Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death.
Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death.
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DOI：
10.1021/acs.jmedchem.9b01990
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发表时间：
2020-06-25
影响因子：
7.3
通讯作者：
Bumpus NN
中科院分区：
文献类型：
--
作者：
Heck CJS;Seneviratne HK;Bumpus NN
抗HIV药物奈韦拉平（NVP）代谢为12-羟基-NVP（12-OHNVP）的细胞色素P450依赖性代谢与NVP毒性有关。我们研究了十二位三氘代（12-D3 NVP）对NVP肝脏代谢和反应的影响。与NVP相比，用10 μM 12-D3 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。在用NVP或12-D3 NVP处理小鼠肝细胞（400 μM）期间，与NVP相比，12-D3 NVP使细胞死亡减少30%，而与NVP相比，12-D3 NVP使葡萄糖醛酸化和谷胱甘肽结合代谢产物增加。使用质谱蛋白质组学，观察到12-D3 NVP与NVP相比肝细胞蛋白表达的变化，包括应激标志物胰岛素样生长因子结合蛋白1（IGFBP-1）的增加。这些结果表明，虽然氘化可以减少P450代谢产物的形成，但在采用氘化降低P450代谢产物相关的肝毒性时，应考虑对II相代谢和肝细胞蛋白表达的影响。
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.
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来自抗HIV药物奈韦拉平的2'-脱氧胸苷加合物。
DOI：
10.3390/molecules18054955
发表时间：
2013-04-26
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Antunes AM;Wolf B;Oliveira MC;Beland FA;Marques MM
通讯作者：
Marques MM
影响因子：
2.9
作者：
Kim, Donghak;Cha, Gun-Su;Nagy, Leslie D.;Yun, Chul-Ho;Guengerich, F. Peter
通讯作者：
Guengerich, F. Peter
影响因子：
4.6
作者：
Buyse, Sophie;Vibert, Eric;Duclos-Vallee, Jean-Charles
通讯作者：
Duclos-Vallee, Jean-Charles
影响因子：
2.1
作者：
Harjivan, Shrika G.;Pinheiro, Pedro F.;Antunes, Alexandra M. M.
通讯作者：
Antunes, Alexandra M. M.
影响因子：
2.9
作者：
Chowdhury G;Calcutt MW;Nagy LD;Guengerich FP
通讯作者：
Guengerich FP