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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)−).

Item type: Article
ID code: 28463
Keywords: 4-thiazolidinedione antidiabetic agent, Troglitazone , hepa-totoxicity , isolated hepatocytes , Bioengineering, Engineering (General). Civil engineering (General), Pharmaceutical Science, Pharmacology
Subjects: Technology > Engineering (General). Civil engineering (General) > Bioengineering
Technology > Engineering (General). Civil engineering (General)
Department: Faculty of Engineering > Bioengineering
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences > Pharmaceutical Sciences
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Ms Ashley Urie
    Date Deposited: 23 Oct 2010 14:08
    Last modified: 05 Sep 2014 04:46
    URI: http://strathprints.strath.ac.uk/id/eprint/28463

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