Mitochondrial Dysfunction and Drug Hepatotoxicity

Summary

Principal Investigator: HARTMUT W JAESCHKE
Abstract: Acetaminophen (AAP) overdose is the second leading cause of toxic drug ingestion and the most frequent cause of acute liver failure in the US. It is well established that the sequence of events leading to AAP-induced cell death is initiated by the formation of a reactive metabolite, which first depletes glutathione and then arylates intracellular macromolecules. However, the sequence of events leading to cell death after protein arylation are incompletely understood. Based on published data and our own preliminary investigations, we propose the following novel hypothesis that cytosolic calpain activation is a key event in causing progressive mitochondrial dysfunction and eventually opening of the membrane permeability transition (MPT) pore, which triggers a cellular bioenergetic crisis resulting in cell death. In particular, we will test this hypothesis by investigating 4 specific aims: First, we will characterize the activation of calpains and establish their significance for mitochondrial dysfunction, MPT and cell death after AAP overdose. Second, we will evaluate the role of translocation to the mitochondria of Bcl-2 family members Bid and Bax for mitochondrial dysfunction, MPT and cell death. Third, we will assess the role of MPT for mitochondrial release of endonuclease G and its functional significance for DMA fragmentation and cell death. Fourth, we will characterize the role of mitochondrial DMA depletion and nuclear DMA fragmentation and poly(ADP-ribose)polymerase (PARP) activation for AAP-induced cell death and regeneration. This proposal is innovative in that it tests a novel concept of an intracellular signaling cascade of necrotic cell death in liver cells. The investigation will establish critical intervention points for preventing liver cell death well beyond the initiation of the process and thus may be more applicable for therapeutic interventions after drug overdose. This new insight into the signaling mechanism of AAP-induced cell death holds the promise of establishing novel therapeutic approaches for preventing AAP-induced liver failure and potentially other forms of drug toxicity in humans.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS
    Hepatology 60:1336-45. 2014
  2. pmc Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice
    Anup Ramachandran
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS
    Hepatology 58:2099-108. 2013
  3. pmc Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Food Chem Toxicol 58:228-35. 2013
  4. pmc Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 269:240-9. 2013
  5. pmc Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas 66160, USA
    Pharm Res 30:2174-87. 2013
  6. pmc Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products
    Hartmut Jaeschke
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Food Chem Toxicol 55:279-89. 2013
  7. pmc Novel insight into mechanisms of cholestatic liver injury
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, United States
    World J Gastroenterol 18:4985-93. 2012
  8. pmc Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation
    Yuchao Xie
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 131:325-35. 2013
  9. pmc Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 264:387-94. 2012
  10. pmc Lysosomal instability and cathepsin B release during acetaminophen hepatotoxicity
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Basic Clin Pharmacol Toxicol 111:417-25. 2012

Scientific Experts

  • HARTMUT W JAESCHKE
  • John Lemasters
  • Daniel James Antoine
  • Chieko Saito
  • Mitchell R McGill
  • C David Williams
  • Mary Lynn Bajt
  • Anwar Farhood
  • Anup Ramachandran
  • Benjamin L Woolbright
  • Yuchao Xie
  • Margitta Lebofsky
  • Hong Min Ni
  • Hui Min Yan
  • Matthew R Sharpe
  • Peter Fickert
  • Wen Xing Ding
  • Michael Trauner
  • Min Yang
  • Steven C Curry
  • Kazuyoshi Kon
  • Akira Uchiyama
  • Cathleen Cover
  • Feng Li
  • Xiaochao Ma
  • Kuo Du
  • Venkat K Ramshesh
  • Nikki Boggess
  • Douglas E Rollins
  • B Kevin Park
  • Bo Kong
  • David H Adams
  • Eduardo N Maldonado
  • Dean P Jones
  • Clarence David Williams
  • Sven Schüngel
  • Ji Young Hong
  • Jae Sung Kim
  • Kelly K Andringa
  • Tadashi Hasegawa
  • Ernst Malle
  • Jie Liu
  • Vincent S Staggs
  • Archie Svetlov
  • James P Luyendyk
  • Timothy M Schmitt
  • BRYAN COPPLE
  • Sean C Kumer
  • Jessica Williams
  • Jameson Forster
  • William M Lee
  • Wei Cui
  • Stanislav I Svetlov
  • Bryan L Copple
  • Mengde Cao
  • Kenneth Dorko
  • Diana G Wilkins
  • Elisabeth Krones
  • Geurt Stokman
  • Hye Ryun K Norris
  • Gosta Eggertsen
  • Matthew H Slawson
  • Helmut Denk
  • Tarek Moustafa
  • Alexander R Rosenkranz
  • Carsten A Wagner
  • Mathieu Vinken
  • Rosalind E Jenkins
  • Dagmar Silbert
  • Andrea Thueringer
  • Cord Langner
  • Kathrin Eller
  • Emina Halilbasic
  • Marion J Pollheimer
  • Rebecca G Wells
  • Meghan Patni
  • Udayan Apte
  • Lauren M Aleksunes
  • Mohammad Taha
  • Grace L Guo
  • Curtis D Klaassen
  • Melinda Broward
  • Abigail Bockus
  • Prachi Borude
  • Iván L Csanaky
  • Scott Weir
  • Qi Chen
  • Patrick J Shaw
  • Craig Benson
  • Gordon J Murray

Detail Information

Publications66

  1. ncbi Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS
    Hepatology 60:1336-45. 2014
    ..05; AUC, time of peak ALT: 0.78, 0.71, and 0.71 or 0.76, respectively, P < 0.05), and the results were similar to those from the Model for End-Stage Liver Disease (MELD; AUC, peak MELD: 0.77; P < 0.05)...
  2. pmc Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice
    Anup Ramachandran
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS
    Hepatology 58:2099-108. 2013
    ..All of these protective effects were lost after 24 hours in vivo or 48 hours in vitro...
  3. pmc Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Food Chem Toxicol 58:228-35. 2013
    ..Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP...
  4. pmc Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 269:240-9. 2013
    ..While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter...
  5. pmc Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, Kansas 66160, USA
    Pharm Res 30:2174-87. 2013
    ..Recent advances in the diagnostic use of serum adducts are covered...
  6. pmc Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products
    Hartmut Jaeschke
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Food Chem Toxicol 55:279-89. 2013
    ..The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms...
  7. pmc Novel insight into mechanisms of cholestatic liver injury
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, United States
    World J Gastroenterol 18:4985-93. 2012
    ....
  8. pmc Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation
    Yuchao Xie
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 131:325-35. 2013
    ..Thus, the protective effect of A438079 against APAP hepatotoxicity in vivo can be explained by its effect on metabolic activation and cell death pathways in hepatocytes without involvement of the Nalp3 inflammasome...
  9. pmc Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 264:387-94. 2012
    ..Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity...
  10. pmc Lysosomal instability and cathepsin B release during acetaminophen hepatotoxicity
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Basic Clin Pharmacol Toxicol 111:417-25. 2012
    ..Low levels of cathepsin B were released into plasma from overdose patients. APAP overdose causes lysosomal instability and release of cathepsin B into the cytosol but does not contribute to liver injury under these conditions...
  11. ncbi Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice
    Peter Fickert
    Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria Department of Pathology, Medical University of Graz, Graz, Austria
    Hepatology 58:2056-69. 2013
    ..Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy...
  12. pmc Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA
    Arch Toxicol 88:391-401. 2014
    ....
  13. pmc The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation
    Kuo Du
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 273:484-91. 2013
    ..We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32-based gap junctions...
  14. ncbi Mechanisms of acetaminophen-induced cell death in primary human hepatocytes
    Yuchao Xie
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 279:266-74. 2014
    ..The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6h after APAP and a partial protection when given at 15 h...
  15. pmc Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States
    J Hepatol 61:617-25. 2014
    ..The purpose of the present study was to investigate the mechanism(s) by which the loss of hepatic autophagy leads to liver inflammation, fibrosis and tumorigenesis...
  16. pmc Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, USA
    Toxicol Lett 228:56-66. 2014
    ....
  17. ncbi Argininosuccinate synthetase as a plasma biomarker of liver injury after acetaminophen overdose in rodents and humans
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Biomarkers 19:222-30. 2014
    ..New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate...
  18. pmc Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 275:122-33. 2014
    ..The similar findings between surviving patients and mice indicate that neutrophil activation may be a critical event for host defense or injury resolution following APAP overdose, but not a contributing factor to APAP-induced injury...
  19. pmc Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 274:417-24. 2014
    ..These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. ..
  20. pmc Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice
    Benjamin L Woolbright
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Appl Pharmacol 273:524-31. 2013
    ..In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis...
  21. pmc Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice
    Min Yang
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Toxicol Lett 224:186-95. 2014
    ..chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice. ..
  22. ncbi Intracellular signaling mechanisms of acetaminophen-induced liver cell death
    Hartmut Jaeschke
    Liver Research Institute, University of Arizona, College of Medicine, Tucson, Arizona 85737, USA
    Toxicol Sci 89:31-41. 2006
    ....
  23. pmc Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury
    Akira Uchiyama
    Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Hepatology 48:1644-54. 2008
    ....
  24. pmc Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose
    Mary Lynn Bajt
    Liver Research Institute, University of Arizona, Tucson, Arizona 85724, USA
    Toxicol Sci 104:419-27. 2008
    ..Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair...
  25. pmc Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: effect on HMG-CoA synthase
    Kelly K Andringa
    Department of Environmental Health Sciences and The Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Toxicol Lett 177:188-97. 2008
    ..The pathophysiological relevance of these limited changes in protein thiols remains to be investigated...
  26. ncbi Mitochondrial bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity
    Mary Lynn Bajt
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    J Pharmacol Exp Ther 324:8-14. 2008
    ..However, the persistent oxidant stress and peroxynitrite formation in mitochondria may eventually trigger the permeability transition pore opening and release intermembrane proteins independently of Bax...
  27. ncbi Modulation of mitochondrial membrane permeability in pathogenesis, autophagy and control of metabolism
    John J Lemasters
    Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Gastroenterol Hepatol 22:S31-7. 2007
    ..Thus, VDAC serves as a global regulator, or governator, of mitochondrial function. Understanding of how these mitochondrial membrane permeability changes are themselves regulated remains incomplete and requires future study...
  28. ncbi Imaging of mitochondrial polarization and depolarization with cationic fluorophores
    John J Lemasters
    Center for Cell Death, Injury and Regeneration, and Departments of Pharmaceutical Sciences and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
    Methods Cell Biol 80:283-95. 2007
  29. ncbi Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice
    Tadashi Hasegawa
    Liver Research Institute, College of Medicine, University of Arizona, Tucson, Arizona, USA
    Am J Physiol Gastrointest Liver Physiol 292:G1385-95. 2007
    ..In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers...
  30. ncbi Role of neutrophils in acute inflammatory liver injury
    Hartmut Jaeschke
    Liver Research Institute, University of Arizona, College of Medicine, Tucson, AZ 85737, USA
    Liver Int 26:912-9. 2006
    ....
  31. ncbi Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury
    Mary Lynn Bajt
    Liver Research Institute, University of Arizona, College of Medicine, Tucson, Arizona 85724, USA
    Toxicol Sci 94:217-25. 2006
    ....
  32. ncbi Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity
    Cathleen Cover
    Liver Research Institute, University of Arizona, Tucson, AZ 85724, USA
    Toxicol Appl Pharmacol 216:98-107. 2006
    ..Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose...
  33. ncbi Mechanisms of Liver Injury. II. Mechanisms of neutrophil-induced liver cell injury during hepatic ischemia-reperfusion and other acute inflammatory conditions
    Hartmut Jaeschke
    Liver Research Institute, College of Medicine, University of Arizona, Tucson, 85724, USA
    Am J Physiol Gastrointest Liver Physiol 290:G1083-8. 2006
    ....
  34. ncbi Role of caspases in acetaminophen-induced liver injury
    Hartmut Jaeschke
    Liver Research Institute University of Arizona 1501 N Campbell Ave, Room 6309 Tucson, AZ 85724, USA
    Life Sci 78:1670-6. 2006
    ....
  35. pmc The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity
    Anup Ramachandran
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 251:226-33. 2011
    ..SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation...
  36. pmc Mechanisms of immune-mediated liver injury
    David H Adams
    Center for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TH, UK
    Toxicol Sci 115:307-21. 2010
    ....
  37. pmc Mechanism of protection by metallothionein against acetaminophen hepatotoxicity
    Chieko Saito
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 242:182-90. 2010
    ....
  38. pmc Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine
    Chieko Saito
    Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Hepatology 51:246-54. 2010
    ..However, increasing the dose of NAC improved the protective effect similar to GSH, suggesting that the amino acids not used for GSH synthesis were used as mitochondrial energy substrates...
  39. pmc The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers
    Sven Schüngel
    Clinic of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany
    Hepatology 50:1558-66. 2009
    ..In contrast to previous in vitro findings, phosphorylation of Bid does not affect the sensitivity of hepatocytes to Fas receptor-mediated apoptosis in vivo...
  40. pmc Mitochondrial calcium and the permeability transition in cell death
    John J Lemasters
    Center for Cell Death, Injury and Regeneration, Medical University of South Carolina, Charleston, SC 29425, USA
    Biochim Biophys Acta 1787:1395-401. 2009
    ..Thus, the exact role of Ca(2+) for inducing the MPT and cell death depends on the particular biologic setting...
  41. pmc Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation
    Ji Young Hong
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA
    Am J Physiol Gastrointest Liver Physiol 296:G572-81. 2009
    ..The data indicate that liver cell death initiated by diquat-induced superoxide formation in vivo is mediated predominantly by oncotic necrosis and is independent of JNK activation...
  42. pmc Apoptosis-inducing factor modulates mitochondrial oxidant stress in acetaminophen hepatotoxicity
    Mary Lynn Bajt
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 122:598-605. 2011
    ..Thus, AIF has a critical function in APAP hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation...
  43. pmc Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria
    Dean P Jones
    Dept of Medicine, Emory University, 4131 Rollins Research Center, Atlanta, GA 30322, USA
    Mol Interv 10:98-111. 2010
    ..The role of mitochondria in cell death due to drug hepatotoxicity has been receiving renewed attention and it is therefore timely to assess the current status of this area...
  44. pmc c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity
    Chieko Saito
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 246:8-17. 2010
    ....
  45. pmc Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 252:289-97. 2011
    ..It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose...
  46. pmc HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity
    Mitchell R McGill
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Hepatology 53:974-82. 2011
    ..APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not protect against APAP-induced cell injury...
  47. pmc Current issues with acetaminophen hepatotoxicity--a clinically relevant model to test the efficacy of natural products
    Hartmut Jaeschke
    Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
    Life Sci 88:737-45. 2011
    ..This review should assist investigators in the optimal use of this model to test the efficacy of natural compounds and obtain reliable mechanistic information...
  48. pmc Free tubulin modulates mitochondrial membrane potential in cancer cells
    Eduardo N Maldonado
    Center for Cell Death, Injury and Regeneration, Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
    Cancer Res 70:10192-201. 2010
    ..Plasma membrane potential assessed by DiBAC(4)(3) was not altered by any of the treatments. We propose that inhibition of VDAC by free tubulin limits mitochondrial metabolism in cancer cells...
  49. pmc Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury
    Anup Ramachandran
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Free Radic Res 45:156-64. 2011
    ..Thus, mitochondrial oxidative stress and induction of the MPT are critical events in APAP hepatotoxicity in vivo and at least part of the APAP-induced oxidant stress and peroxynitrite formation occurs downstream of the MPT...
  50. pmc Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Appl Pharmacol 247:169-78. 2010
    ..Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury...
  51. pmc Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes
    Kazuyoshi Kon
    Departments of Pharmaceutical and Biomedical Sciences and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Toxicol Sci 117:101-8. 2010
    ..Disrupted lysosomes are the likely source of iron, and chelation of this iron decreases acetaminophen toxicity to hepatocytes...
  52. pmc Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity
    Hartmut Jaeschke
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Liver Int 32:8-20. 2012
    ....
  53. pmc Activation of autophagy protects against acetaminophen-induced hepatotoxicity
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
    Hepatology 55:222-32. 2012
    ..Pharmacological inhibition of autophagy by 3-methyladenine or chloroquine further exacerbated APAP-induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP-induced hepatotoxicity...
  54. ncbi Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice
    Clarence David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Liver Int 30:1280-92. 2010
    ..However, conflicting results were obtained when using immunological intervention strategies...
  55. pmc Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity
    Bo Kong
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 261:189-95. 2012
    ..Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury...
  56. pmc Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 127:438-50. 2012
    ..Taken together, our data suggest that persistent activation of Nrf2 and increased hepatocyte proliferation protect against APAP-induced liver injury in Atg5 liver-specific knockout mice...
  57. pmc Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species
    Hartmut Jaeschke
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Transplant Rev (Orlando) 26:103-14. 2012
    ....
  58. pmc The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation
    Mitchell R McGill
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    J Clin Invest 122:1574-83. 2012
    ..Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death...
  59. pmc Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity
    Daniel J Antoine
    Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
    J Hepatol 56:1070-9. 2012
    ..The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity...
  60. pmc Imaging of mitochondrial pH using SNARF-1
    Venkat K Ramshesh
    Center for Cell Death, Injury and Regeneration, Medical University of South Carolina, 86 Jonathan Lucas Street, 250955, Charleston, SC 29425, USA
    Methods Mol Biol 810:243-8. 2012
    ..These results illustrate the ability of laser scanning confocal microscopy to image the intracellular distribution of pH in living cells and to determine mitochondrial ΔpH...
  61. pmc Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation
    C David Williams
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
    Toxicol Appl Pharmacol 257:449-58. 2011
    ..Additionally, the infiltration of hepatic neutrophils was not altered by the fed state of either mouse strain...
  62. pmc The oxygen tension modulates acetaminophen-induced mitochondrial oxidant stress and cell injury in cultured hepatocytes
    Hui Min Yan
    Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
    Toxicol Sci 117:515-23. 2010
    ..These results suggest that oxygen tension can modulate hepatocyte responses to APAP, with low physiological levels (10%) decreasing mitochondrial oxidant stress and delaying hepatocyte cell death...