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Cited by 1,006Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyCell death mechanisms and regulation

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Mechanisms of Acetaminophen-Induced Liver Necrosis

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Hinson, Jack A., Roberts, Dean W., James, Laura P.·2010·Handbook of Experimental Pharmacology
DOI 10.1007/978-3-642-00663-0_12PMC PMC2836803
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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.

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  • The results of the present study are in agreement with previous studies; treatment of paracetamol caused depletion of GSH, cell damage (MDA levels) and mitochondrial dysfunction.

    “The results of present study are in agreement with previous studies; we found that treatment of paracetamol caused depletion of GSH, cell damage (MDA levels) and mitochondrial dysfunction. 4,7,38”

    From Caralluma umbellata Haw. protects liver against paracetamol toxicity and inhibits CYP2E1 (2017) · cites this paper as [4]

  • Paracetamol is a major cause of drug-induced acute liver failure and has been extensively studied for its liver damage.

    “Paracetamol is considered as one of the major causes for drug-induced ALF, and has been extensively studied for its liver damage. 3,4”

    From Caralluma umbellata Haw. protects liver against paracetamol toxicity and inhibits CYP2E1 (2017) · cites this paper as [4]

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Metadata

Authors
Hinson, J. A., Roberts, D. W., & James, L. P.
Affiliations
University of Arkansas for Medical Sciences (US)
Corresponding author
Hinson, Jack A.
ORCID
James, Laura P.
Venue
Handbook of Experimental Pharmacology
Publisher
Springer Berlin Heidelberg
Published
2009-09-21
Issue
196
Pages
369-405
ISSN
  • 0171-2004 (ISSN-L)
  • 1865-0325
DOI
10.1007/978-3-642-00663-0_12
PMC
PMC2836803
OpenAlex
W1527821398
Cited by
1,006
References
10
Citations by year
2026: 36 · 2025: 38 · 2024: 37 · 2023: 60 · 2022: 48 · 2021: 63 · 2020: 84 · 2019: 167 · 2018: 82 · 2017: 70 · 2016: 67 · 2015: 71 · 2014: 52 · 2013: 52 · 2012: 32
FWCI
48.02
Type
book chapter
Language
en
Open access
Locations
  • Handbook of experimental pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01dk079008-05)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK079008, R01DK075936, DK079008)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
acetaminophen toxicity, liver necrosis, centrilobular necrosis, acute liver failure, cytochrome P450 metabolism, N-acetyl-p-benzoquinone imine, glutathione depletion, oxidative stress, reactive oxygen species, reactive nitrogen species, mitochondrial permeability transition, mitochondrial membrane potential, ATP depletion, cytokines, chemokines, hepatocyte regeneration, hepatotoxicity mechanisms
MeSH terms
Acetaminophen, Animals, Biotransformation, Humans, Liver, Liver Circulation, Liver Regeneration, Mitochondria, Liver, Necrosis, Signal Transduction, Cytokines, Analgesics, Non-Narcotic, Chemokines, Chemical and Drug Induced Liver Injury

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