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Phosphorylated troglitazone activates PPARgamma and inhibits vascular smooth muscle cell proliferation and

Peter J Little1, Mandy L Ballinger, Soniya Survase

  • 1Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia. peter.little@baker.edu.au

Journal of Cardiovascular Pharmacology
|March 22, 2008
PubMed

Insights

Phosphorylation of troglitazone to phosphoglitazone retains its PPARgamma agonist and antiatherogenic properties. This modification may reduce toxicity, offering a potential new therapy for insulin resistance and Type 2 diabetes.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Troglitazone, an alpha-tocopherol derivative, is an antidiabetic agent with known hepatotoxicity.
  • Phosphorylation of alpha-tocopherol can enhance antiatherogenic properties.

Purpose of the Study:

  • To investigate the effects of phosphorylating troglitazone on its pharmacological properties.
  • To assess phosphoglitazone's potential as a PPARgamma agonist and its ability to inhibit vascular smooth muscle cell (vSMC) proliferation and proteoglycan synthesis.

Main Methods:

  • PPARgamma activity was measured using a transfection assay.
  • vSMC proliferation was assessed via [3H]-thymidine incorporation and cell counting.
  • vSMC proteoglycan synthesis was evaluated using [35S]-sulfate incorporation.

Main Results:

  • Phosphoglitazone demonstrated full PPARgamma agonist activity, comparable to troglitazone.
  • Phosphoglitazone effectively inhibited vSMC proliferation and proteoglycan synthesis, similar to troglitazone.
  • Phosphorylation decreased troglitazone's lipophilicity.

Conclusions:

  • Phosphorylation preserves the pharmacological activity of troglitazone.
  • Phosphoglitazone shows potential for reduced toxicity compared to troglitazone.
  • Phosphorylated 2,4-thiazolidinedione derivatives warrant further investigation for treating insulin resistance and Type 2 diabetes.

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