Centre for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, PO. Box 330 440, 28334, Bremen, Germany.
Neurochem Res. 2014 May;39(5):883-92. doi: 10.1007/s11064-014-1284-4. Epub 2014 Mar 25.
Antiretroviral protease inhibitors are crucial components of the antiretroviral combination therapy that is successfully used for the treatment of patients with HIV infection. To test whether such protease inhibitors affect the glutathione (GSH) metabolism of neurons, cultured cerebellar granule neurons were exposed to indinavir, nelfinavir, lopinavir or ritonavir. In low micromolar concentrations these antiretroviral protease inhibitors did not acutely compromise the cell viability, but caused a time- and concentration-dependent increase in the accumulation of extracellular GSH which was accompanied by a matching loss in cellular GSH. The stimulating effect by indinavir, lopinavir and ritonavir on GSH export was immediately terminated upon removal of the protease inhibitors, while the nelfinavir-induced stimulated GSH export persisted after washing the cells. The stimulation of neuronal GSH export by protease inhibitors was completely prevented by MK571, an inhibitor of the multidrug resistance protein 1, suggesting that this transporter mediates the accelerated GSH export during exposure of neurons to protease inhibitors. These data suggest that alterations in brain GSH metabolism should be considered as potential side-effects of a treatment with antiretroviral protease inhibitors.
抗逆转录病毒蛋白酶抑制剂是抗逆转录病毒联合疗法的重要组成部分，该疗法成功用于治疗 HIV 感染患者。为了测试这些蛋白酶抑制剂是否会影响神经元的谷胱甘肽 (GSH) 代谢，培养的小脑颗粒神经元暴露于茚地那韦、奈非那韦、洛匹那韦或利托那韦中。在低微摩尔浓度下，这些抗逆转录病毒蛋白酶抑制剂不会急性损害细胞活力，但会导致细胞外 GSH 积累的时间和浓度依赖性增加，同时细胞内 GSH 相应减少。当去除蛋白酶抑制剂时，茚地那韦、洛匹那韦和利托那韦对 GSH 输出的刺激作用立即终止，而在洗涤细胞后，奈非那韦诱导的刺激 GSH 输出仍然存在。多药耐药蛋白 1 的抑制剂 MK571 完全阻止了蛋白酶抑制剂对神经元 GSH 输出的刺激，表明该转运蛋白介导了神经元暴露于蛋白酶抑制剂时 GSH 输出的加速。这些数据表明，在考虑用抗逆转录病毒蛋白酶抑制剂治疗时，应考虑大脑 GSH 代谢的改变作为潜在的副作用。
