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Published on: November 27, 2019

BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury

Gábor Nagy1, András Szarka, Gábor Lotz

  • 1Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, HAS Pathobiochemistry Research Group, H-1444 Budapest POB 260, Hungary.

Toxicology and Applied Pharmacology
|November 26, 2009
PubMed

Insights

Acetaminophen overdose causes liver cell death via endoplasmic reticulum stress. The drug BGP-15 protected against this by inhibiting apoptosis-inducing factor (AIF) translocation, suggesting a new therapeutic approach.

Area of Science:

  • Hepatology
  • Toxicology
  • Cellular Biology

Background:

  • Acute acetaminophen toxicity induces endoplasmic reticulum (ER) redox stress and apoptosis in liver cells.
  • Caspase-independent cell death pathways are implicated in acetaminophen-induced liver injury.
  • The drug BGP-15 demonstrates protective effects in conditions of redox imbalance.

Purpose of the Study:

  • To investigate the role of caspase-independent mechanisms in acetaminophen-induced programmed cell death.
  • To evaluate the protective potential of BGP-15 against acetaminophen toxicity.
  • To explore the effects of BGP-15 on ER redox stress and apoptotic signaling pathways.

Main Methods:

  • Co-administration of BGP-15 with a sublethal dose of acetaminophen in an experimental model.
  • Assessment of ER redox alterations, ER-stress-related signaling events (e.g., eIF2alpha, JNK, GADD153 phosphorylation), and glutathione levels.
  • Evaluation of apoptosis-inducing factor (AIF) translocation, mitochondrial depolarization, apoptotic index, and serum enzyme release.

Main Results:

  • Acetaminophen induced ER redox alterations and early ER-stress signaling, which were not affected by BGP-15.
  • BGP-15 effectively prevented AIF translocation from mitochondria to the nucleus and mitochondrial depolarization.
  • BGP-15 co-treatment significantly attenuated the rate of acetaminophen-induced cell death, as evidenced by reduced apoptotic index and lower serum enzyme levels.

Conclusions:

  • Acute acetaminophen toxicity triggers oxidative stress-mediated, caspase-independent cell death.
  • Inhibition of AIF translocation by BGP-15 offers significant protection against acetaminophen-induced liver injury.
  • Targeting AIF translocation represents a potential therapeutic strategy to mitigate acetaminophen hepatotoxicity.

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