Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats

A.J. Meechan, C. Henderson, Catharine D. Bates, M.H. Grant, J.N.A. Tettey

Research output: Contribution to journalArticle

2 Citations (Scopus)

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)−).
Original languageEnglish
Pages (from-to)1359-1365
Number of pages6
JournalJournal of Pharmacy and Pharmacology
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 2006

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troglitazone
Hepatocytes
Type 2 Diabetes Mellitus
Cytochromes b5
Glucuronides
Streptozocin
Glutathione Transferase
Hypoglycemic Agents
Cytochrome P-450 Enzyme System
Glutathione
Half-Life
Fats

Keywords

  • 4-thiazolidinedione antidiabetic agent
  • Troglitazone
  • hepa-totoxicity
  • isolated hepatocytes

Cite this

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title = "Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats",
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)−).",
keywords = "4-thiazolidinedione antidiabetic agent, Troglitazone , hepa-totoxicity , isolated hepatocytes",
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Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats. / Meechan, A.J.; Henderson, C.; Bates, Catharine D.; Grant, M.H.; Tettey, J.N.A.

In: Journal of Pharmacy and Pharmacology, Vol. 58, No. 10, 10.2006, p. 1359-1365.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metabolism of troglitazone in hepatocytes isolated from experimentally induced diabetic rats

AU - Meechan, A.J.

AU - Henderson, C.

AU - Bates, Catharine D.

AU - Grant, M.H.

AU - Tettey, J.N.A.

PY - 2006/10

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N2 - 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)−).

AB - 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)−).

KW - 4-thiazolidinedione antidiabetic agent

KW - Troglitazone

KW - hepa-totoxicity

KW - isolated hepatocytes

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DO - 10.1211/jpp.58.10.0009

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