Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut, USA
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00691-18. Print 2018 Sep.
Efavirenz (EFV), the most popular nonnucleoside reverse transcriptase inhibitor, has been associated with mitochondrial dysfunction in most studies. However, in real life the prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the agents given in combination with EFV moderate the effect of EFV on mitochondrial function. To test this hypothesis, we cultured a human T lymphoblastoid cell line (CEM cells) with EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis. There was a statistically significant concentration- and time-dependent apoptosis, reduction in mitochondrial membrane potential, and increase in production of reactive oxygen species in cells treated with either EVF alone or in combination with TDF plus FTC. Compared to dimethyl sulfoxide-treated cells, EFV-treated cells had significant reduction in oxygen consumption rate contributed by basal mitochondrial respiration and decreased protein expression of electron transport chain complexes (CI, CII, and CIV). Treatment with EFV resulted in a decrease in mitochondrial DNA content and perturbation of more coding genes ( = 13); among these were 11 genes associated with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. Interestingly, combining TDF and FTC with EFV did not alter the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-induced mitochondrial toxicity in and studies could be due to individual differences in the pharmacokinetics of EFV.
依非韦伦（EFV）是最常用的非核苷类逆转录酶抑制剂，大多数研究均表明其与线粒体功能障碍有关。然而，在实际生活中，EFV 引起的线粒体毒性的发生率相对较低。我们假设与 EFV 联合使用的药物会调节 EFV 对线粒体功能的影响。为了验证这一假设，我们培养了一株人 T 淋巴母细胞系（CEM 细胞），并用 EFV 单独以及与恩曲他滨（FTC）和富马酸替诺福韦二吡呋酯（TDF）联合用药来研究其对线粒体呼吸和功能以及胆固醇生物合成的影响。结果显示，无论是单独使用 EFV 还是联合使用 TDF 和 FTC，细胞均会出现统计学上显著的浓度和时间依赖性凋亡、线粒体膜电位降低以及活性氧生成增加。与 DMSO 处理的细胞相比，EFV 处理的细胞基础线粒体呼吸的耗氧量显著降低，电子传递链复合物（CI、CII 和 CIV）的蛋白表达减少。EFV 处理导致线粒体 DNA 含量减少和更多编码基因（=13）的扰动；其中包括 11 个与脂质或胆固醇生物合成相关的基因。我们的研究结果支持越来越多的关于 EFV 对线粒体呼吸和功能以及胆固醇生物合成的影响的知识。有趣的是，与 EFV 联合使用 TDF 和 FTC 并未改变 EFV 对线粒体呼吸和功能以及胆固醇生物合成的影响。这与临床研究中 EFV 引起的线粒体毒性的流行率之间的差距可能是由于 EFV 药代动力学的个体差异所致。
