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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

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Correlation between troglitazone cytotoxicity and drug metabolic enzyme activities in cryopreserved human hepatocytes

Nicola J Hewitt1, Scott Lloyd, Mike Hayden

  • 1In Vitro Technologies, Inc., 1450 South Rolling Road, Baltimore, MD 21227, USA. hewittn@invitrotech.com

Chemico-Biological Interactions
|October 26, 2002
PubMed

Insights

Troglitazone causes liver damage, but its mechanism is unclear. This study suggests that while Troglitazone and its sulfate are toxic, specific metabolic pathways like CYP3A4 oxidation and glucuronidation may detoxify the drug.

Area of Science:

  • Hepatotoxicity and Drug Metabolism
  • Pharmacology and Toxicology

Background:

  • Troglitazone (TRO), a former type II diabetes drug, was withdrawn due to severe liver damage.
  • The exact mechanism of TRO-induced idiosyncratic liver injury remains undetermined.
  • It is unclear if toxicity stems from TRO or its metabolites.

Purpose of the Study:

  • To investigate the role of xenobiotic metabolism in Troglitazone cytotoxicity.
  • To evaluate the correlation between human hepatocyte drug-metabolizing enzyme activities and TRO's EC50 values.

Main Methods:

  • Cytotoxicity of TRO was assessed in human hepatocytes from 27 donors using cellular adenosine triphosphate content as a viability endpoint.
  • Activities of major cytochrome P450 (CYP) isoforms (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4) and phase 2 enzymes (UGT, PST) were measured.
  • Correlation analysis was performed between individual and combined enzyme activities and TRO's EC50.

Main Results:

  • No single Phase 1 or Phase 2 enzyme activity correlated with TRO's EC50.
  • A significant correlation (r²=0.53) was observed when a combination of CYP3A4, UGT, and PST activities were considered: (CYP3A4 x UGT)/PST.
  • This suggests a complex interplay of metabolic pathways in TRO toxicity.

Conclusions:

  • The findings support a hypothesis that TRO and its sulfate metabolite are direct toxicants.
  • CYP3A4-mediated oxidation and UGT-mediated glucuronidation appear to be detoxification pathways for TRO.
  • Understanding these metabolic interactions is crucial for predicting and mitigating drug-induced liver injury.

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