Thiazolidinedione bioactivation:: A comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry
Thiazolidinedione bioactivation:: A comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry
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DOI：
10.1021/tx050353h
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发表时间：
2006-08-21
影响因子：
4.1
通讯作者：
Paehler, Axel
中科院分区：
文献类型：
--
作者：
Alvarez-Sanchez, Ruben;Montavon, Francois;Paehler, Axel
曲格列酮是一种用于治疗糖尿病的噻唑烷二酮(TZD)型胰岛素增敏剂，在发生几起致命的肝毒性病例后，已从美国市场撤出。虽然这些特殊不良反应的机制(S)还不完全清楚，但间接证据表明，至少部分是反应性代谢物的形成所致。尽管有肝毒性的孤立病例报道，但TZD的其他衍生物吡格列酮和罗格列酮相对安全。在此，我们报道了这些药物及其TZD环同位素标记的2-N-15-3，4，5-C-13(3)类似物在添加谷胱甘肽(GSH)的大鼠和人肝微粒体中的生物激活潜力。用液相色谱-串联质谱法筛选GSH加合物作为反应中间体形成的替代标志物。GSH结合物的化学表征是通过获取它们各自的产物离子光谱以及比较未标记和稳定同位素标记的TZD衍生物来进行的。这些数据表明，所有药物都通过TZD环上共同的代谢激活过程进行生物活化，产生二硫键类型的GSH偶联物，TZD部分标记位置的丢失证明了这一点。导致GSH加合物不涉及TZD环断裂的其他生物激活过程对于曲格列酮来说是明显的。在低底物浓度的人肝微粒体中，只有曲格列酮产生了一个不涉及TZD环断裂的主要GSH加合物。这一性质可能与其他因素，如相对较高的剂量以及它诱导肝脏胆汁淤积和氧化应激的可能性一起，导致该药物的肝毒性。
Troglitazone, a thiazolidinedione (TZD) type insulin sensitizer for the treatment of diabetes, was withdrawn from the U.S. market after several fatal cases of hepatotoxicity. Although the mechanism(s) of these idiosyncratic adverse reactions are not completely understood, circumstantial evidence suggests at least a partial contribution of reactive metabolite formation. Despite isolated case reports of hepatotoxicity, the other TZD derivatives pioglitazone and rosiglitazone are comparatively safe. Herein, we report on the bioactivation potential of these drugs and their TZD ring isotope-labeled 2-N-15-3,4,5-C-13(3) analogues in rat and human liver microsomes supplemented with glutathione (GSH). Screening for GSH adducts as surrogate markers for reactive intermediate formation was performed by liquid chromatography tandem mass spectrometry. Chemical characterization of the GSH conjugates was conducted by acquisition of their respective product ion spectra and the comparison between unlabeled and stable isotope-labeled TZD derivatives. The data suggest that all drugs undergo bioactivation processes via a common metabolic activation on the TZD ring, yielding disulfide type GSH conjugates as evidenced by the loss of labeled positions in the TZD moiety. Additional bioactivation processes leading to GSH adducts not involving TZD ring scission were evident for troglitazone. In human liver microsomes at low substrate concentrations, only troglitazone yielded a predominant GSH adduct not involving TZD ring scission. This property may contribute, together with other factors such as the relatively high dose administered as well as its potential to induce hepatic cholestasis and oxidative stress, to the hepatotoxicity of this drug.