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Identification of glutathione conjugates of troglitazone in human hepatocytes

Saileta Prabhu1, Andrew Fackett, Scott Lloyd

  • 1In Vitro Technologies, Inc., 1450 South Rolling Road, Baltimore, MD 21202, USA.

Chemico-Biological Interactions
|October 26, 2002
PubMed

Insights

Troglitazone (TGZ) metabolism in human hepatocytes produced glucuronide, sulfate, and glutathione conjugates. Sensitive individuals formed fewer TGZ glutathione conjugates, suggesting a role in toxicity.

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Metabolism

Background:

  • Troglitazone (TGZ) is an antihyperglycemic agent withdrawn due to liver failure.
  • The precise mechanism of TGZ-induced toxicity remains unclear.
  • Metabolite formation is a suspected contributor to TGZ toxicity.

Purpose of the Study:

  • To investigate the biotransformation of Troglitazone (TGZ) in human hepatocytes.
  • To identify and characterize TGZ metabolites.
  • To explore the role of cytochrome P450 enzymes in TGZ metabolism.

Main Methods:

  • Incubation of TGZ with cryopreserved human hepatocytes at 50 microM.
  • Analysis of TGZ metabolites using chromatographic and spectroscopic techniques.
  • Assessment of TGZ metabolism in the presence of cytochrome P450 inhibitors.

Main Results:

  • Four TGZ metabolites were identified: glucuronide, sulfate, and two glutathione (GSH) conjugates.
  • Sulfate conjugate was the predominant metabolite.
  • Cytochrome P450 inhibitors did not significantly affect TGZ metabolism.
  • Sensitive individuals produced lower levels of TGZ GSH and glucuronide conjugates compared to resistant individuals.

Conclusions:

  • Human hepatocytes metabolize TGZ into sulfate, glucuronide, and GSH conjugates.
  • The lack of inhibition by CYP inhibitors suggests a complex metabolic pathway.
  • Reduced GSH and glucuronide conjugate formation in sensitive individuals may be linked to TGZ toxicity.

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