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Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells

Y Yamamoto1, M Nakajima, H Yamazaki

  • 1Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.

Life Sciences
|January 19, 2002
PubMed

Insights

Troglitazone, an antidiabetic drug, can cause liver injury by inducing apoptotic cell death in hepatocytes. This mechanism, linked to its metabolite M-3, may explain its toxicity in humans.

Area of Science:

  • Hepatology
  • Pharmacology
  • Toxicology

Background:

  • Troglitazone is an antidiabetic drug used for non-insulin-dependent diabetes mellitus.
  • Previous reports indicate troglitazone can cause severe hepatic injury in some individuals.

Purpose of the Study:

  • To investigate the mechanism of troglitazone-induced liver injury.
  • To examine the role of troglitazone metabolites in hepatotoxicity.

Main Methods:

  • Human hepatoma HepG2 cells were incubated with troglitazone and its metabolites (M-1, M-2, M-3).
  • Cytotoxicity and apoptosis were assessed.
  • Other thiazolidinediones (pioglitazone, rosiglitazone) were used for comparison.

Main Results:

  • Troglitazone demonstrated time- and concentration-dependent cytotoxicity.
  • Metabolite M-3 (quinone) showed weak cytotoxicity.
  • Troglitazone induced apoptotic cell death, characterized by DNA fragmentation and nuclear condensation.
  • Pioglitazone and rosiglitazone did not induce cell death or apoptosis.

Conclusions:

  • Troglitazone induces apoptotic hepatocyte death, potentially contributing to liver injury in humans.
  • The induction of apoptosis by troglitazone may not be related to its affinity for PPARgamma.
  • Metabolite M-3 might play a role in troglitazone's hepatotoxicity.

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