern D, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings. Adv Drug Deliv Rev 2002;54(12):1615-25
  • Abraham E, Arcaroli J, Carmody A, et al. HMG-1 as a mediator of acute lung inflammation. J Immunol 2000;165(6):2950-4
  • Taniguchi N, Kawahara K, Yone K, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine [see comment]. Arthritis Rheum 2003;48(4):971-81
  • Tsung A, Sahai R, Tanaka H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 2005;201(7):1135-43
  • Ulloa L, Batliwalla FM, Andersson U, et al. High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis [comment]. Arthritis Rheum 2003;48(4):876-81
  • Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 2007;220:35-46
  • Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008;8(4):279-89
  • Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999;285(5425):248-51
  • Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev 2006;17(3):189-201
  • Randle LE, Sathish JG, Kitteringham NR, et al. alpha1;-Adrenoceptor antagonists prevent paracetamol-induced hepatotoxicity in mice. Br J Pharmacol 2008;153(4):820-30
  • Bruchfeld A, Qureshi AR, Lindholm B, et al. High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med 2008;14(3-4):109-15
  • Hogaboam CM, Bone-Larson CL, Steinhauser ML, et al. Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. Am J Pathol 2000;156(4):1245-52
  • Tinel M, Berson A, Vadrot N, et al. Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice. Hepatology 2004;39(3):655-66
  • Bourdi M, Eiras DP, Holt MP, et al. Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury. Chem Res Toxicol 2007;20(2):208-16
  • Zhang H, Cook J, Nickel J, et al. Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat Biotechnol 2000;18(8):862-7
  • Bone-Larson CL, Hogaboam CM, Evanhoff H, et al. IFN-gamma-inducible protein-10 (CXCL10) is hepatoprotective during acute liver injury through the induction of CXCR2 on hepatocytes. J Immunol 2001;167(12):7077-83
  • Hogaboam CM, Bone-Larson CL, Steinhauser ML, et al. Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines. FASEB J 1999;13(12):1565-74
  • Hogaboam CM, Simpson KJ, Chensue SW, et al. Macrophage inflammatory protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury. Gene Ther 1999;6(4):573-84
  • Trepicchio WL, Bozza M, Bouchard P, Dorner AJ. Protective effect of rhIL-11 in a murine model of acetaminophen-induced hepatotoxicity. Toxicol Pathol 2001;29(2):242-9
  • Welch KD, Reilly TP, Bourdi M, et al. Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem Res Toxicol 2006;19(2):223-33
  • Bourdi M, Reilly TP, Elkahloun AG, et al. Macrophage migration inhibitory factor in drug-induced liver injury: a role in susceptibility and stress responsiveness. Biochem Biophys Res Commun 2002;294(2):225-30
  • Yohe HC, O'Hara KA, Hunt JA, et al. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity. Am J Physiol Gastrointest Liver Physiol 2006;290(6):G1269-79
  • Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2006;2(4):493-503

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