Mechanisms of Acetaminophen-Induced Liver Necrosis

  • Jack A. Hinson
  • Dean W. Roberts
  • Laura P. James
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.

Keywords

Acetaminophen Liver Glutathione Covalent binding Mitochondria Oxidative stress JNK 

Notes

Acknowledgements

Support from the National Institutes of Health (DK075936 to L.P.J. and DK079008 to J.A.H.), from the University of Arkansas for Medical Sciences, from the Arkansas Children’s Hospital Research Institute, and from the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000 is gratefully acknowledged.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Jack A. Hinson
    • 1
  • Dean W. Roberts
  • Laura P. James
  1. 1.Department of Pharmacology and ToxicologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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