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Related Experiment Videos

Acetaminophen-induced hepatotoxicity.

Laura P James1, Philip R Mayeux, Jack A Hinson

  • 1Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. jameslaurap@uams.edu

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 20, 2003
PubMed
Summary
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Acetaminophen overdose causes liver damage through a reactive metabolite depleting glutathione (GSH). New research suggests nitric oxide (NO) and reactive species play roles in toxicity and repair, independent of iNOS.

Area of Science:

  • Hepatology
  • Toxicology
  • Biochemistry

Background:

  • Acetaminophen overdose leads to potentially fatal hepatic centrilobular necrosis.
  • Metabolic activation by cytochrome P450 produces a reactive metabolite (NAPQI) that depletes glutathione (GSH) and binds to proteins.
  • N-acetylcysteine is the current antidote, developed based on the finding that GSH repletion prevents toxicity.

Purpose of the Study:

  • Investigate the role of reactive nitrogen and oxygen species in acetaminophen-induced liver toxicity.
  • Explore the involvement of nitric oxide (NO) and its related pathways in acetaminophen toxicity and repair.
  • Determine the source of superoxide and its contribution to liver injury.

Main Methods:

  • Utilized inducible nitric oxide synthase (iNOS) knockout mice and NADPH oxidase knockout mice.

Related Experiment Videos

  • Measured NO synthesis (serum nitrate plus nitrite), tyrosine nitration, and hepatic lipid peroxidation.
  • Assessed acetaminophen adducts and cytokine/chemokine levels (IL-1beta, IL-10, MIP-2, MCP-1).

    • Main Results:

    • Acetaminophen increased NO synthesis and tyrosine nitration, but iNOS knockout mice showed no difference in toxicity despite reduced NO synthesis and tyrosine nitration.
    • iNOS knockout mice, unlike wild-type mice, exhibited hepatic lipid peroxidation, suggesting NO's role in controlling it.
    • Superoxide generation was not linked to Kupffer cell activation (NADPH oxidase knockout mice).
    • Elevated IL-1beta suggests a role in iNOS induction, while IL-10, MIP-2, and MCP-1 are implicated in repair and inflammation regulation.

    Conclusions:

    • Nitric oxide (NO) may regulate lipid peroxidation, and reactive nitrogen/oxygen species are important in acetaminophen toxicity.
    • The source of superoxide is likely NAPQI-mediated mitochondrial injury, not Kupffer cell activation.
    • Cytokines and chemokines are significantly involved in both the development and repair of acetaminophen-induced liver injury.