Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
Br J Pharmacol. 2010 Aug;160(8):2069-84. doi: 10.1111/j.1476-5381.2010.00866.x.
Efavirenz (EFV) is widely used in the treatment of HIV-1 infection. Though highly efficient, there is growing concern about EFV-related side effects, the molecular basis of which remains elusive.
In vitro studies were performed to address the effect of clinically relevant concentrations of EFV (10, 25 and 50 microM) on human hepatic cells.
Cellular proliferation and viability were reduced in a concentration-dependent manner. Analyses of the cell cycle and several cell death parameters (chromatin condensation, phosphatidylserine exteriorization, mitochondrial proapoptotic protein translocation and caspase activation) revealed that EFV triggered apoptosis via the intrinsic pathway. In addition, EFV directly affected mitochondrial function in a reversible manner, inducing a decrease in mitochondrial membrane potential and an increase in mitochondrial superoxide production, followed by a reduction in cellular glutathione content. The rapidity of these actions rules out any involvement of mitochondrial DNA replication, which, until now, was thought to be the main mechanism of mitochondrial toxicity of antiretroviral drugs. Importantly, we also observed an increase in mitochondrial mass, manifested as an elevated cardiolipin content and enhanced expression of mitochondrial proteins, which was not paralleled by an increase in the mtDNA/nuclear DNA copy number ratio. The toxic effect of EFV was partially reversed by antioxidant pretreatment, which suggests ROS generation is involved in this effect.
Clinically relevant concentrations of EFV were shown to be mitotoxic in human hepatic cells in vitro, which may be pertinent to the understanding of the hepatotoxicity associated with this drug.
依非韦伦（EFV）广泛用于治疗 HIV-1 感染。尽管其非常有效，但人们越来越关注与 EFV 相关的副作用，但其分子基础仍难以捉摸。
进行了体外研究，以解决临床相关浓度的 EFV（10、25 和 50μM）对人肝细胞的影响。
细胞增殖和活力呈浓度依赖性降低。细胞周期和几种细胞死亡参数（染色质浓缩、磷脂酰丝氨酸外翻、线粒体促凋亡蛋白易位和半胱天冬酶激活）的分析表明，EFV 通过内在途径触发细胞凋亡。此外，EFV 以可逆的方式直接影响线粒体功能，诱导线粒体膜电位降低和线粒体超氧化物产生增加，随后导致细胞谷胱甘肽含量减少。这些作用的快速性排除了线粒体 DNA 复制的任何参与，到目前为止，线粒体 DNA 复制被认为是抗逆转录病毒药物线粒体毒性的主要机制。重要的是，我们还观察到线粒体质量增加，表现为心磷脂含量升高和线粒体蛋白表达增强，而 mtDNA/核 DNA 拷贝数比值没有增加。抗氧化预处理部分逆转了 EFV 的毒性作用，这表明 ROS 的产生与此作用有关。
体外研究表明，临床相关浓度的 EFV 对人肝细胞具有线粒体毒性，这可能与理解该药物相关的肝毒性有关。
