Skip to main content
SpringerLink
Log in

Immune Mechanisms in Drug-Induced Hepatotoxicity

Therapeutic Implications

  • Chapter
Liver Immunology

Abstract

Drug-induced liver injury (DILI) is a common cause of liver disease. It accounts for approximately one-half of cases of acute liver failure and significant numbers of deaths in the United States and many other countries (1–5). An estimated 1000 or more drugs have been implicated in causing liver disease on more than one occasion (5). Clinically, DILI mimics all forms of liver diseases, with the liver damage varying in severity from mild and transient increases in serum aminotransferases to fulminant hepatic failure. This represents an important diagnostic and therapeutic challenge for physicians. Idiosyncratic drug toxicity refers to toxic reactions occurring in a small subset of patients; it usually cannot be predicted during preclinical or early phases of clinical trials. The occurrence of idiosyncratic drug hepatotoxicity is also a major problem in all phases of clinical drug development and the most frequent cause of postmarketing warnings and withdrawals (1–5). DILI is usually initiated by a toxic drug and its metabolite, followed by either immune-mediated mechanisms and/or intracellular biochemical mechanisms of hepatocytes (2–5).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 199.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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; 137:947–954.

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Zimmerman H. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver, 2nd ed. Philadelphia: Lippincott, Williams & Wilkins, 1999.

    Google Scholar 

  4. Kaplowitz N. Mechanisms of cell death and relevance to drug hepatotoxicity. In: Kaplowitz N, DeLeve LD, eds. Drug-Induced Liver Disease. New York: Marcel Dekker, 2002:85–95.

    Google Scholar 

  5. Kaplowitz N. Drug-induced liver injury. Clin Infect Dis 2004; 38(Suppl 2):S44–S48.

    Article  PubMed  Google Scholar 

  6. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006; 354:731–739.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Shear N, Spielberg S. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 1988; 82:1826–1832.

    Article  PubMed  CAS  Google Scholar 

  9. Thompson N, Caplin M, Hamilton M, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995; 8:1384–1388.

    Article  PubMed  CAS  Google Scholar 

  10. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002; 6:467–486.

    Google Scholar 

  11. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005; 4:489–499.

    Article  PubMed  CAS  Google Scholar 

  12. Manns MP, Obermayer-Straub P. Cytochrome P450 and uridine triphosphate-glucuronosyltransferase: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. Hepatology 1997; 26:1054–1066.

    Article  PubMed  CAS  Google Scholar 

  13. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis 2002; 22:137–144.

    Article  PubMed  CAS  Google Scholar 

  14. Knowles S, Uetrecht J, Shear NH. Idiosyncratic drug reactions: the reactive metabolite syndrome. Lancet 2000; 356:1587–1591.

    Article  PubMed  CAS  Google Scholar 

  15. Park B, Pirmohamed M, Kitteringham N. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical prospective. Chem Res Toxicol 1998; 11:969–988.

    Article  PubMed  CAS  Google Scholar 

  16. Kitteringham NR: Drug-protein conjugation and its immunological consequences. Drug Metabol Rev 1990; 22:87–144.

    Article  Google Scholar 

  17. Bourdi M, Gautier JC, Mircheva J, et al. Anti-liver microsomes autoantibodies and dihydralazine-induced hepatitis: specificity of autoantibodies and inductive capacity of the drug. Mol Pharmacol 1992; 42:280–285.

    PubMed  CAS  Google Scholar 

  18. Maria V, Victorino R: Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury. Gut 1997; 41:534–540.

    Article  PubMed  CAS  Google Scholar 

  19. Robin MA, Le Roy M, Descatoire V, et al. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in druginduced hepatitis. J Hepatol 1997; 26(Suppl 1):23–30.

    Article  PubMed  CAS  Google Scholar 

  20. Tsutsui H, Terano Y, Hasegawa I, et al. Drug-specific T cells derived from patients with drug-induced hepatitis. J Immunol 1992; 149:706–716.

    PubMed  CAS  Google Scholar 

  21. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296:301–305.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Levy, M. Role of viral infections in the induction of adverse drug reactions. Drug Saf1997; 16:1–8.

    Article  PubMed  CAS  Google Scholar 

  24. Ozick LA, Jacob L, Comer GM, et al. Hepatotoxicity from isoniazid and rifampin in inner-city AIDS patients. Am J Gastroenterol 1995; 90:1978–1980.

    PubMed  CAS  Google Scholar 

  25. Wong WM, Wu PC, Yuen MF, et al. Antituberculous drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 31:201–206.

    Article  PubMed  CAS  Google Scholar 

  26. Luyendyk JP, Maddox JF, Cosma GN, et al. Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 2003; 307:9–16.

    Article  PubMed  CAS  Google Scholar 

  27. Buchweitz JP, Ganey PE, Bursian SJ, and Roth RA. Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? J Pharmacol Exp Ther 2002; 300:460–467.

    Article  PubMed  CAS  Google Scholar 

  28. Waring JF, Liguori MJ, Luyendyk JP, et al. Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 2006; 316:1080–1087.

    Article  PubMed  CAS  Google Scholar 

  29. Pichler WJ. Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2002; 2:301–305.

    Article  PubMed  Google Scholar 

  30. Gerber BO, Pichler WJ. Cellular mechanisms of T cell mediated drug hypersensitivity. Curr Opin Immunol 2004; 16:732–737.

    Article  PubMed  CAS  Google Scholar 

  31. Naisbitt DJ, Britschgi M, Wong G, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones. Mol Pharmacol 2003; 63:732–741.

    Article  PubMed  CAS  Google Scholar 

  32. Polakos NK, Cornejo JC, Murray DA, et al. Kupffer cell-dependent hepatitis occurs during influenza infection. Am J Pathol 2006; 168:1169–1178.

    Article  PubMed  CAS  Google Scholar 

  33. Bourdi M, Larrey D, Nataf J, et al. Anti-liver endoplasmic reticulum autoantibodies are directed against human liver cytochrome P-450 IA2. A specific marker of dihydralazine-induced hepatitis. J Clin Invest 1990; 85:1967–1973.

    PubMed  CAS  Google Scholar 

  34. Beaune PH, Lecoeur S. Immunotoxicity of the liver: adverse reactions to drugs. J Hepatol 1997; 26(Suppl 2):37–42.

    Article  PubMed  CAS  Google Scholar 

  35. Loeper J, Descatoire V, Maurice M, et al. Cytochromes P-450 on human hepatocyte plasma membrane. Recognition by several autoantibodies. Gastroenterology 1993; 104:203–216.

    PubMed  CAS  Google Scholar 

  36. 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; 303:66–71.

    Article  PubMed  CAS  Google Scholar 

  37. Njoku DB, Greenberg RS, Bourdi M, et al. Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists. Anesth Analg 2002; 94:243–249.

    Article  PubMed  Google Scholar 

  38. Watkins PB. Mechanisms of drug-induced liver disease. In: Schiff E, Sorrell M, Maddrey WC, eds. Schiff’s Diseases of the Liver. Philadelphia: Lippincott-Raven, 1999; 1065–1080.

    Google Scholar 

  39. Larson AM, Polson J, Fontana RJ,et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372.

    Article  PubMed  CAS  Google Scholar 

  40. Jaeschke H. Role of inflammation in the mechanism of acetaminophen hepatotoxicity. Exp Opin Drug Metab Toxicol 2005; 1: 389–397.

    Article  CAS  Google Scholar 

  41. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminopheninduced hepatotoxicity. Exp Opin Drug Metab Toxicol 2006; 2:493–503.

    Article  CAS  Google Scholar 

  42. Nelson SD, Bruschi SA. Mechanism of acetaminophen-Induced Liver Disease. In: Kaplowitz N, Deleve LD, eds. Drug-Induced Liver Disease. Marcel-Dekker, New York. 2003; 287–325.

    Google Scholar 

  43. Lee SS, Buters JT, Pineau T, et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 271:12,063–12,067.

    Article  PubMed  CAS  Google Scholar 

  44. Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973; 187:211–217.

    PubMed  CAS  Google Scholar 

  45. Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 1973; 187:195–202.

    PubMed  CAS  Google Scholar 

  46. Jaeschke H, Knight TR, Bajt ML. The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 2003; 144:279–288.

    Article  PubMed  CAS  Google Scholar 

  47. Burcham PC, Harman AW. Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 1991; 266:5049–5054.

    PubMed  CAS  Google Scholar 

  48. Jaeschke H, Bajt ML.Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 2006; 89:31–41.

    Article  PubMed  CAS  Google Scholar 

  49. Chan K, Han XD, Kan YW. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A 2001; 98:4611–4616.

    Article  PubMed  CAS  Google Scholar 

  50. Gunawan B, Liu ZX, Han D, Hanawa N, Gaarde WA, and Neil Kaplowitz N. c-Jun-N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006; 131: 165–178.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Blazka ME, Wilmer JL, Holladay SD, et al. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995; 133:43–52.

    Article  PubMed  CAS  Google Scholar 

  53. Dambach DM, Watson LM, Gray KR,et al. Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse. Hepatology 2002; 35:1093–1103.

    Article  PubMed  CAS  Google Scholar 

  54. 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; 16:1227–1236.

    Article  PubMed  CAS  Google Scholar 

  55. Masubuchi Y. Masubuchi Y, Bourdi M, et al. Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease. Biochem Biophys Res Commun 2003; 304:207–212.

    Article  PubMed  CAS  Google Scholar 

  56. 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; 35:289–298.

    Article  PubMed  CAS  Google Scholar 

  57. Ishida Y, Kondo T, Tsuneyama K,et al. The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice. J Leukoc Biol 2004; 75:59–67.

    Article  PubMed  CAS  Google Scholar 

  58. 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; 36:1028–1038.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. 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; 156:1245–1252.

    PubMed  CAS  Google Scholar 

  61. 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; 167:7077–7083.

    PubMed  CAS  Google Scholar 

  62. Hogaboam CM, Simpson KJ, Chensue SW,et al. Macrophage inflammatory protein-2 gene therapy attenuates adenovirus-and acetaminophen-mediated hepatic injury. Gene Ther 1999; 6:573–584.

    Article  PubMed  CAS  Google Scholar 

  63. 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; 19:223–233.

    Article  PubMed  CAS  Google Scholar 

  64. Diao H, Kon S, Iwabuchi K, et al. Osteopontin as a mediator of NKT cell function in T cell-mediated liver diseases. Immunity 2004; 21:539–550.

    Article  PubMed  CAS  Google Scholar 

  65. Pollack SB, Linnemeyer PA, Gill S. Induction of osteopontin mRNA expression during activation of murine NK cells. J Leukocyte Biol 1994; 55:398–400.

    PubMed  CAS  Google Scholar 

  66. 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; 18:862–867.

    Article  PubMed  CAS  Google Scholar 

  67. Knight TR, Jaeschke H. Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion. Toxicol Appl Pharmacol 2002; 181:133–141.

    Article  PubMed  CAS  Google Scholar 

  68. Ray SD, Mumaw VR, Raje RR, Fariss MW. Protection of acetamin-ophen-induced hepatocellular apoptosis and necrosis by cholesteryl hemisuccinate pretreatment. J Pharmacol Exp Ther 1996; 279: 1470–1483.

    PubMed  CAS  Google Scholar 

  69. Tsutsui H, Kayagaki N, Kuida K, et al. Caspase-1-independent, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice. Immunity 1999; 11:359–367.

    Article  PubMed  CAS  Google Scholar 

  70. Faouzi S, Burckhardt BE, Hanson JC, et al. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem 2001; 276:49,077–49,082.

    Article  PubMed  CAS  Google Scholar 

  71. Bourdi M, Chen WQ, Peter RM,et al. Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 1996; 9:1159–1166.

    Article  PubMed  CAS  Google Scholar 

  72. Eliasson E, Kenna JG. Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis. Mol Pharmacol 1996; 50: 573–582.

    PubMed  CAS  Google Scholar 

  73. Kharasch ED, Hankins D, Mautz D, et al. Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis. Lancet 1996; 347: 1367–1371.

    Article  PubMed  CAS  Google Scholar 

  74. Satoh H, Fukuda Y, Aderson DK,et al. Immunological studies on the mechanism of halothane-induced hepatotoxicity: immunohisto-chemical evidence of trifluoroacetylated hepatocytes. J Pharmaocol Exp Ther 1985; 233:857–862.

    CAS  Google Scholar 

  75. Njoku DB, Mellerson JL, Talor MV, et al. Role of CYP2E1 immunoglobulin G4 subclass antibodies and complement in pathogenesis of idiosyncratic drug-induced hepatitis. Clin Vaccine Immunol 2006; 13:258–265.

    Article  PubMed  CAS  Google Scholar 

  76. Bourdi M, Tinel M, Beaune P, et al. Interactions of dihydralazine with cytochrome P4501A: a possible explanation for the appearance of anti-P4501A2 autoantibodies. Mol Pharmacol 1994; 45:1287–1295.

    PubMed  CAS  Google Scholar 

  77. Leeder JS, Gaedigk A, Lu X, et al. Epitope mapping studies with human anti-cytochrome P450 3A antibodies. Mol Pharmacol 1996; 649: 234–243.

    Google Scholar 

  78. Riley RJ, Smith G, Wolf CR, et al. Human anti-endoplasmic reticulum autoantibodies produced in aromatic anticonvulsant hypersensitivity reactions recognise rodent CYP3A proteins and a similarly regulated human P450 enzyme(s). Biochem Biophys Res Commun 1993; 191:32–40.

    Article  PubMed  CAS  Google Scholar 

  79. Zimmerman HJ: Drug-induced liver disease. In: Schiff E, Sorrell M, Maddrey WC, eds. Schiff’s Diseases of the Liver. Philadelphia: Lippincott-Raven, 1999:973–1064.

    Google Scholar 

  80. Homberg JC, Abuaf N, Helmy-Khalil S,et al. Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. Hepatology 1985; 5:722–727.

    Article  PubMed  CAS  Google Scholar 

  81. Lecoeur S, Andre C, Beaune PH. Tienilic acid-induced autoimmune hepatitis: anti-liver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P450 2C9. Mol Pharmacol 1996; 50:326–333.

    PubMed  CAS  Google Scholar 

  82. Pons C, Dansette PM, Amar C, et al. Detection of human hepatitis anti-liver kidney microsomes (LKM2) autoantibodies on rat liver sections is predominantly due to reactivity with rat liver P-450 IIC1 1. J Pharmacol Exp Ther 1991; 259:1328–1334.

    PubMed  CAS  Google Scholar 

  83. Scully L, Clarke D, Barr R. Diclofenac-induced hepatitis: 3 cases with features of autoimmune chronic active hepatitis. Dig Dis Sci 1993; 38:744–751.

    Article  PubMed  CAS  Google Scholar 

  84. Berardinis V, Moulis C, Maurice M, et al. Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. Mol Pharm 2000; 58:542–551.

    Google Scholar 

  85. Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997; 92:703–704.

    PubMed  CAS  Google Scholar 

  86. A1-Kawas FH, Seeff LB, Berendson RA, et al. Allopurinol hepatotoxicity: report of two cases and review of literature. Ann Intern Med 1981; 95:588–590.

    Google Scholar 

  87. Maddrey WC, Boitnott JK. Severe hepatitis from methyldopa. Gastroenterology 1975; 68:351–360.

    Google Scholar 

  88. Stricker B, Blok A, Claas F, et al. Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases. Hepatology 1988; 8:599–606.

    Article  PubMed  CAS  Google Scholar 

  89. Marotta PJ, Roberts EA. Pemoline hepatotoxicity in children. J Pediatr 1998; 132:894–897.

    Article  PubMed  CAS  Google Scholar 

  90. Kim HJ, Kim BH, Han YS,et al. The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study. Am J Gastroenterol 2001; 96:165–169.

    Article  PubMed  CAS  Google Scholar 

  91. Moradpour D, Altorfer J, Flury R, et al. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 1994; 20:1437–1441.

    Article  PubMed  CAS  Google Scholar 

  92. Daly AK. Molecular basis of polymorphic drug metabolism. J Mol Med 1995; 73:539–553.

    Article  PubMed  CAS  Google Scholar 

  93. Hoft PH, Bunker JP, Goodman HI, et al. Halothane hepatitis in three pairs of closely related women. NEnglJMed 1981; 304:1023–1024.

    CAS  Google Scholar 

  94. O’Donohue J, Oien KA, Donaldson P, et al. Co-amoxiclav jaundice: clinical and histological features and HLA class n association. Gut 2000; 47:717–720.

    Article  PubMed  CAS  Google Scholar 

  95. Andrade RJ, Lucena MI, Alonso A,et al. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 2004; 39:1603–1612.

    Article  PubMed  CAS  Google Scholar 

  96. Clayton TA, Lindon JC, Cloarec O, et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 2006; 440:1073–1077.

    Article  PubMed  CAS  Google Scholar 

  97. Bowen DG, McCaughan GW, Bertolino P. Intrahepatic immunity: a tale of two sites. Trends Immunol 2005; 26:512–517.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  99. Naisbitt DJ. Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests.Toxicology 2004; 194:179–196.

    Article  PubMed  CAS  Google Scholar 

  100. Armeanu S, Bitzer M, Lauer UM, et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res 2005; 65:6321–6329.

    Article  PubMed  CAS  Google Scholar 

  101. Louis H, Le Moine A, Flamand V,et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastroenterology 2002; 122:2001–2010.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL

    Zhang-Xu Liu MD, PhD

  2. Division of Gastrointestinal and Liver Diseases, Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA

    Neil Kaplowitz MD

Authors
  1. Zhang-Xu Liu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil Kaplowitz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA

    M. Eric Gershwin MD, FACP

  2. Departments of Medicine and Surgery Baylor Liver Health, Baylor College of Medicine, Houston, TX

    John M. Vierling MD, FACP

  3. Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover, Hannover, Germany

    Michael P. Manns MD

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Liu, ZX., Kaplowitz, N. (2007). Immune Mechanisms in Drug-Induced Hepatotoxicity. In: Gershwin, M.E., Vierling, J.M., Manns, M.P. (eds) Liver Immunology. Humana Press. https://doi.org/10.1007/978-1-59745-518-3_29

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-518-3_29

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-818-8

  • Online ISBN: 978-1-59745-518-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation