• 1
    Lee WM, Ostapowicz G: Acetaminophen: pathology and clinical presentation of hepatotoxicity. In: KaplowitzN, DeLeveL, eds. Drug-Induced Liver Disease. New York: Marcel Dekker; 2003: 327344.
  • 2
    Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 472483.
  • 3
    Cohen SD, Hoivik DJ, Khairallah EA. Acetaminophen-induced hepatotoxicity. In: PlaaGL, HewittWR, eds. Toxicology of the Liver. Washington, DC: Taylor & Francis; 1998: 159186.
  • 4
    James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003; 31: 14991506.
  • 5
    Jaeschke H, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 2006; 89: 3141.
  • 6
    Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. HEPATOLOGY 2004; 40: 11701179.
  • 7
    Masubuchi Y, Suda C, Horie T. Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 2005; 42: 110116.
  • 8
    Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: Apoptosis or oncotic necrosis? Toxicol Sci 2002; 67: 322328.
  • 9
    Gunawan B, Liu ZX, Han D, Hanawa N, Gaarde WA, et al. c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006; 131: 165178.
  • 10
    Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 1973; 187: 195202.
  • 11
    Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev 1998; 3: 114127.
  • 12
    Bajt ML, Knight TR, Lemasters JJ, Jaeschke H. Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine. Toxicol Sci 2004; 80: 343349.
  • 13
    Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319: 15571562.
  • 14
    Latchoumycandane C, Seah QM, Tan RCH, Sattabongkot J, Beerheide W, Boelsterli UA. Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. Toxicol Appl Pharmacol 2006; 217: 125133.
  • 15
    Imose M, Nagaki M, Kimura K, Takai S, Imao M, Naiki T, et al. Leflunomide protects from T-cell-mediated liver injury in mice through inhibition of nuclear factor κB. HEPATOLOGY 2004; 40: 11601169.
  • 16
    Yao HW, Li J, Jin Y, Zhang YF, Li CY, Xu SY. Effect of leflunomide on immunological liver injury in mice. World J Gastroenterol 2003; 9: 320323.
  • 17
    Ong MMK, Wang AS, Leow KY, Khoo YM, Boelsterli UA. Nimesulide-induced hepatic mitochondrial injury in heterozygous Sod2+/− mice. Free Radic Biol Med 2006; 40: 420429.
  • 18
    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: 17601774.
  • 19
    Bhatia M, Saluja AK, Hofbauer B, Lee HS, Frossard JL, Castagliuolo I, et al. Role of NK1 receptor in the development of acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci U S A 1998; 95: 47604765.
  • 20
    Welch KD, Reilly TP, Bourdi M, Hays T, Pise-Masison CA, Radonovich MF, 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: 223233.
  • 21
    Boess F, Bopst M, Althaus R, Polsky S, Cohen SD, Eugster HP, et al. Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-α gene knockout mice. HEPATOLOGY 1998; 27: 10211029.
  • 22
    Liu J, Li CX, Waalkes MP, Clark J, Myers P, Saavedra JE, et al. The nitric oxide donor, V-PYYRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. HEPATOLOGY 2003; 37: 324333.
  • 23
    Berson A, Cazanave S, Descatoire V, Tinel M, Grodet A, Wolf C, et al. The anti-inflammatory drug, nimesulide uncouples mitochondria and induces mitochondrial permeability transition in human hepatoma cells. Protection by albumin. J Pharmacol Exp Ther 2006; 318: 444454.
  • 24
    Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. HEPATOLOGY 1998; 26: 748754.
  • 25
    Hinson JA, Pike SL, Pumford NR, Mayeux PR. Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice. Chem Res Toxicol 1998; 11: 604607.
  • 26
    Knight T, Kurtz A, Bajt ML, Hinson JA, Jaeschke H. Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: Role of mitochondrial oxidant stress. Toxicol Sci 2001; 62: 212220.
  • 27
    Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, et al. Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2005; 315: 879887.
  • 28
    Vuolteenaho K, Kujala P, Moilanen T, Moilanen E. Aurothiomalate and hydroxychloroquine inhibit nitric oxide production in chondrocytes and in human osteoarthritic cartilage. Scand J Rheumatol 2005; 34: 475479.
  • 29
    Oltvai ZN, Korsmeyer SJ. Checkpoints of dueling dimers foil death wishes. Cell 1994; 79: 189192.
  • 30
    Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G2/M. Mol Cell Biol 1999; 19: 84698478.
  • 31
    Migita K, Miyashita T, Maeda Y, Nakamura M, Yatsuhashi H, Ishibashi H, et al. An active metabolite of leflunomide, A77 1726, inhibits the production of serum amyloid A protein in human hepatocytes. Rheumatology 2005; 44: 443448.
  • 32
    Migita K, Miyashita T, Ishibashi H, Maeda Y, Nakamura M, Yatsuhashi H, et al. Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts. Clin Exp Immunol 2004; 137: 612616.
  • 33
    Schwabe RF, Uchinami H, Qian T, Bennett BL, Lemasters JJ, Brenner DA. Differential requirement for c-Jun NH2-terminal kinase in TNFα- and Fas-mediated apoptosis in hepatocytes. FASEB J 2004; 18: 720722.
  • 34
    Wang YJ, Singh R, Lefkowitch JH, Rigoli RM, Czaja MJ. Toxic liver injury from GalN/LPS results from JNK2-dependent activation of the mitochondrial death pathway [Abstract]. HEPATOLOGY 2005; 42(Suppl): 251A.
  • 35
    Shen HM, Liu ZG. JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med 2006; 40: 928939.
  • 36
    Bae MA, Pie JE, Song BJ. Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH2-terminal protein kinase-related cell death pathway. Mol Pharmacol 2001; 60: 847856.
  • 37
    Czaja MJ, Liu H, Wang Y. Oxidant-induced hepatocyte injury from menadione is regulated by ERK and AP-1 signaling. HEPATOLOGY 2003; 37: 14051413.
  • 38
    Nakano H, Nakajima A, Sakon-Komazawa S, Piao JH, Xue X, Okumura K. Reactive oxygen species mediate crosstalk between NF-κB and JNK. Cell Death Different 2006; 13: 730737.
  • 39
    Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May WS Jr. Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 2001; 276: 2368123688.
  • 40
    Kim BJ, Ryu SW, Song BJ. 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 2006; 281: 2125621265.
  • 41
    Gardner CR, Laskin JD, Dambach DM, Sacco M, Durham SK, Bruno MK, et al. Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: Potential role of tumor necrosis factor-alpha and interleukin-10. Toxicol Appl Pharmacol 2002; 184: 2736.
  • 42
    Bourdi M, Masubuchi Y, Reilly TP, Amouzadeh HR, Martin JL, George JW, et al. Protection against acetaminophen-induced liver injury and lethality by interleukin 10: Role of inducible nitric oxide synthase. HEPATOLOGY 2002; 35: 289298.
  • 43
    Kamanaka Y, Kawabata A, Matsuya H, Taga C, Sekiguchi F, Kawao N. Effect of a potent iNOS inhibitor (ONO-1714) on acetaminophen-induced hepatotoxicity in the rat. Life Sci 2003; 74: 793802.
  • 44
    Chan ED, Riches DW. IFN-γ + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 (mapk) in a mouse macrophage cell line. Am J Physiol (Cell Physiol) 2001; 280: C441C450.
  • 45
    Lahti A, Sareila O, Kankaanranta H, Moilanen E. Inhibition of p38 mitogen-activated protein kinase enhances c-Jun N-terminal kinase activity: Implication in inducible nitric oxide synthase expression. BMC Pharmacol 2006; 6: 5.
  • 46
    Go YM, Patel RP, Maland MC, Park H, Beckman JS, Darley-Usmar VM, et al. Evidence for peroxynitrite as a signaling molecule in flow-dependent activation of c-Jun NH2-terminal kinase. Am J Physiol Heart Circ Physiol 1999; 277: H1647H1653.
  • 47
    Ferret PJ, Hammoud R, Tulliez M, Tran A, Trebeden H, Jaffray P, et al. Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse. HEPATOLOGY 2001; 33: 11731180.