Troglitazone selectively inhibits glyoxalase I gene expression

Diabetologia. 2001 Nov;44(11):2004-12. doi: 10.1007/s001250100004.

Abstract

Aims/hypothesis: The hyperglycaemia associated with diabetes causes excessive production of cytotoxic methylglyoxal, an alpha-oxo-aldehyde. The glyoxalase system, composed of glyoxalase I and glyoxalase II, with glutathione (GSH) as the cofactor, plays an important role in the detoxification of alpha-oxo-aldehydes. We tested the hypothesis that troglitazone, an insulin-sensitizing drug previously used in the treatment of Type II (non-insulin-dependent) diabetes mellitus, up-regulates the glyoxalase system either by increasing phase 2 enzyme activities and thereby increasing cellular GSH, or, by inducing glyoxalase enzyme activities.

Methods: Human astroglial cells, rat hepatocytes and cardiac myocytes were cultured and exposed to either troglitazone, or tertiary-butylhydroquinone (tBHQ, a phase 2 enzyme inducer). Glutathione content, advanced glycation end products (AGEs) and enzyme (glyoxalase I, glyoxalase II as well as the phase 2 enzymes, glutathione S-transferase and thioredoxin reductase) activities were determined. Glyoxalase I mRNA was also measured.

Results: Troglitazone had no effect on cellular GSH nor phase 2 enzyme activities but significantly reduced the activities of glyoxalase I and II; this inhibitory effect was concentration-dependent and time-dependent and was associated with reduced mRNA contents and increased AGEs formation. Rosiglitazone had no effect on glyoxalase I gene expression. tBHQ, a classic phase 2 enzyme inducer, had no effect on the glyoxalase system but did increase glutathione contents and the activities of glutathione S-transferase and thioredoxin reductase.

Conclusion/interpretation: Our study shows that troglitazone is a selective inhibitor of the glyoxalase system. This inhibition of the glyoxalase system could contribute to troglitazone's hepatotoxic action which has previously been reported in a small percentage of individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Astrocytoma
  • Cell Culture Techniques / methods
  • Cells, Cultured
  • Chromans / pharmacology*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glutathione / metabolism
  • Hepatocytes / enzymology*
  • Humans
  • Hydroquinones / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • Kinetics
  • Lactoylglutathione Lyase / genetics*
  • Liver / enzymology
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Thiolester Hydrolases / genetics
  • Time Factors
  • Troglitazone
  • Tumor Cells, Cultured

Substances

  • Antioxidants
  • Chromans
  • Hydroquinones
  • Hypoglycemic Agents
  • Thiazoles
  • Thiazolidinediones
  • 2-tert-butylhydroquinone
  • Thiolester Hydrolases
  • hydroxyacylglutathione hydrolase
  • Lactoylglutathione Lyase
  • Glutathione
  • Troglitazone