Cytochrome P450-dependent metabolism of the anti-HIV drug nevirapine (NVP) to 12-hydroxy-NVP (12-OHNVP) has been implicated in NVP toxicities. We investigated the impact of twelfth-position trideuteration (12-D₃NVP) on the hepatic metabolism of and response to NVP. Formation of 12-OHNVP decreased in human (10.6-fold) and mouse (4.6-fold) hepatocytes incubated with 10 μM 12-D₃NVP vs NVP. An observed kinetic isotope effect of 10.1 was measured in human liver microsomes. During mouse hepatocyte treatment (400 μM) with NVP or 12-D₃NVP, cell death was reduced 30% with 12-D₃NVP vs NVP, while glucuronidated and glutathione-conjugated metabolites increased with 12-D₃NVP vs NVP. Using mass spectrometry proteomics, changes in hepatocyte protein expression, including an increase in stress marker insulin-like growth factor-binding protein 1 (IGFBP-1), were observed with 12-D₃NVP vs NVP. These results demonstrate that while deuteration can reduce P450 metabolite formation, impacts on phase II metabolism and hepatocyte protein expression should be considered when employing deuteration to reduce P450 metabolite-related hepatotoxicity.

中文翻译：

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奈韦拉平第十二位氘代减少了12-羟基-Nevirapine的形成和奈韦拉平诱导的肝细胞死亡。

抗HIV药物奈韦拉平（NVP）对12-羟基-NVP（12-OHNVP）的细胞色素P450依赖性代谢与NVP毒性有关。我们调查了十二位三氘化（12-D ₃ NVP）对NVP肝代谢和反应的影响。用10μM12-D ₃ NVP与NVP孵育的人（10.6倍）和小鼠（4.6倍）肝细胞中12-OHNVP的形成减少。在人肝微粒体中测得的动力学同位素效应为10.1。在小鼠肝细胞治疗（400μM）与NVP或12 d ₃ NVP，细胞死亡减少30％，12-d ₃ NVP VS NVP，而糖醛酸化，谷胱甘肽共轭的代谢产物具有12-d增加₃NVP与NVP。使用质谱蛋白质组学，使用12-D ₃ NVP vs NVP观察到肝细胞蛋白质表达的变化，包括应激标记胰岛素样生长因子结合蛋白1（IGFBP-1）的增加。这些结果表明，尽管氘化可以减少P450代谢物的形成，但在采用氘化降低P450代谢物相关的肝毒性时，应考虑对II期代谢和肝细胞蛋白表达的影响。