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Tacrine-induced Reactive Oxygen Species in a Human Liver Cell Line: The Role of Anethole Dithiolethione as a

R A Osseni1, C Debbasch, M O Christen

  • 1Unite de Pharmaco-Toxicologie Cellulaire, CHNO des XV-XX- 28, rue de Charenton, 75012 Paris, France.

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|July 27, 2010
PubMed

Insights

Tacrine (THA) causes liver injury by increasing reactive oxygen species (ROS) and depleting glutathione (GSH). A free radical scavenger, anethole dithiolethione (ADT), protected liver cells from THA toxicity in vitro.

Area of Science:

  • Hepatotoxicity and oxidative stress research.
  • Drug-induced liver injury mechanisms.
  • In vitro cell-based assays for toxicology.

Background:

  • Tacrine (THA) is used to treat Alzheimer's disease but can cause liver damage.
  • Mechanisms of THA hepatotoxicity are not fully understood.
  • Reactive oxygen species (ROS) overproduction and glutathione (GSH) depletion are implicated in drug toxicity.

Purpose of the Study:

  • To investigate if THA induces ROS production and GSH depletion in human liver cells (HepG2) at therapeutic concentrations.
  • To assess the protective effect of anethole dithiolethione (ADT), a free radical scavenger, against THA-induced liver cell injury.

Main Methods:

  • Utilized the human liver cell line HepG2.
  • Measured ROS production using 2',7'-dichlorofluorescin diacetate (DCFH-DA).
  • Quantified reduced glutathione (GSH) and cell viability using monochlorobimane (mBCl) and neutral red assays, respectively.
  • Employed microplate cytofluorimetry with cold light fluorimetry for sensitive detection in living cells.

Main Results:

  • THA caused a concentration-dependent increase in ROS production in HepG2 cells.
  • THA led to a significant decrease in intracellular GSH levels.
  • ADT (10-100 µM) protected HepG2 cells against THA-induced ROS stimulation and GSH depletion.

Conclusions:

  • Oxidative stress, characterized by increased ROS and GSH depletion, is a key mechanism in THA-induced cytotoxicity.
  • ADT demonstrates a protective effect against THA-induced liver cell injury in vitro.
  • These findings highlight the role of oxidative stress in THA toxicity and suggest ADT as a potential therapeutic agent.

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