Enzyme-Induction Dependent Bioactivation of Troglitazone and Troglitazone Quinone In Vivo
详细信息 查看全文
- 作者：Justice N. Tettey ; James L. Maggs ; W. Garth Rapeport ; Munir Pirmohamed ; and B. Kevin Park
- 刊名：Chemical Research in Toxicology
- 出版年：2001
- 出版时间：August 2001
- 年：2001
- 卷：14
- 期：8
- 页码：965 - 974
- 全文大小：119K
- 年卷期：v.14,no.8(August 2001)
- ISSN：1520-5010
文摘
Troglitazone (TGZ), a 2,4-thiazolidinedione antidiabetic, causes hepatotoxicity in 1.9% ofpatients. TGZ is an inducer of, and substrate for, hepatic P450 3A. Microsomal metabolismyields a benzoquinone (TGZQ) and reactive intermediates. Kassahun et al. [Kassahun et al.(2001) Chem. Res. Toxicol. 14, 62-70] have trapped the intermediates as thioester, thioether,and disulfide conjugates of glutathione and found five conjugates in rat bile. The thioetherwas substituted in the chromane moiety. We have investigated the effect of the P450 3A inducer,dexamethasone (DEX), on metabolism of TGZ and TGZQ in rats and assessed the compounds'cytotoxicity. TGZ-glucuronide and sulfonate were confirmed as principal biliary metabolitesof TGZ (50 mg/kg, iv). Bile from noninduced animals also contained a TGZ-glutathione thioetheradduct (ML3) but it was substituted in the thiazolidinedione moiety. Pretreatment with DEX(50 mg/kg/day for 3 days) resulted in a 2-5-fold increase in the biliary concentration of ML3and a 2-fold increase in the concentration of TGZQ, which was commensurate with the inductionof hepatic P450 3A. Three of the known glutathione-conjugated metabolites were also found.TGZQ (50 mg/kg, iv) was metabolized to an analogue of one of the TGZ-glutathione thioestersand a glutathione adduct of TGZQ hydroquinone after DEX pretreatment. TGZ quinolglucuronide was a biliary metabolite of TGZ and TGZQ. Its formation would representdeactivation of TGZQ. TGZ was toxic to rat hepatocytes and Hep-G2 cells at concentrationsexceeding 50 and 25 
M, respectively, after 24 h. In contrast, TGZQ was nontoxic to rathepatocytes and toxic to Hep G2 cells only at concentrations exceeding 100 M. Our resultsshow that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation isenhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to eitherTGZQ or its metabolites.
M, respectively, after 24 h. In contrast, TGZQ was nontoxic to rathepatocytes and toxic to Hep G2 cells only at concentrations exceeding 100 M. Our resultsshow that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation isenhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to eitherTGZQ or its metabolites.