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The Strathprints institutional repository is a digital archive of University of Strathclyde research outputs.

Strathprints serves world leading Open Access research by the University of Strathclyde, including research by the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), where research centres such as the Industrial Biotechnology Innovation Centre (IBioIC), the Cancer Research UK Formulation Unit, SeaBioTech and the Centre for Biophotonics are based.

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Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats

Meechan, A.J. and Henderson, C. and Bates, Catharine D. and Grant, M.H. and Tettey, J.N.A. (2006) Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats. Journal of Pharmacy and Pharmacology, 58 (10). pp. 1359-1365. ISSN 0022-3573

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Abstract

Troglitazone (TGZ), the prototype 2,4-thiazolidinedione antidiabetic agent, is associated with hepatotoxicity in patients with Type 2 diabetes. Although the mechanism of toxicity has not been established, alterations in the clearance of TGZ from in-vitro hepatocyte cultures through metabolic conjugation reactions are believed to modulate the toxicity of the compound. In this study, the metabolism of TGZ in freshly isolated hepatocytes from the fat-fed streptozotocin-treated rat model of Type 2 diabetes is described. Biochemical parameters such as cellular reduced glutathione content, content of cytochromes P450 and b5, and the expression of glutathione-S-transferase α (subunits Ya and Yc2) were not affected by the induced diabetes. TGZ was metabolized primarily to a sulfonate, a quinone and a glucuronide in both control and experimentally diabetic animals. However, metabolism after induction of diabetes was characterized by a moderate increase in sulfation, a decrease in the elimination half-life of TGZ and the absence of the minor metabolites of TGZ, notably the glutathione adduct of the putative reactive intermediate (m/z = 747 (M + H)+; m/z = 745 (M - H)−).