ToxSci Advance Access originally published online on September 21, 2005
Toxicological Sciences 2006 89(1):31-41; doi:10.1093/toxsci/kfi336
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
REVIEW |
Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death
Liver Research Institute, University of Arizona, Tucson, Arizona 85737
Received August 22, 2005; accepted September 16, 2005
Acetaminophen hepatotoxicity is the leading cause of drug-induced liver failure. Despite substantial efforts in the past, the mechanisms of acetaminophen-induced liver cell injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, and alkylation of proteins, especially mitochondrial proteins, are critical initiating events for the toxicity. Bcl-2 family members Bax and Bid then form pores in the outer mitochondrial membrane and release intermembrane proteins, e.g., apoptosis-inducing factor (AIF) and endonuclease G, which then translocate to the nucleus and initiate chromatin condensation and DNA fragmentation, respectively. Mitochondrial dysfunction, due to covalent binding, leads to formation of reactive oxygen and peroxynitrite, which trigger the membrane permeability transition and the collapse of the mitochondrial membrane potential. In addition to the diminishing capacity to synthesize ATP, endonuclease G and AIF are further released. Endonuclease G, together with an activated nuclear Ca2+,Mg2+-dependent endonuclease, cause DNA degradation, thereby preventing cell recovery and regeneration. Disruption of the Ca2+ homeostasis also leads to activation of intracellular proteases, e.g., calpains, which can proteolytically cleave structural proteins. Thus, multiple events including massive mitochondrial dysfunction and ATP depletion, extensive DNA fragmentation, and modification of intracellular proteins contribute to the development of oncotic necrotic cell death in the liver after acetaminophen overdose. Based on the recognition of the temporal sequence and interdependency of these mechanisms, it appears most promising to therapeutically target either the initiating event (metabolic activation) or the central propagating event (mitochondrial dysfunction and peroxynitrite formation) to prevent acetaminophen-induced liver cell death.
Key Words: acetaminophen hepatotoxicity; oncotic necrosis; apoptosis; endonucleases; DNA fragmentation; oxidant stress; peroxynitrite; covalent binding; reactive metabolites.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Jun, V. Savransky, A. Nanayakkara, S. Bevans, J. Li, P. L. Smith, and V. Y. Polotsky Intermittent hypoxia has organ-specific effects on oxidative stress Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1274 - R1281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Aleksunes, S. N. Campion, M. J. Goedken, and J. E. Manautou Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes Toxicol. Sci., August 1, 2008; 104(2): 261 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Bajt, H.-M. Yan, A. Farhood, and H. Jaeschke Plasminogen Activator Inhibitor-1 Limits Liver Injury and Facilitates Regeneration after Acetaminophen Overdose Toxicol. Sci., August 1, 2008; 104(2): 419 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Bajt, A. Farhood, J. J. Lemasters, and H. Jaeschke Mitochondrial Bax Translocation Accelerates DNA Fragmentation and Cell Necrosis in a Murine Model of Acetaminophen Hepatotoxicity J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 8 - 14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Ramaiah and H. Jaeschke Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury Toxicol Pathol, October 1, 2007; 35(6): 757 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Manov, Y. Bashenko, A. Eliaz-Wolkowicz, M. Mizrahi, O. Liran, and T. C. Iancu High-Dose Acetaminophen Inhibits the Lethal Effect of Doxorubicin in HepG2 Cells: The Role of P-glycoprotein and Mitogen-Activated Protein Kinase p44/42 Pathway J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1013 - 1022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Aleksunes and J. E. Manautou Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease Toxicol Pathol, June 1, 2007; 35(4): 459 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke Troglitazone Hepatotoxicity: Are We Getting Closer to Understanding Idiosyncratic Liver Injury? Toxicol. Sci., May 1, 2007; 97(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Numata, M. Kubo, H. Watanabe, K. Takagi, H. Mizuta, S. Okada, S. L. Kunkel, T. Ito, and A. Matsukawa Overexpression of Suppressor of Cytokine Signaling-3 in T Cells Exacerbates Acetaminophen-Induced Hepatotoxicity J. Immunol., March 15, 2007; 178(6): 3777 - 3785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Heinloth, G. A. Boorman, J. F. Foley, N. D. Flagler, and R. S. Paules Gene Expression Analysis Offers Unique Advantages to Histopathology in Liver Biopsy Evaluations Toxicol Pathol, February 1, 2007; 35(2): 276 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Bajt, C. Cover, J. J. Lemasters, and H. Jaeschke Nuclear Translocation of Endonuclease G and Apoptosis-Inducing Factor during Acetaminophen-Induced Liver Cell Injury Toxicol. Sci., November 1, 2006; 94(1): 217 - 225. [Abstract] [Full Text] [PDF]
|
|