Studies on the Metabolism of Troglitazone to Reactive Intermediates in Vitro and in Vivo. Evidence for Novel Biotransformation Pathways Involving Quinone Methide Formation and Thiazolidinedione Ring S
详细信息 查看全文
- 作者：Kelem Kassahun ; Paul G. Pearson ; Wei Tang ; Ian McIntosh ; Kwan Leung ; Charles Elmore ; Dennis Dean ; Regina Wang ; George Doss ; and Thomas A. Baillie
- 刊名：Chemical Research in Toxicology
- 出版年：2001
- 出版时间：January 2001
- 年：2001
- 卷：14
- 期：1
- 页码：62 - 70
- 全文大小：135K
- 年卷期：v.14,no.1(January 2001)
- ISSN：1520-5010
文摘
Therapy with the oral antidiabetic agent troglitazone (Rezulin) has been associated withcases of severe hepatotoxicity and drug-induced liver failure, which led to the recent withdrawalof the product from the U.S. market. While the mechanism of this toxicity remains unknown,it is possible that chemically reactive metabolites of the drug play a causative role. In an effortto address this possibility, this study was undertaken to determine whether troglitazoneundergoes metabolism in human liver microsomal preparations to electrophilic intermediates.Following incubation of troglitazone with human liver microsomes and with cDNA-expressedcytochrome P450 isoforms in the presence of glutathione (GSH), a total of five GSH conjugates(M1-M5) were detected and identified tentatively by LC-MS/MS analysis. In two cases (M1and M5), the structures of the adducts were confirmed by NMR spectroscopy and/or bycomparison with an authentic standard prepared by synthesis. The formation of GSH conjugatesM1-M5 revealed the operation of two distinct metabolic activation pathways for troglitazone,one of which involves oxidation of the substituted chromane ring system to a reactive o-quinonemethide derivative, while the second involves a novel oxidative cleavage of the thiazolidinedione(TZD) ring, potentially generating highly electrophilic 
-ketoisocyanate and sulfenic acidintermediates. When troglitazone was administered orally to a rat, samples of bile were foundto contain GSH conjugates which reflected the operation of these same metabolic pathways invivo. The finding that metabolism of the TZD ring of troglitazone was catalyzed selectively byP450 3A enzymes is significant in light of the recent report that troglitazone is an inducer ofthis isoform in human hepatocytes. The implications of these results are discussed in the contextof the potential for troglitazone to covalently modify hepatic proteins and to cause oxidativestress through redox cycling processes, either of which may play a role in drug-induced liverinjury.
-ketoisocyanate and sulfenic acidintermediates. When troglitazone was administered orally to a rat, samples of bile were foundto contain GSH conjugates which reflected the operation of these same metabolic pathways invivo. The finding that metabolism of the TZD ring of troglitazone was catalyzed selectively byP450 3A enzymes is significant in light of the recent report that troglitazone is an inducer ofthis isoform in human hepatocytes. The implications of these results are discussed in the contextof the potential for troglitazone to covalently modify hepatic proteins and to cause oxidativestress through redox cycling processes, either of which may play a role in drug-induced liverinjury.