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Signal Transduction Pathways Involved in Drug-Induced Liver Injury

  • Derick HanEmail author
  • Mie Shinohara
  • Maria D. Ybanez
  • Behnam Saberi
  • Neil Kaplowitz
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Hepatocyte death following drug intake is the critical event in the clinical manifestation of drug-induced liver injury (DILI). Traditionally, hepatocyte death caused by drugs had been attributed to overwhelming oxidative stress and mitochondria dysfunction caused by reactive metabolites formed during drug metabolism. However, recent studies have also shown that signal transduction pathways activated/inhibited during oxidative stress play a key role in DILI. In acetaminophen (APAP)-induced liver injury, hepatocyte death requires the sustained activation of c-Jun kinase (JNK), a kinase important in mediating apoptotic and necrotic death. Inhibition of JNK using chemical inhibitors or knocking down JNK can prevent hepatocyte death even in the presence of extensive glutathione (GSH) depletion, covalent binding, and oxidative stress. Once activated, JNK translocates to mitochondria, to induce mitochondria permeability transition and trigger hepatocyte death. Mitochondria are central targets where prodeath kinases such as JNK, prosurvival death proteins such as bcl-xl, and oxidative damage converge to determine hepatocyte survival. The importance of mitochondria in DILI is also observed in the Mn-SOD heterozygous (+/−) model, where mice with less mitochondrial Mn-SOD are sensitized to liver injury caused by certain drugs. An extensive body of research is accumulating suggesting a central role of mitochondria in DILI. Drugs can also cause redox changes that inhibit important prosurvival pathways such as NF-κB. The inhibition of NF-κB by subtoxic doses of APAP sensitizes hepatocyte to the cytotoxic actions of tumor necrosis factor (TNF). Many drugs will induce liver injury if simultaneously treated with LPS, which promotes inflammation and cytokine release. Drugs may be sensitizing hepatocytes to the cytotoxic effects of cytokines such as TNF, or vice versa. Overall many signaling pathways are important in regulating DILI, and represent potential therapeutic targets to reduce liver injury caused by drugs.

Keywords

Acetaminophen Oxidative stress Redox JNK Mitochondria 

Abbreviations

APAP

Acetaminophen

AMAP

N-acetyl-m-aminophenol

ASK-1

Apoptosis signaling-regulating kinase 1

CYP

Cytochrome P450

DILI

Drug-induced liver injury

DNASE1

Deoxyribonuclease 1

GSH

Glutathione

GSK-3β

Glycogen synthase kinase-3β

JNK

cJun N-terminal protein kinase

LPS

Lipopolysaccharide

MPT

Mitochondria permeability transition

NAC

N-acetylcysteine

NAPQI

N-acetyl-p-benzo-quinoneimine

NO

Nitric oxide

Nrf-2

NF E2-related factor 2

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

TNF

Tumor necrosis factor

References

  1. Adams ML, Pierce RH, Vail ME, White CC, Tonge RP, Kavanagh TJ, Fausto N, Nelson SD, Bruschi SA (2001) Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. Mol Pharmacol 60(5):907–915PubMedGoogle Scholar
  2. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ, Ronai Z (1999) Regulation of JNK signaling by GSTp. EMBO J 18(5):1321–1334PubMedCrossRefGoogle Scholar
  3. Alvarez-Sanchez R, Montavon F, Hartung T, Pahler A (2006) Thiazolidinedione bioactivation: a comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem Res Toxicol 19(8):1106–1116PubMedCrossRefGoogle Scholar
  4. Andringa KK, Bajt ML, Jaeschke H, Bailey SM (2008) Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: effect on HMG-CoA synthase. Toxicol Lett 177(3):188–197PubMedCrossRefGoogle Scholar
  5. Aoki H, Kang PM, Hampe J, Yoshimura K, Noma T, Matsuzaki M, Izumo S (2002) Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes. J Biol Chem 277(12):10244–10250PubMedCrossRefGoogle Scholar
  6. Bae MA, Song BJ (2003) Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells. Mol Pharmacol 63(2):401–408PubMedCrossRefGoogle Scholar
  7. Bajt ML, Farhood A, Lemasters JJ, Jaeschke H (2007) Mitochondrial Bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 324(1): 8–14Google Scholar
  8. Bajt ML, Yan HM, Farhood A, Jaeschke H (2008) Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose. Toxicol Sci 104(2):419–427PubMedCrossRefGoogle Scholar
  9. Berson A, De Beco V, 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(4):764–774PubMedCrossRefGoogle Scholar
  10. Berson A, Cazanave S, Descatoire V, Tinel M, Grodet A, Wolf C, Feldmann G, Pessayre D (2006) The anti-inflammatory drug, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide), uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells: protection by albumin. J Pharmacol Exp Ther 318(1):444–454PubMedCrossRefGoogle Scholar
  11. Boelsterli UA (2003) Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol Appl Pharmacol 192(3):307–322PubMedCrossRefGoogle Scholar
  12. Boelsterli UA, Lim PL (2007) Mitochondrial abnormalities – a link to idiosyncratic drug hepatotoxicity? Toxicol Appl Pharmacol 220(1):92–107PubMedCrossRefGoogle Scholar
  13. Bogoyevitch MA (2006) The isoform-specific functions of the c-Jun N-terminal Kinases (JNKs): differences revealed by gene targeting. Bioessays 28(9):923–934PubMedCrossRefGoogle Scholar
  14. Botta D, Shi S, White CC, Dabrowski MJ, Keener CL, Srinouanprachanh SL, Farin FM, Ware CB, Ladiges WC, Pierce RH, Fausto N, Kavanagh TJ (2006) Acetaminophen-induced liver injury is attenuated in male glutamate-cysteine ligase transgenic mice. J Biol Chem 281(39): 28865–28875PubMedCrossRefGoogle Scholar
  15. Boyd CS, Cadenas E (2002) Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis. Biol Chem 383(3–4):411–423PubMedCrossRefGoogle Scholar
  16. Buchweitz JP, Ganey PE, Bursian SJ, Roth RA (2002) Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy? J Pharmacol Exp Ther 300(2):460–467PubMedCrossRefGoogle Scholar
  17. Burcham PC, Harman AW (1991) Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes. J Biol Chem 266(8):5049–5054PubMedGoogle Scholar
  18. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med 29(3–4):222–230PubMedCrossRefGoogle Scholar
  19. Castell JV, Castell M (2006) Allergic hepatitis induced by drugs. Curr Opin Allergy Clin Immunol 6(4):258–265PubMedGoogle Scholar
  20. Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Munshi N, Kharbanda S, Anderson KC (2003) JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J Biol Chem 278(20):17593–17596PubMedCrossRefGoogle Scholar
  21. Chowdhury A, Santra A, Bhattacharjee K, Ghatak S, Saha DR, Dhali GK (2006) Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice. J Hepatol 45(1):117–126PubMedCrossRefGoogle Scholar
  22. Churchill EN, Mochly-Rosen D (2007) The roles of PKCdelta and epsilon isoenzymes in the regulation of myocardial ischaemia/reperfusion injury. Biochem Soc Trans 35(Pt 5): 1040–1042PubMedGoogle Scholar
  23. Coen M, Lenz EM, Nicholson JK, Wilson ID, Pognan F, Lindon JC (2003) An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. Chem Res Toxicol 16(3):295–303PubMedCrossRefGoogle Scholar
  24. Cover C, Fickert P, Knight TR, Fuchsbichler A, Farhood A, Trauner M, Jaeschke H (2005) Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice. Toxicol Sci 84(1):201–208PubMedCrossRefGoogle Scholar
  25. Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341(Pt 2):233–249PubMedCrossRefGoogle Scholar
  26. Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81(5): 1327–1331PubMedCrossRefGoogle Scholar
  27. Dai G, He L, Chou N, Wan YJ (2006) Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse. Toxicol Sci 92(1):33–41PubMedCrossRefGoogle Scholar
  28. Dambach DM, Durham SK, Laskin JD, Laskin DL (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 211(2):157–165PubMedCrossRefGoogle Scholar
  29. Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C (2008) Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res 103(9): 910–913Google Scholar
  30. 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(2):852–861PubMedCrossRefGoogle Scholar
  31. Deschamps D, DeBeco V, Fisch C, Fromenty B, Guillouzo A, Pessayre D (1994) Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 19(4):948–961PubMedCrossRefGoogle Scholar
  32. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99(18):11908–11913PubMedCrossRefGoogle Scholar
  33. Dixit R, Boelsterli UA (2007) Healthy animals and animal models of human disease(s) in safety assessment of human pharmaceuticals, including therapeutic antibodies. Drug Discov Today 12(7–8):336–342PubMedCrossRefGoogle Scholar
  34. Donahower B, McCullough SS, Kurten R, Lamps LW, Simpson P, Hinson JA, James LP (2006) Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity. Am J Physiol Gastrointest Liver Physiol 291(1):G102–G109PubMedCrossRefGoogle Scholar
  35. Donnelly PJ, Walker RM, Racz WJ (1994) Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. Arch Toxicol 68(2):110–118PubMedCrossRefGoogle Scholar
  36. 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(2):335–345PubMedCrossRefGoogle Scholar
  37. Esterline RL, Ray SD, Ji S (1989) Reversible and irreversible inhibition of hepatic mitochondrial respiration by acetaminophen and its toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Biochem Pharmacol 38(14):2387–2390PubMedCrossRefGoogle Scholar
  38. Eyer F, Felgenhauer N, Gempel K, Steimer W, Gerbitz KD, Zilker T (2005) Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol 25(4):376–380PubMedCrossRefGoogle Scholar
  39. Fan M, Goodwin M, Vu T, Brantley-Finley C, Gaarde WA, Chambers TC (2000) Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J Biol Chem 275(39):29980–29985PubMedCrossRefGoogle Scholar
  40. Fiorucci S, Antonelli E, Distrutti E, Mencarelli A, Farneti S, Del Soldato P, Morelli A (2004) Liver delivery of NO by NCX-1000 protects against acute liver failure and mitochondrial dysfunction induced by APAP in mice. Br J Pharmacol 143(1):33–42PubMedCrossRefGoogle Scholar
  41. Ganey PE, Luyendyk JP, Maddox JF, Roth RA (2004) Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor. Chem Biol Interact 150(1):35–51PubMedCrossRefGoogle Scholar
  42. Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, Laskin JD, Laskin DL (1998) Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology 27(3):748–754PubMedCrossRefGoogle Scholar
  43. Goldring CE, Kitteringham NR, Elsby R, Randle LE, Clement YN, Williams DP, McMahon M, Hayes JD, Itoh K, Yamamoto M, Park BK (2004) Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology 39(5):1267–1276PubMedCrossRefGoogle Scholar
  44. Gomez-Lechon MJ, Ponsoda X, O’Connor E, Donato T, Castell JV, Jover R (2003) Diclofenac induces apoptosis in hepatocytes by alteration of mitochondrial function and generation of ROS. Biochem Pharmacol 66(11):2155–2167PubMedCrossRefGoogle Scholar
  45. Granneman GR, Wang SI, Kesterson JW, Machinist JM (1984) The hepatotoxicity of valproic acid and its metabolites in rats. II. Intermediary and valproic acid metabolism. Hepatology 4(6):1153–1158PubMedCrossRefGoogle Scholar
  46. Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H (2002) Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 67(2):322–328PubMedCrossRefGoogle Scholar
  47. Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N (2006) c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 131(1):165–178PubMedCrossRefGoogle Scholar
  48. Haasio K, Koponen A, Penttila KE, Nissinen E (2002) Effects of entacapone and tolcapone on mitochondrial membrane potential. Eur J Pharmacol 453(1):21–26PubMedCrossRefGoogle Scholar
  49. Han D, Loukianoff S, McLaughlin L (2000) Oxidative stress indices: analytical aspects and significance. In: Sen CK, Packer L, Hanninen O (eds) Handbook of oxidants and antioxidants in exercise. Elsevier, New York, pp 433–484Google Scholar
  50. Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003a) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278(8):5557–5563PubMedCrossRefGoogle Scholar
  51. Han D, Canali R, Rettori D, Kaplowitz N (2003b) Effect of glutathione depletion on sites and topology of superoxide and hydrogen peroxide production in mitochondria. Mol Pharmacol 64(5):1136–1144PubMedCrossRefGoogle Scholar
  52. Han D, Hanawa N, Saberi B, Kaplowitz N (2006a) Hydrogen peroxide and redox modulation sensitize primary mouse hepatocytes to TNF-induced apoptosis. Free Radic Biol Med 41(4):627–639PubMedCrossRefGoogle Scholar
  53. Han D, Hanawa N, Saberi B, Kaplowitz N (2006b) Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. Am J Physiol Gastrointest Liver Physiol 291(1):G1–G7PubMedCrossRefGoogle Scholar
  54. Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N (2008) Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 283(20):13565–13577PubMedCrossRefGoogle Scholar
  55. Hansen JM, Go YM, Jones DP (2006) Nuclear and mitochondrial compartmentation of oxidative stress and redox signaling. Annu Rev Pharmacol Toxicol 46:215–234PubMedCrossRefGoogle Scholar
  56. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210PubMedCrossRefGoogle Scholar
  57. Heeres JT, Hergenrother PJ (2007) Poly(ADP-ribose) makes a date with death. Curr Opin Chem Biol 11(6):644–653PubMedCrossRefGoogle Scholar
  58. Henderson NC, Pollock KJ, Frew J, Mackinnon AC, Flavell RA, Davis RJ, Sethi T, Simpson KJ (2007) Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure. Gut 56(7):982–990PubMedCrossRefGoogle Scholar
  59. Hinson JA, Mays JB, Cameron AM (1983) Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice. Biochem Pharmacol 32(13):1979–1988PubMedCrossRefGoogle Scholar
  60. Hinson JA, Reid AB, McCullough SS, James LP (2004) Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 36(3–4):805–822PubMedCrossRefGoogle Scholar
  61. Hirayama C, Murawaki Y, Yamada S, Aoto Y, Ikeda F (1983) The target portion of acetaminophen induced hepatotoxicity in rats: modification by thiol compounds. Res Commun Chem Pathol Pharmacol 42(3):431–448PubMedGoogle Scholar
  62. Hu B, Colletti LM (2008) Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice. Am J Physiol Gastrointest Liver Physiol 295(1): G45–G53Google Scholar
  63. Iancu TC, Mason WH, Neustein HB (1977) Ultrastructural abnormalities of liver cells in Reye’s syndrome. Hum Pathol 8(4):421–431PubMedCrossRefGoogle Scholar
  64. Iida C, Fujii K, Kishioka T, Nagae R, Onishi Y, Ichi I, Kojo S (2007) Activation of mitogen activated protein kinase (MAPK) during carbon tetrachloride intoxication in the rat liver. Arch Toxicol 81(7):489–493PubMedCrossRefGoogle Scholar
  65. Ito Y, Abril ER, Bethea NW, McCuskey RS (2004) Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. Am J Physiol Gastrointest Liver Physiol 286(1):G60–G67PubMedCrossRefGoogle Scholar
  66. Ito Y, Abril ER, Bethea NW, McCuskey MK, McCuskey RS (2006) Dietary steatotic liver attenuates acetaminophen hepatotoxicity in mice. Microcirculation 13(1):19–27PubMedCrossRefGoogle Scholar
  67. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8(4):379–391PubMedCrossRefGoogle Scholar
  68. Itoh K, Tong KI, Yamamoto M (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36(10):1208–1213PubMedCrossRefGoogle Scholar
  69. Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89(1):31–41PubMedCrossRefGoogle Scholar
  70. Jaeschke H, Knight TR, Bajt ML (2003) The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 144(3):279–288PubMedCrossRefGoogle Scholar
  71. Jaeschke H, Gujral JS, Bajt ML (2004) Apoptosis and necrosis in liver disease. Liver Int 24(2):85–89PubMedCrossRefGoogle Scholar
  72. Jaeschke H, Cover C, Bajt ML (2006) Role of caspases in acetaminophen-induced liver injury. Life Sci 78(15):1670–1676PubMedCrossRefGoogle Scholar
  73. James LP, Mayeux PR, Hinson JA (2003) Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 31(12):1499–1506PubMedCrossRefGoogle Scholar
  74. Jeon BW, Kim KT, Chang SI, Kim HY (2002) Phosphoinositide 3-OH kinase/protein kinase B inhibits apoptotic cell death induced by reactive oxygen species in Saccharomyces cerevisiae. J Biochem 131(5):693–699PubMedCrossRefGoogle Scholar
  75. Johnson GL, Nakamura K (2007) The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta 1773(8):1341–1348PubMedCrossRefGoogle Scholar
  76. Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 187(1):195–202PubMedGoogle Scholar
  77. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113(11):1535–1549PubMedGoogle Scholar
  78. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120(5):649–661PubMedCrossRefGoogle Scholar
  79. Kaplowitz N (2000) Mechanisms of liver cell injury. J Hepatol 32(1 Suppl):39–47PubMedCrossRefGoogle Scholar
  80. Kaplowitz N (2002) Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis 22(2):137–144PubMedCrossRefGoogle Scholar
  81. Kaplowitz N (2005) Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 4(6):489–499PubMedCrossRefGoogle Scholar
  82. Kaplowitz N, Aw TY, Ookhtens M (1985) The regulation of hepatic glutathione. Annu Rev Pharmacol Toxicol 25:715–744PubMedCrossRefGoogle Scholar
  83. Kaplowitz N, Shinohara M, Liu ZX, Han D (2008) How to protect against acetaminophen: don’t ask for JUNK. Gastroenterology 135(4):1047–1051Google Scholar
  84. Kass GE (2006) Mitochondrial involvement in drug-induced hepatic injury. Chem Biol Interact 163(1–2):145–159PubMedCrossRefGoogle Scholar
  85. Kaufmann P, Torok M, Hanni A, Roberts P, Gasser R, Krahenbuhl S (2005) Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology 41(4):925–935PubMedCrossRefGoogle Scholar
  86. Kim BJ, Ryu SW, Song BJ (2006) JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells. J Biol Chem 281(30):21256–21265PubMedCrossRefGoogle Scholar
  87. Klatt P, Lamas S (2000) Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem 267(16):4928–4944PubMedCrossRefGoogle Scholar
  88. Korlipara LV, Cooper JM, Schapira AH (2004) Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells. Neuropharmacology 46(4):562–569PubMedCrossRefGoogle Scholar
  89. Kovalovich K, Li W, DeAngelis R, Greenbaum LE, Ciliberto G, Taub R (2001) Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL. J Biol Chem 276(28):26605–26613PubMedCrossRefGoogle Scholar
  90. Kowaltowski AJ, Vercesi AE, Castilho RF (1997) Mitochondrial membrane protein thiol reactivity with N-ethylmaleimide or mersalyl is modified by Ca2+: correlation with mitochondrial permeability transition. Biochim Biophys Acta 1318(3):395–402PubMedCrossRefGoogle Scholar
  91. Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA (2007) Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. Hepatology 45(2):412–421PubMedCrossRefGoogle Scholar
  92. Lei XG, Zhu JH, McClung JP, Aregullin M, Roneker CA (2006) Mice deficient in Cu, Zn-superoxide dismutase are resistant to acetaminophen toxicity. Biochem J 399(3):455–461PubMedCrossRefGoogle Scholar
  93. Lewis W, Levine ES, Griniuviene B, Tankersley KO, Colacino JM, Sommadossi JP, Watanabe KA, Perrino FW (1996) Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts. Proc Natl Acad Sci U S A 93(8):3592–3597PubMedCrossRefGoogle Scholar
  94. Lewis W, Griniuviene B, Tankersley KO, Levine ES, Montione R, Engelman L, de Courten-Myers G, Ascenzi MA, Hornbuckle WE, Gerin JL, Tennant BC (1997) Depletion of mitochondrial DNA, destruction of mitochondria, and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax). Lab Invest 76(1):77–87PubMedGoogle Scholar
  95. Liu H, Lo CR, Czaja MJ (2002) NF-kappaB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun. Hepatology 35(4):772–778PubMedCrossRefGoogle Scholar
  96. 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(6):1760–1774PubMedCrossRefGoogle Scholar
  97. Liu ZX, Han D, Gunawan B, Kaplowitz N (2006) Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 43(6):1220–1230PubMedCrossRefGoogle Scholar
  98. Lores Arnaiz S, Llesuy S, Cutrin JC, Boveris A (1995) Oxidative stress by acute acetaminophen administration in mouse liver. Free Radic Biol Med 19(3):303–310PubMedCrossRefGoogle Scholar
  99. Lou H, Kaplowitz N (2007) Glutathione depletion down-regulates tumor necrosis factor alpha-induced NF-kappaB activity via IkappaB kinase-dependent and -independent mechanisms. J Biol Chem 282(40):29470–29481PubMedCrossRefGoogle Scholar
  100. Luyendyk JP, Maddox JF, Cosma GN, Ganey PE, Cockerell GL, Roth RA (2003) Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats. J Pharmacol Exp Ther 307(1):9–16PubMedCrossRefGoogle Scholar
  101. Luyendyk JP, Shaw PJ, Green CD, Maddox JF, Ganey PE, Roth RA (2005) Coagulation-mediated hypoxia and neutrophil-dependent hepatic injury in rats given lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 314(3):1023–1031PubMedCrossRefGoogle Scholar
  102. Malhi H, Gores GJ, Lemasters JJ (2006) Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43(2 Suppl 1):S31–S44PubMedCrossRefGoogle Scholar
  103. Masubuchi Y, Suda C, Horie T (2005) Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 42(1):110–116PubMedCrossRefGoogle Scholar
  104. Matsumaru K, Ji C, Kaplowitz N (2003) Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes. Hepatology 37(6):1425–1434PubMedCrossRefGoogle Scholar
  105. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006) Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21(6):749–760PubMedCrossRefGoogle Scholar
  106. McDougall P, Markham A, Cameron I, Sweetman AJ (1983) The mechanism of inhibition of mitochondrial oxidative phosphorylation by the nonsteroidal anti-inflammatory agent diflunisal. Biochem Pharmacol 32(17):2595–2598PubMedCrossRefGoogle Scholar
  107. Michael SL, Mayeux PR, Bucci TJ, Warbritton AR, Irwin LK, Pumford NR, Hinson JA (2001) Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity. Nitric Oxide 5(5):432–441PubMedCrossRefGoogle Scholar
  108. Mingatto FE, Santos AC, Uyemura SA, Jordani MC, Curti C (1996) In vitro interaction of nonsteroidal anti-inflammatory drugs on oxidative phosphorylation of rat kidney mitochondria: respiration and ATP synthesis. Arch Biochem Biophys 334(2):303–308PubMedCrossRefGoogle Scholar
  109. Mingatto FE, Rodrigues T, Pigoso AA, Uyemura SA, Curti C, Santos AC (2002) The critical role of mitochondrial energetic impairment in the toxicity of nimesulide to hepatocytes. J Pharmacol Exp Ther 303(2):601–607PubMedCrossRefGoogle Scholar
  110. Mirochnitchenko O, Weisbrot-Lefkowitz M, Reuhl K, Chen L, Yang C, Inouye M (1999) Acetaminophen toxicity. Opposite effects of two forms of glutathione peroxidase. J Biol Chem 274(15):10349–10355PubMedCrossRefGoogle Scholar
  111. Nagai H, Matsumaru K, Feng G, Kaplowitz N (2002) Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes. Hepatology 36(1):55–64PubMedCrossRefGoogle Scholar
  112. Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A, Sakamoto K, Ogura K, Noguchi T, Karin M, Ichijo H, Omata M (2008) Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology 135(4):1311–1321Google Scholar
  113. Napirei M, Basnakian AG, Apostolov EO, Mannherz HG (2006) Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice. Hepatology 43(2):297–305PubMedCrossRefGoogle Scholar
  114. Nishihara M, Miura T, Miki T, Tanno M, Yano T, Naitoh K, Ohori K, Hotta H, Terashima Y, Shimamoto K (2007) Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection. J Mol Cell Cardiol 43(5):564–570PubMedCrossRefGoogle Scholar
  115. Ong MM, Wang AS, Leow KY, Khoo YM, Boelsterli UA (2006) Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2(+/−) mice. Free Radic Biol Med 40(3):420–429PubMedCrossRefGoogle Scholar
  116. Ong MM, Latchoumycandane C, Boelsterli UA (2007) Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci 97(1):205–213PubMedCrossRefGoogle Scholar
  117. 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 Intern Med 137(12):947–954PubMedGoogle Scholar
  118. Osterloh J, Cunningham W, Dixon A, Combest D (1989) Biochemical relationships between Reye’s and Reye’s-like metabolic and toxicological syndromes. Med Toxicol Adverse Drug Exp 4(4):272–294PubMedGoogle Scholar
  119. Park Y, Smith RD, Combs AB, Kehrer JP (1988) Prevention of acetaminophen-induced hepatotoxicity by dimethyl sulfoxide. Toxicology 52(1–2):165–175PubMedCrossRefGoogle Scholar
  120. Powell CL, Kosyk O, Ross PK, Schoonhoven R, Boysen G, Swenberg JA, Heinloth AN, Boorman GA, Cunningham ML, Paules RS, Rusyn I (2006) Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. Toxicol Sci 93(1):213–222PubMedCrossRefGoogle Scholar
  121. Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283(1):1–16PubMedCrossRefGoogle Scholar
  122. Rashed MS, Myers TG, Nelson SD (1990) Hepatic protein arylation, glutathione depletion, and metabolite profiles of acetaminophen and a non-hepatotoxic regioisomer, 3’-hydroxyacetanilide, in the mouse. Drug Metab Dispos 18(5):765–770PubMedGoogle Scholar
  123. Ray SD, Balasubramanian G, Bagchi D, Reddy CS (2001) Ca(2+)-calmodulin antagonist chlorpromazine and poly(ADP-ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of BCL-XL and P53 and protect against acetaminophen-induced programmed and unprogrammed ce. Free Radic Biol Med 31(3):277–291PubMedCrossRefGoogle Scholar
  124. Rumack BH, Peterson RC, Koch GG, Amara IA (1981) Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 141(3 Spec No):380–385Google Scholar
  125. Saberi B, Shinohara M, Ybanez MD, Hanawa N, Gaarde WA, Kaplowitz N, Han D (2008) Regulation of H(2) O(2)-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes. Am J Physiol Cell Physiol 295(1):C50–C63PubMedCrossRefGoogle Scholar
  126. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17(9):2596–2606PubMedCrossRefGoogle Scholar
  127. Salminen WF Jr, Voellmy R, Roberts SM (1997) Differential heat shock protein induction by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Pharmacol Exp Ther 282(3):1533–1540PubMedGoogle Scholar
  128. Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43(1):163–172PubMedCrossRefGoogle Scholar
  129. Schwab CE, Tuschl H (2003) In vitro studies on the toxicity of isoniazid in different cell lines. Hum Exp Toxicol 22(11):607–615PubMedCrossRefGoogle Scholar
  130. Seguin B, Uetrecht J (2003) The danger hypothesis applied to idiosyncratic drug reactions. Curr Opin Allergy Clin Immunol 3(4):235–242PubMedCrossRefGoogle Scholar
  131. Setzer B, Lebrecht D, Walker UA (2008) Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine. Am J Pathol 172(3):681–690PubMedCrossRefGoogle Scholar
  132. Sharpe JC, Arnoult D, Youle RJ (2004) Control of mitochondrial permeability by Bcl-2 family members. Biochim Biophys Acta 1644(2–3):107–113PubMedCrossRefGoogle Scholar
  133. Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA (2007) Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 100(1):259–266PubMedCrossRefGoogle Scholar
  134. Shishido S, Koga H, Harada M, Kumemura H, Hanada S, Taniguchi E, Kumashiro R, Ohira H, Sato Y, Namba M, Ueno T, Sata M (2003) Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes. Hepatology 37(1):136–147PubMedCrossRefGoogle Scholar
  135. Sills RC, French JE, Cunningham ML (2001) New models for assessing carcinogenesis: an ongoing process. Toxicol Lett 120(1–3):187–198PubMedCrossRefGoogle Scholar
  136. Singh R, Czaja MJ (2007) Regulation of hepatocyte apoptosis by oxidative stress. J Gastroenterol Hepatol 22(Suppl 1):S45–S48PubMedCrossRefGoogle Scholar
  137. Sobaniec-Lotowska ME (1997) Effects of long-term administration of the antiepileptic drug – sodium valproate upon the ultrastructure of hepatocytes in rats. Exp Toxicol Pathol 49(3–4):225–232PubMedCrossRefGoogle Scholar
  138. Spahr L, Rubbia-Brandt L, Burkhard PR, Assal F, Hadengue A (2000) Tolcapone-related fulminant hepatitis: electron microscopy shows mitochondrial alterations. Dig Dis Sci 45(9):1881–1884PubMedCrossRefGoogle Scholar
  139. Stadtman ER, Moskovitz J, Levine RL (2003) Oxidation of methionine residues of proteins: biological consequences. Antioxid Redox Signal 5(5):577–582PubMedCrossRefGoogle Scholar
  140. Sumioka I, Matsura T, Kai M, Yamada K (2004) Potential roles of hepatic heat shock protein 25 and 70i in protection of mice against acetaminophen-induced liver injury. Life Sci 74(20):2551–2561PubMedCrossRefGoogle Scholar
  141. Thames G (2004) Drug-induced liver injury: what you need to know. Gastroenterol Nurs 27(1):31–33PubMedCrossRefGoogle Scholar
  142. Theruvath TP, Czerny C, Ramshesh VK, Zhong Z, Chavin KD, Lemasters JJ (2008) C-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation. Am J Transplant 8(9):1819–1828PubMedCrossRefGoogle Scholar
  143. Thome-Kromer B, Bonk I, Klatt M, Nebrich G, Taufmann M, Bryant S, Wacker U, Kopke A (2003) Toward the identification of liver toxicity markers: a proteome study in human cell culture and rats. Proteomics 3(10):1835–1862PubMedCrossRefGoogle Scholar
  144. Tirmenstein MA, Hu CX, Gales TL, Maleeff BE, Narayanan PK, Kurali E, Hart TK, Thomas HC, Schwartz LW (2002) Effects of troglitazone on HepG2 viability and mitochondrial function. Toxicol Sci 69(1):131–138PubMedCrossRefGoogle Scholar
  145. Tolson JK, Dix DJ, Voellmy RW, Roberts SM (2006) Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice. Toxicol Appl Pharmacol 210(1–2):157–162PubMedCrossRefGoogle Scholar
  146. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288(5467):870–874PubMedCrossRefGoogle Scholar
  147. Trudell JR, Bosterling B, Trevor AJ (1982) Reductive metabolism of carbon tetrachloride by human cytochromes P-450 reconstituted in phospholipid vesicles: mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine. Proc Natl Acad Sci U S A 79(8):2678–2682PubMedCrossRefGoogle Scholar
  148. Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y (2004) JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 23(8):1889–1899PubMedCrossRefGoogle Scholar
  149. Turnbull DM, Bone AJ, Bartlett K, Koundakjian PP, Sherratt HS (1983) The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochem Pharmacol 32(12):1887–1892PubMedCrossRefGoogle Scholar
  150. Tzung SP, Fausto N, Hockenbery DM (1997) Expression of Bcl-2 family during liver regeneration and identification of Bcl-x as a delayed early response gene. Am J Pathol 150(6):1985–1995PubMedGoogle Scholar
  151. Uehara T, Bennett B, Sakata ST, Satoh Y, Bilter GK, Westwick JK, Brenner DA (2005) JNK mediates hepatic ischemia reperfusion injury. J Hepatol 42(6):850–859PubMedCrossRefGoogle Scholar
  152. Uetrecht J (2008) Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol 21(1):84–92PubMedCrossRefGoogle Scholar
  153. Ulrich RG (2007) Idiosyncratic toxicity: a convergence of risk factors. Annu Rev Med 58:17–34PubMedCrossRefGoogle Scholar
  154. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16(1):29–37PubMedCrossRefGoogle Scholar
  155. Varbiro G, Toth A, Tapodi A, Veres B, Sumegi B, Gallyas F Jr (2003) Concentration dependent mitochondrial effect of amiodarone. Biochem Pharmacol 65(7):1115–1128PubMedCrossRefGoogle Scholar
  156. Velsor LW, Kovacevic M, Goldstein M, Leitner HM, Lewis W, Day BJ (2004) Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. Toxicol Appl Pharmacol 199(1):10–19PubMedCrossRefGoogle Scholar
  157. Waldhauser KM, Torok M, Ha HR, Thomet U, Konrad D, Brecht K, Follath F, Krahenbuhl S (2006) Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives. J Pharmacol Exp Ther 319(3):1413–1423PubMedCrossRefGoogle Scholar
  158. Wang Y, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ (2006) Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. J Biol Chem 281(22):15258–15267PubMedCrossRefGoogle Scholar
  159. Watkins PB (2005) Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol 33(1):1–5PubMedCrossRefGoogle Scholar
  160. Welch KD, Wen B, Goodlett DR, Yi EC, Lee H, Reilly TP, Nelson SD, Pohl LR (2005) Proteomic identification of potential susceptibility factors in drug-induced liver disease. Chem Res Toxicol 18(6):924–933PubMedCrossRefGoogle Scholar
  161. Welch KD, Reilly TP, Bourdi M, Hays T, Pise-Masison CA, Radonovich MF, Brady JN, Dix DJ, Pohl LR (2006) Genomic identification of potential risk factors during acetaminophen-induced liver disease in susceptible and resistant strains of mice. Chem Res Toxicol 19(2):223–233PubMedCrossRefGoogle Scholar
  162. 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 105(1):97–105PubMedCrossRefGoogle Scholar
  163. Yap LP, Chang AHK, Han D, Cadenas E (2008) Free radical biology, mitochondrial functions, and nitric oxide. In: Zierhut M, Cadenas E, Rao NA (eds) Free radicals in ophthalmic disorders. Informa Healthcare, New YorkGoogle Scholar
  164. Yin XM, Ding WX, Gao W (2008) Autophagy in the liver. Hepatology 47(5):1773–1785PubMedCrossRefGoogle Scholar
  165. Zhang R, Al-Lamki R, Bai L, Streb JW, Miano JM, Bradley J, Min W (2004) Thioredoxin-2 inhibits mitochondria-located ASK1-mediated apoptosis in a JNK-independent manner. Circ Res 94(11):1483–1491PubMedCrossRefGoogle Scholar
  166. Zhou Q, Lam PY, Han D, Cadenas E (2007) c-Jun N-terminal kinase regulates mitochondrial bioenergetics by modulating pyruvate dehydrogenase activity in primary cortical neurons. J Neurochem 104(2):325–335Google Scholar
  167. Zhu JH, Zhang X, McClung JP, Lei XG (2006) Impact of Cu, Zn-superoxide dismutase and Se-dependent glutathione peroxidase-1 knockouts on acetaminophen-induced cell death and related signaling in murine liver. Exp Biol Med (Maywood) 231(11):1726–1732Google Scholar
  168. Zimmerman HJ, Maddrey WC (1995) Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 22(3):767–773PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Derick Han
    • 1
    Email author
  • Mie Shinohara
  • Maria D. Ybanez
  • Behnam Saberi
  • Neil Kaplowitz
  1. 1.Research Center for Liver DiseasesKeck School of Medicine, University of Southern CaliforniaLos AngelesUSA

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