Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar, Punjab-160062, India.
Chem Res Toxicol. 2011 Jul 18;24(7):1113-22. doi: 10.1021/tx200110h. Epub 2011 Jun 21.
The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been performed to analyze the possible reaction pathways for the metabolism of the TGZ side chain, 6-hydroxy-2,2,5,7,8-pentamethylchromane (HPMC). From this analysis, a new pathway including oxidation at the C13 and C14 atoms of HPMC has been proposed for the formation of o-quinone methide (M2), while oxidation at the hydroxyl group leads to the formation of the quinone metabolite (M7). o-Quinone methide reactive metabolites have been shown to be more electrophilic at the reactive methylene center using quantum chemically estimated parameters.
曲格列酮（TGZ）的肝毒性归因于活性代谢物的形成，TGZ 的主要活性代谢物已被确认为邻醌亚甲基。也已知色烷部分的氧化会产生含有醌的代谢物。已进行量子化学研究来分析 TGZ 侧链 6-羟基-2,2,5,7,8-五甲基色烷（HPMC）代谢的可能反应途径。通过该分析，提出了一种新的途径，包括 HPMC 的 C13 和 C14 原子的氧化，以形成邻醌亚甲基（M2），而羟基的氧化导致醌代谢物（M7）的形成。使用量子化学估计的参数表明，邻醌亚甲基活性代谢物在反应性亚甲基中心具有更高的亲电性。
