Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats.
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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 alpha (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)-).
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| Authors | A J Meechan, C Henderson, C D Bates, M H Grant, J N A Tettey |
| Journal | The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 58 Issue 10 Pg. 1359-65 (Oct 2006) ISSN: 0022-3573 [Print] England |
| PMID | 17034659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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