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The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and

Mitchell R McGill1, Matthew R Sharpe, C David Williams

  • 1Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

The Journal of Clinical Investigation
|March 2, 2012
PubMed

Insights

Acetaminophen overdose causes liver failure through mitochondrial damage and DNA fragmentation. These events, identified by biomarkers in patient plasma, lead to necrotic cell death, not apoptosis.

Area of Science:

  • Hepatology
  • Toxicology
  • Biochemistry

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure in the US.
  • APAP toxicity involves a reactive metabolite, mitochondrial dysfunction, and DNA fragmentation in rodents.
  • Human APAP toxicity mechanisms, particularly downstream events, remain under-investigated.

Purpose of the Study:

  • To investigate biomarkers of mitochondrial damage and nuclear DNA fragmentation in human acetaminophen overdose.
  • To determine if acetaminophen overdose induces apoptosis or necrosis in human liver injury.
  • To correlate plasma biomarker levels with the extent of hepatic injury.

Main Methods:

  • Measured plasma glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA), and nuclear DNA fragments in APAP-overdose patients.
  • Compared biomarker levels between patients with abnormal liver function tests (LTs) and a normal LT control group, plus healthy volunteers.
  • Conducted parallel studies in mice and analyzed caspase-3 activity to differentiate cell death pathways.

Main Results:

  • Elevated plasma GDH activity and mtDNA concentration in patients with abnormal LTs.
  • Increased plasma nuclear DNA fragmentation in the abnormal LT cohort compared to controls.
  • Plasma biomarkers correlated with tissue injury in mice; caspase-3 was not elevated, indicating necrosis, not apoptosis.

Conclusions:

  • Mitochondrial damage and nuclear DNA fragmentation are critical events in human APAP hepatotoxicity.
  • These events likely result in necrotic cell death, consistent with rodent models.
  • Plasma biomarkers can reflect the severity of APAP-induced liver injury.

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