Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz
Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz
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DOI：
10.1093/jac/dku262
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发表时间：
2014-11-01
影响因子：
5.2
通讯作者：
Esplugues, Juan V.
中科院分区：
文献类型：
--
作者：
Blas-Garcia, Ana;Polo, Miriam;Esplugues, Juan V.
越来越多的证据表明非核苷类逆转录酶抑制剂依法韦仑与几种不良事件有关。较新的抗逆转录病毒药物，如整合酶抑制剂雷特格韦、非核苷逆转录酶抑制剂利匹韦林和蛋白酶抑制剂地瑞那韦，声称具有比依法韦仑更好的毒理学特征，同时产生相似水平的疗效和病毒学抑制。本研究的目的是通过评价这三种新型抗逆转录病毒药物对肝细胞和神经元中依法韦仑改变的线粒体和细胞参数的影响来确定其体外毒理学特征。使用标准细胞生物学技术评估了线粒体功能、细胞毒性以及氧化和内质网应激的参数。这些新化合物都没有改变肝细胞或神经元的线粒体功能，而依法韦仑降低了两种细胞类型的线粒体膜电位，并增加了超氧化物的产生，已知这些作用会显著损害线粒体功能、细胞活力，并最终影响肝细胞或神经元的功能。手机号在四种药物中，依法韦仑是唯一一种改变LC 3-II（自噬的指标）和CHOP（内质网应激和未折叠蛋白反应的标志物）蛋白表达的药物。达芦那韦、利匹韦林和雷特格韦对Hep 3B细胞和原代大鼠神经元不产生毒性作用，这表明依法韦仑比依法韦仑更安全的肝脏和神经系统特征。
Growing evidence associates the non-nucleoside reverse transcriptase inhibitor efavirenz with several adverse events. Newer antiretrovirals, such as the integrase inhibitor raltegravir, the non-nucleoside reverse transcriptase inhibitor rilpivirine and the protease inhibitor darunavir, claim to have a better toxicological profile than efavirenz while producing similar levels of efficacy and virological suppression. The objective of this study was to determine the in vitro toxicological profile of these three new antiretrovirals by evaluating their effects on the mitochondrial and cellular parameters altered by efavirenz in hepatocytes and neurons.Hep3B cells and primary rat neurons were treated with clinically relevant concentrations of efavirenz, darunavir, rilpivirine or raltegravir. Parameters of mitochondrial function, cytotoxicity and oxidative and endoplasmic reticulum stress were assessed using standard cell biology techniques.None of the new compounds altered the mitochondrial function of hepatic cells or neurons, while efavirenz decreased mitochondrial membrane potential and enhanced superoxide production in both cell types, effects that are known to significantly compromise the functioning of mitochondria, cell viability and, ultimately, cell number. Of the four drugs assayed, efavirenz was the only one to alter the protein expression of LC3-II, an indicator of autophagy, and CHOP, a marker of endoplasmic reticulum stress and the unfolded protein response.Darunavir, rilpivirine and raltegravir do not induce toxic effects on Hep3B cells and primary rat neurons, which suggests a safer hepatic and neurological profile than that of efavirenz.