Identification of glutathione conjugates of troglitazone in human hepatocytes

• Published in: Chemico-biological interactions 2002-11, Vol.142 (1), p.83-97
• Main Authors: Prabhu, Saileta, Fackett, Andrew, Lloyd, Scott, McClellan, Holly A, Terrell, Chris M, Silber, Paul M, Li, Albert P
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Chromans - metabolism; Chromans - toxicity; Chromatography, Liquid; Cryopreserved; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Female; Glucuronides - metabolism; Glutathione; Glutathione - analogs & derivatives; Glutathione - metabolism; Hepatocytes; Hepatocytes - metabolism; Humans; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - toxicity; Isoenzymes; Male; Mass Spectrometry; Metabolism; Middle Aged; Sulfates - metabolism; Thiazoles - metabolism; Thiazoles - toxicity; Thiazolidinediones; Troglitazone
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/S0009-2797(02)00056-X

Troglitazone (TGZ) is an orally active antihyperglycemic agent used in the treatment of noninsulin-dependent diabetes mellitus. Several cases of liver failure following TGZ administration led to its withdrawal from the market. The mechanism of toxicity is still not understood. The formation of toxic metabolites is believed to play an important role. Herein, we report the biotransformation of TGZ in human hepatocytes. TGZ at 50 μM concentration was incubated with cryopreserved human hepatocytes. Four metabolites were found—glucuronide, sulfate, and two glutathione (GSH) conjugates of TGZ. The two GSH metabolites could be conjugation at the 6-hydroxychromane nucleus and the thiazolidinedione ring. Alternatively, the conjugation could be one of the two rings, with the two GSH metabolites are diastereomers. The sulfate conjugate was the major metabolite found. The cytochrome P450 (CYP) inhibitors furafylline (CYP1A1/2), omeprazole (CYP2C19), ketoconazole (CYP3A4), and sulfaphenazole (CYP2C9) had no inhibitory effect on the TGZ metabolism suggesting that several P450s may play a role in the TGZ metabolic pathway. Previous studies in our laboratory have shown a large interindividual variation between different donors in cytotoxicity after dosing with TGZ. Based on EC 50 values, donors were classified as sensitive or resistant. The sensitive human donors were found to form significantly less troglitazone GSH conjugates and glucuronides than the resistant donors.