Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats.
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)-).
Meechan
A J
AJ
Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK.
Henderson
C
C
Bates
C D
CD
Grant
M H
MH
Tettey
J N A
JN
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D045162:Thiazolidinediones / Q000378:metabolism*; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D013311:Streptozocin; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D005978:Glutathione; D000077288:Troglitazone