Kohler James J, Hosseini Seyed H
Department of Pediatrics, Laboratory of Biochemical Pharmacology, Emory University School of Medicine, Decatur, GA, USA.
Methods Mol Biol. 2011;755:267-77. doi: 10.1007/978-1-61779-163-5_22.
Nucleoside reverse transcriptase inhibitors (NRTIs) are drugs used in the treatment of HIV/AIDS. Despite the distinct benefits of NRTI-based therapies, tissue specific toxicity is a limiting factor. Although the mechanisms of these specific antiretroviral drug-related toxicities remain unclear, it has been hypothesized that as analogs to native nucleosides, NRTIs may potentially inhibit mammalian DNA polymerases, including mitochondrial DNA (mtDNA) polymerase γ. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog of adenosine monophosphate and the only NRTI that is associated with renal disease. The inherent heterogeneity of kidney tissues could affect the outcome and interpretation of molecular studies to define the mechanism(s) of tenofovir tubular toxicity. Laser-capture microdissection (LCM) provided a specific, single-cell isolation of proximal tubules from fixed heterogeneous kidney tissues. LCM-captured renal proximal tubules from transgenic mice (TGs) showed decreased mtDNA abundance with tenofovir, demonstrating a subcellular specific mitochondrial toxicity of tenofovir in an AIDS model.
核苷类逆转录酶抑制剂（NRTIs）是用于治疗HIV/AIDS的药物。尽管基于NRTIs的疗法有明显益处，但组织特异性毒性是一个限制因素。虽然这些特定抗逆转录病毒药物相关毒性的机制仍不清楚，但据推测，作为天然核苷的类似物，NRTIs可能会抑制哺乳动物DNA聚合酶，包括线粒体DNA（mtDNA）聚合酶γ。替诺福韦酯（TDF）是单磷酸腺苷的核苷酸类似物，也是唯一与肾脏疾病相关的NRTI。肾组织固有的异质性可能会影响确定替诺福韦肾小管毒性机制的分子研究结果及解读。激光捕获显微切割（LCM）可从固定的异质性肾组织中特异性地分离出近端小管单个细胞。从转基因小鼠（TGs）中通过LCM捕获的肾近端小管显示，使用替诺福韦后mtDNA丰度降低，这在艾滋病模型中证明了替诺福韦具有亚细胞特异性线粒体毒性。
