Gan Jinping, Qu Qinling, He Bing, Shyu Wen C, Rodrigues A David, He Kan
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543, USA.
Drug Metab Lett. 2008 Aug;2(3):184-9. doi: 10.2174/187231208785425773.
Troglitazone (TGZ) induced hepatotoxicity has been linked to cytochrome P450 (CYP)-catalyzed reactive metabolite formation. Therefore, the kinetics and CYP specificity of reactive metabolite formation were studied using dansyl glutathione (dGSH) as a trapping agent after incubation of TGZ with human liver microsomes (HLM) and recombinant human CYP proteins. CYP2C8 exhibited the highest rate of TGZ adduct (TGZ-dGS) formation, followed by CYP3A4, CYP3A5, and CYP2C19. The involvement of CYP2C8 and CYP3A4 was confirmed with CYP form-selective chemical inhibitors. The impact of TGZ concentration on the rate of TGZ-dGS formation was also evaluated. In this instance, two distinctly different profiles were observed with recombinant CYP3A4 and CYP2C8. It is concluded that both CYP3A4/5 and CYP2C8 play a major role in the formation of TGZ adduct in HLM. However, the contribution of these CYPs varies depending on their relative expression and the concentration of TGZ.
曲格列酮（TGZ）诱导的肝毒性与细胞色素P450（CYP）催化的活性代谢物形成有关。因此，在将TGZ与人肝微粒体（HLM）和重组人CYP蛋白孵育后，使用丹磺酰谷胱甘肽（dGSH）作为捕获剂研究了活性代谢物形成的动力学和CYP特异性。CYP2C8表现出最高的TGZ加合物（TGZ-dGS）形成速率，其次是CYP3A4、CYP3A5和CYP2C19。用CYP形式选择性化学抑制剂证实了CYP2C8和CYP3A4的参与。还评估了TGZ浓度对TGZ-dGS形成速率的影响。在这种情况下，重组CYP3A4和CYP2C8观察到两种明显不同的情况。得出的结论是，CYP3A4/5和CYP2C8在HLM中TGZ加合物的形成中都起主要作用。然而，这些CYP的贡献因它们的相对表达和TGZ的浓度而异。
