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Glycogen synthase kinase-3 mediates acetaminophen-induced apoptosis in human hepatoma cells

Patricia Macanas-Pirard1, Nik-Soriani Yaacob, Pauline C Lee

  • 1School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UK.

The Journal of Pharmacology and Experimental Therapeutics
|January 25, 2005
PubMed

Insights

Acetaminophen (AAP) overdose causes liver injury via apoptosis, progressing to necrosis. This study reveals AAP-induced apoptosis in liver cells involves the mitochondrial pathway, mediated by GSK-3 and endoplasmic reticulum stress.

Area of Science:

  • Hepatology
  • Cellular Biology
  • Toxicology

Background:

  • Acetaminophen (AAP) overdose is a leading cause of acute liver failure.
  • Initial liver injury from AAP overdose involves apoptosis, which can progress to necrosis.
  • Understanding the precise mechanisms of AAP-induced apoptosis is crucial for developing targeted therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying acetaminophen (AAP)-induced apoptosis in human hepatoma cells (HuH7).
  • To investigate the role of the mitochondrial pathway and specific signaling molecules in the early stages of AAP hepatotoxicity.
  • To identify potential therapeutic targets for mitigating AAP-induced liver injury.

Main Methods:

  • Utilized human HuH7 hepatoma cells as an in vitro model system.
  • Assessed apoptosis through chromatin condensation, Bax translocation, and cytochrome c/Smac/DIABLO release.
  • Measured mitochondrial membrane potential and caspase activation (caspases-3 and -7).
  • Investigated the effects of inhibitors for caspases, calpains, cathepsins, serine proteases, mitochondrial permeability transition pore, MAP kinases, and GSK-3.

Main Results:

  • AAP induced apoptosis in HuH7 cells, characterized by chromatin condensation, Bax translocation to mitochondria, and release of cytochrome c and Smac/DIABLO.
  • A loss of mitochondrial membrane potential and activation of executioner caspases-3 and -7 were observed.
  • Caspase inhibitors blocked AAP-induced apoptosis, while inhibitors of other proteases or the mitochondrial permeability transition pore did not.
  • Pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) significantly delayed and reduced AAP-induced apoptosis.
  • GSK-3 inhibition affected endoplasmic reticulum stress-induced apoptosis but not prooxidant-induced apoptosis.

Conclusions:

  • AAP-induced apoptosis in liver cells primarily involves the mitochondrial pathway.
  • Glycogen synthase kinase-3 (GSK-3) plays a mediating role in AAP-induced apoptosis.
  • The initiation of AAP-induced apoptosis is likely linked to endoplasmic reticulum stress.

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