Dalakas M C
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1382, USA.
J Peripher Nerv Syst. 2001 Mar;6(1):14-20. doi: 10.1046/j.1529-8027.2001.006001014.x.
Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.
接受核苷类似物逆转录酶抑制剂（NRTIs）治疗的患者在长期治疗后会出现不同程度的肌病或神经病变。齐多夫定（AZT）可导致肌病；扎西他滨（ddC）、去羟肌苷（ddI）和拉米夫定（3TC）可导致神经病变；司他夫定（d4T）和氟尿苷（FIAU）可导致神经病变或肌病以及乳酸性酸中毒。负责NRTIs磷酸化的磷酸化酶的组织分布与其选择性组织毒性有关。肌病的特征为肌肉萎缩、肌痛、疲劳、无力以及肌酸激酶升高。神经病变表现为疼痛、感觉性和轴索性。在体外，NRTIs抑制负责线粒体DNA（mtDNA）复制的γ-DNA聚合酶，并导致mtDNA功能障碍。在体内，接受研究最多的NRTI即AZT治疗的患者会出现线粒体肌病，伴有mtDNA耗竭、细胞色素氧化酶（复合体IV）缺乏、细胞内脂肪蓄积、高乳酸生成以及明显的磷酸肌酸耗竭，这是通过体内磁共振波谱测定的，原因是氧化磷酸化受损。用NRTIs处理的动物或培养细胞会出现神经病变、肌病或细胞破坏，线粒体也有类似变化。有证据表明，与NRTI相关的神经病变也归因于线粒体毒性。NRTIs（AZT、ddC、ddI、d4T、3TC）含有叠氮基，这些叠氮基可与天然三磷酸胸苷竞争作为DNA聚合酶γ的底物，并终止mtDNA合成。相比之下，含有3'-羟基的FIAU可作为三磷酸胸苷与DNA聚合酶γ的替代底物，并被掺入DNA中，导致永久性mtDNA功能障碍。NRTI诱导的线粒体功能障碍会影响这些药物的临床应用，尤其是在高剂量使用和联合使用时。它们在人类中产生了一类新的获得性线粒体毒素，可导致类似于遗传性线粒体疾病的临床表现。
