Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Avda. Blasco Ibáñez n.15-17, 46010 Valencia, Spain.
Curr Pharm Des. 2011;17(20):2130-44. doi: 10.2174/138161211796904731.
The combined antiretroviral therapeutic approach currently employed for the treatment of HIV infection, known as Higly Active Antiretroviral Therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, the adverse reactions associated with the long term use of this therapy have now become a major issue and researchers have focused on understanding the cellular mechanisms underlying these drug-induced detrimental effects which englobe a large list of different events including rash and hypersensibility reactions, hepatotoxicity, metabolic disturbances including lipodystrophy, and other metabolic syndrome-like disturbances such as hyperlactatemia, hyperlipedimia, insulin resistance and pancreatitis. Other events include CNS toxic effects, peripheral neuropathies as well as nephrotoxicity and increased risk of cardiovascular diseases. Many of these reactions have been shown to develop as e result of mitochondrial dysfunction. The mitochondrial effect of N(t)RTI (Nucleos(t)ide Reverse Transcriptase Inhibitors) class of drugs, which has been widely studied, is believed to originate from the inhibitory action of these drugs on DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA. However, additional mitochondrial targets have also been described and need to be considered. As to NNRTI (Non-Nucleoside-Transcriptase Inhibitor) or PI (Protease Inhibitors), evidence of the implication of mitochondria has also been reported, however the details of the mechanisms underlying these actions are still not fully known. This review covers the current knowledge of mitochondrial toxicities, particularly the available in vitro evidence, regarding the most commonly used groups of HIV drugs. Novel findings of mtDNA-independent mitochondrial dysfunction have received special attention.
目前用于治疗 HIV 感染的联合抗逆转录病毒治疗方法，即高效抗逆转录病毒疗法（HAART），显著降低了与艾滋病相关的发病率和死亡率。然而，长期使用这种疗法所带来的不良反应已成为一个主要问题，研究人员专注于了解这些药物引起的有害作用的细胞机制，这些作用包括一系列不同的事件，包括皮疹和过敏反应、肝毒性、代谢紊乱，包括脂肪营养不良，以及其他代谢综合征样紊乱，如高乳酸血症、高脂血症、胰岛素抵抗和胰腺炎。其他事件包括中枢神经系统毒性作用、周围神经病以及肾毒性和心血管疾病风险增加。许多这些反应已被证明是由于线粒体功能障碍而发生的。已广泛研究的 N(t)RTI（核苷酸逆转录酶抑制剂）类药物的线粒体作用被认为源于这些药物对 DNA 聚合酶γ的抑制作用，该酶负责线粒体 DNA 的复制。然而，也已经描述了其他线粒体靶点，需要加以考虑。至于 NNRTI（非核苷类转录酶抑制剂）或 PI（蛋白酶抑制剂），也有报道称线粒体受到影响，但这些作用的机制细节仍不完全清楚。这篇综述涵盖了线粒体毒性的最新知识，特别是关于最常用的 HIV 药物组的体外证据。特别关注了 mtDNA 非依赖性线粒体功能障碍的新发现。
