Kohler James J, Lewis William
Department of Pathology, Emory University, Atlanta, Georgia.
Environ Mol Mutagen. 2007 Apr-May;48(3-4):166-72. doi: 10.1002/em.20223.
Nucleoside reverse transcriptase inhibitors (NRTIs) in combinations with other antiretrovirals (highly active antiretroviral therapy, HAART) are the cornerstones of AIDS therapy, turning HIV infection into a manageable clinical entity. Despite the initial positive impact of NRTIs, therapeutic experience revealed serious side effects that appeared to originate in the mitochondria and which ultimately manifested as dysfunction of that organelle. It may be reasonable to consider that as the AIDS epidemic continues and as survival with HIV infection is prolonged by treatment with HAART, long-term side effects of NRTIs may become increasingly common. This consideration may be underscored in children who are born to HIV-infected mothers who received NRTI therapy in utero during gestation. The long-term effect of that NRTI exposure in utero is not clear yet. This review examines some proposed mechanisms of NRTI mitochondrial toxicity, including genetic predisposition, defects in mitochondria DNA replication, the encompassing "DNA pol-gamma hypothesis," the relationship between mitochondrial nucleotide and NRTI pools, mitochondrial DNA mutation and dysfunction, and oxidative stresses related to HIV infection and NRTIs. Mechanisms of mitochondrial toxicity are reviewed with respect to key cell biological, pathological, and pharmacological events.
核苷类逆转录酶抑制剂（NRTIs）与其他抗逆转录病毒药物联合使用（高效抗逆转录病毒治疗，HAART）是艾滋病治疗的基石，使HIV感染转变为一种可控制的临床病症。尽管NRTIs最初产生了积极影响，但治疗经验显示出严重的副作用，这些副作用似乎起源于线粒体，最终表现为该细胞器的功能障碍。可以合理地认为，随着艾滋病疫情的持续以及通过HAART治疗延长HIV感染者的生存期，NRTIs的长期副作用可能会越来越普遍。这种考虑在感染HIV的母亲在孕期子宫内接受NRTI治疗所生的儿童中可能更为突出。子宫内接触NRTI的长期影响尚不清楚。本综述探讨了一些关于NRTI线粒体毒性的提出机制，包括遗传易感性、线粒体DNA复制缺陷、涵盖的“DNA聚合酶γ假说”、线粒体核苷酸与NRTI库之间的关系、线粒体DNA突变与功能障碍，以及与HIV感染和NRTIs相关的氧化应激。关于关键的细胞生物学、病理学和药理学事件，对线粒体毒性机制进行了综述。
