Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity

Background: Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. Although substantial progress regarding the mechanisms of APAP hepatotoxicity has been made in the past several decades, therapeutic options are still limited and novel treatments are clearly needed. c-jun N-terminal Kinase (JNK) has emerged as a promising therapeutic target in recent years. Areas covered: Early studies established the critical role of JNK activation and mitochondrial translocation in APAP hepatotoxicity. However, this concept has also been challenged. Initial studies failed to reproduce the protection of JNK deficiency in APAP toxicity and concerns over off-target effects of JNK inhibitors and even in knock-out mice are increasing. Interestingly, recent studies have even shown that liver injury can be altered with or without effects on JNK activation. The current review addresses these discrepancies and tries to explain or reconcile some of the conflicting results. Expert opinion: JNK is a potential therapeutic target for APAP poisoning. However, controversies still exist regarding its actual role in APAP hepatotoxicity. Future studies are warranted for more in-depth testing of specific inhibitors in well-defined preclinical models and human hepatocytes before JNK can be considered a relevant therapeutic target for APAP poisoning.

[1]  N. Kaplowitz,et al.  Receptor interacting protein kinase 1 mediates murine acetaminophen toxicity independent of the necrosome and not through necroptosis , 2015, Hepatology.

[2]  H. Chung,et al.  The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction , 2015, Archives of Toxicology.

[3]  Mitchell R. McGill,et al.  Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells , 2015, Xenobiotica; the fate of foreign compounds in biological systems.

[4]  H. Jaeschke,et al.  Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury. , 2015, Toxicology and applied pharmacology.

[5]  Mitchell R. McGill,et al.  Resveratrol prevents protein nitration and release of endonucleases from mitochondria during acetaminophen hepatotoxicity. , 2015, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[6]  Mitchell R. McGill,et al.  The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury , 2015, Xenobiotica; the fate of foreign compounds in biological systems.

[7]  Elizabeth M. Lancaster,et al.  Acetaminophen hepatotoxicity: an updated review , 2014, Archives of Toxicology.

[8]  Mitchell R. McGill,et al.  Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase. , 2014, Toxicology and applied pharmacology.

[9]  B. Bhushan,et al.  Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model. , 2014, American Journal of Pathology.

[10]  Mitchell R. McGill,et al.  Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. , 2014, Toxicology and applied pharmacology.

[11]  Á. Valverde,et al.  Essential Role of Protein-tyrosine Phosphatase 1B in the Modulation of Insulin Signaling by Acetaminophen in Hepatocytes* , 2014, The Journal of Biological Chemistry.

[12]  Y. Oike,et al.  Protection afforded by pre- or post-treatment with 4-phenylbutyrate against liver injury induced by acetaminophen overdose in mice. , 2014, Pharmacological research.

[13]  Cheng Zhang,et al.  Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice. , 2014, Toxicology letters.

[14]  Mitchell R. McGill,et al.  Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning. , 2014, Toxicology and applied pharmacology.

[15]  M. Vinken,et al.  The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation. , 2013, Toxicology and applied pharmacology.

[16]  Mitchell R. McGill,et al.  Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen‐induced hepatocyte necrosis in mice , 2013, Hepatology.

[17]  D. Spyker,et al.  2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report , 2013, Clinical toxicology.

[18]  Takao Iwawaki,et al.  CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. , 2013, Journal of hepatology.

[19]  Hartmut Jaeschke,et al.  Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications. , 2013, Toxicology and applied pharmacology.

[20]  Fei Li,et al.  Disruption of thioredoxin reductase 1 protects mice from acute acetaminophen-induced hepatotoxicity through enhanced NRF2 activity. , 2013, Chemical research in toxicology.

[21]  P. Rada,et al.  Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity , 2013, Cell Death and Disease.

[22]  Mitchell R. McGill,et al.  Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis , 2013, Pharmaceutical Research.

[23]  C. Trautwein,et al.  ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis. , 2013, Journal of hepatology.

[24]  A. Jaeschke,et al.  Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity , 2012, Molecular Pharmacology.

[25]  Michael Karin,et al.  A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. , 2012, Gastroenterology.

[26]  Xiaomei Meng,et al.  Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury , 2012, Toxicologic pathology.

[27]  Hartmut Jaeschke,et al.  The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. , 2012, The Journal of clinical investigation.

[28]  Philip Chamberlain,et al.  Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. , 2012, Bioorganic & medicinal chemistry letters.

[29]  Mitchell R. McGill,et al.  Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity , 2012, Drug metabolism reviews.

[30]  H. Jaeschke,et al.  Activation of autophagy protects against acetaminophen‐induced hepatotoxicity , 2012, Hepatology.

[31]  U. Boelsterli,et al.  Acetaminophen overdose‐induced liver injury in mice is mediated by peroxynitrite independently of the cyclophilin D‐regulated permeability transition , 2011, Hepatology.

[32]  N. Kaplowitz,et al.  c-Jun N-terminal Kinase (JNK)-dependent Acute Liver Injury from Acetaminophen or Tumor Necrosis Factor (TNF) Requires Mitochondrial Sab Protein Expression in Mice* , 2011, The Journal of Biological Chemistry.

[33]  H. Jaeschke,et al.  Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  M. Lovegrove,et al.  Characterization of acetaminophen overdose‐related emergency department visits and hospitalizations in the United States , 2011, Pharmacoepidemiology and drug safety.

[35]  L. Pohl,et al.  Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. , 2011, Chemical research in toxicology.

[36]  A. Crosby,et al.  Emergency department visits for overdoses of acetaminophen-containing products. , 2011, American journal of preventive medicine.

[37]  S. Gupta,et al.  Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients , 2011, Arzneimittelforschung.

[38]  Mitchell R. McGill,et al.  HepaRG cells: A human model to study mechanisms of acetaminophen hepatotoxicity , 2011, Hepatology.

[39]  H. Jaeschke,et al.  Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury , 2011, Free radical research.

[40]  H. Jaeschke,et al.  c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. , 2010, Toxicology and applied pharmacology.

[41]  G. Nagy,et al.  BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury. , 2010, Toxicology and applied pharmacology.

[42]  N. Kaplowitz,et al.  Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1* , 2010, The Journal of Biological Chemistry.

[43]  C. Zwingmann,et al.  Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N‐acetylcysteine , 2010, Hepatology.

[44]  E. Krenzelok.  The FDA Acetaminophen Advisory Committee Meeting – what is the future of acetaminophen in the United States? The perspective of a committee member , 2009, Clinical toxicology.

[45]  E. Wagner,et al.  Signal integration by JNK and p38 MAPK pathways in cancer development , 2009, Nature Reviews Cancer.

[46]  E. Wagner,et al.  Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. , 2008, The Journal of clinical investigation.

[47]  Maurizio Pellecchia,et al.  Identification of a new JNK inhibitor targeting the JNK-JIP interaction site , 2008, Proceedings of the National Academy of Sciences.

[48]  M. Karin,et al.  Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. , 2008, Gastroenterology.

[49]  N. Kaplowitz,et al.  How to protect against acetaminophen: don't ask for JUNK. , 2008, Gastroenterology.

[50]  L. Pohl,et al.  Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury. , 2008, Biochemical and biophysical research communications.

[51]  L. Pohl,et al.  Pathogenic role of natural killer T and natural killer cells in acetaminophen‐induced liver injury in mice is dependent on the presence of dimethyl sulfoxide , 2008, Hepatology.

[52]  E. Chan,et al.  Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine. , 2008, Toxicology letters.

[53]  Neil Kaplowitz,et al.  Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury* , 2008, Journal of Biological Chemistry.

[54]  H. Ichijo,et al.  Apoptosis signal-regulating kinase 1 in stress and immune response. , 2008, Annual review of pharmacology and toxicology.

[55]  M. Czaja,et al.  Cell signaling in oxidative stress-induced liver injury. , 2007, Seminars in liver disease.

[56]  Yusen Liu,et al.  Regulation of innate immune response by MAP kinase phosphatase-1. , 2007, Cellular signalling.

[57]  U. Boelsterli,et al.  Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen‐induced liver injury , 2007, Hepatology.

[58]  R. Flavell,et al.  Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure , 2006, Gut.

[59]  J. Sattabongkot,et al.  Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. , 2006, Toxicology and applied pharmacology.

[60]  H. Jaeschke,et al.  Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[61]  N. Kaplowitz,et al.  c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. , 2006, Gastroenterology.

[62]  H. Jaeschke,et al.  Role of caspases in acetaminophen-induced liver injury. , 2006, Life sciences.

[63]  J. Inoue,et al.  Recruitment of Tumor Necrosis Factor Receptor-associated Factor Family Proteins to Apoptosis Signal-regulating Kinase 1 Signalosome Is Essential for Oxidative Stress-induced Cell Death* , 2005, Journal of Biological Chemistry.

[64]  H. Jaeschke,et al.  Peroxynitrite-Induced Mitochondrial and Endonuclease-Mediated Nuclear DNA Damage in Acetaminophen Hepatotoxicity , 2005, Journal of Pharmacology and Experimental Therapeutics.

[65]  Jeppe Falsig,et al.  Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway , 2005, The Journal of Neuroscience.

[66]  J. Holder,et al.  Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells , 2005, Journal of Pharmacology and Experimental Therapeutics.

[67]  William M. Lee,et al.  AASLD Position Paper: The Management of Acute Liver Failure: Update 2011 , 2011 .

[68]  H. Jaeschke,et al.  Mitochondrial permeability transition in acetaminophen‐induced necrosis and apoptosis of cultured mouse hepatocytes , 2004, Hepatology.

[69]  R. Jope,et al.  The glamour and gloom of glycogen synthase kinase-3. , 2004, Trends in biochemical sciences.

[70]  N. Kaplowitz,et al.  Mechanisms for sensitization to TNF‐induced apoptosis by acute glutathione depletion in murine hepatocytes , 2003, Hepatology.

[71]  R. Flavell,et al.  JunD mediates survival signaling by the JNK signal transduction pathway. , 2003, Molecular cell.

[72]  R. Schwabe,et al.  c‐Jun‐N‐terminal kinase drives cyclin D1 expression and proliferation during liver regeneration , 2003, Hepatology.

[73]  F. Haj,et al.  Regulation of Receptor Tyrosine Kinase Signaling by Protein Tyrosine Phosphatase-1B* , 2003, The Journal of Biological Chemistry.

[74]  H. Jaeschke,et al.  Peroxynitrite Is a Critical Mediator of Acetaminophen Hepatotoxicity in Murine Livers: Protection by Glutathione , 2002, Journal of Pharmacology and Experimental Therapeutics.

[75]  M. Tremblay,et al.  Regulation of Insulin-Like Growth Factor Type I (IGF-I) Receptor Kinase Activity by Protein Tyrosine Phosphatase 1B (PTP-1B) and Enhanced IGF-I-Mediated Suppression of Apoptosis and Motility in PTP-1B-Deficient Fibroblasts , 2002, Molecular and Cellular Biology.

[76]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[77]  David W. Anderson,et al.  SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[78]  R. Jope,et al.  The multifaceted roles of glycogen synthase kinase 3β in cellular signaling , 2001, Progress in Neurobiology.

[79]  J. Pié,et al.  Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway. , 2001, Molecular pharmacology.

[80]  D. Barford,et al.  Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. , 2000, Molecular cell.

[81]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[82]  S. Keyse,et al.  Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. , 2000, Current opinion in cell biology.

[83]  P. Rakic,et al.  The Jnk1 and Jnk2 Protein Kinases Are Required for Regional Specific Apoptosis during Early Brain Development , 1999, Neuron.

[84]  Kohei Miyazono,et al.  Mammalian thioredoxin is a direct inhibitor of apoptosis signal‐regulating kinase (ASK) 1 , 1998, The EMBO journal.

[85]  Steven D. Cohen,et al.  Selective protein covalent binding and target organ toxicity. , 1997, Toxicology and applied pharmacology.

[86]  Minoru Takagi,et al.  Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways , 1997, Science.

[87]  C. Proud,et al.  GSK3: a SHAGGY frog story. , 1996, Trends in cell biology.

[88]  H. Jaeschke,et al.  Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. , 1990, The Journal of pharmacology and experimental therapeutics.

[89]  M. Tirmenstein,et al.  Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3'-hydroxyacetanilide, in mouse liver. , 1989, The Journal of biological chemistry.

[90]  G. Knapp,et al.  Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) , 1988, The New England journal of medicine.

[91]  Steven D. Cohen,et al.  Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice. , 1988, Toxicology and applied pharmacology.

[92]  B. Wong,et al.  Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. , 1986, The Journal of pharmacology and experimental therapeutics.

[93]  V. Shah,et al.  M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury. , 2015, Free radical biology & medicine.

[94]  M. Black,et al.  Acetaminophen hepatotoxicity. , 1980, Gastroenterology.