MASSIVE CONVERSION OF GUANOSINE TO 8-HYDROXY-GUANOSINE IN MOUSE-LIVER MITOCHONDRIAL-DNA BY ADMINISTRATION OF AZIDOTHYMIDINE
MASSIVE CONVERSION OF GUANOSINE TO 8-HYDROXY-GUANOSINE IN MOUSE-LIVER MITOCHONDRIAL-DNA BY ADMINISTRATION OF AZIDOTHYMIDINE
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DOI：
10.1016/0006-291x(91)90893-c
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发表时间：
1991-04-15
影响因子：
3.1
通讯作者：
OZAWA, T
中科院分区：
文献类型：
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作者：
HAYAKAWA, M;OGAWA, T;OZAWA, T
据报道，在许多接受长期azidothymidine （AZT）治疗的艾滋病患者中表达了典型的线粒体肌病，因此我们检测了给予AZT 4周后小鼠肝脏线粒体DNA （mtDNA）的变化。即使低于给药剂量的1 / 10 （AZT， 1 mg/kg/天），总脱氧鸟苷（dG）也有25%转化为8-羟基脱氧鸟苷（8-OH-dG）。在AZT 5 mg/kg/d的作用下，总dG转化为8-OH-dG的比例为38%。体外，通过在含NADH和KCN的线粒体内膜氧自由基生成系统中培养mtDNA，证实了dG向8-OH-dG的转化。由此得出结论，由于缺乏修复系统，AZT损伤的mtDNA导致线粒体呼吸链受损，产生负责8-OH-dG形成的氧自由基。这些结果表明，线粒体dna的氧损伤是AZT治疗线粒体肌病的主要原因。
As typical mitochondrial myopathy has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy, we examined changes in mouse liver mitochondrial DNA (mtDNA) after 4-week administration of AZT. Even below 1 10 th the dose given to the patients (AZT, 1 mg/kg/day), 25% of the total deoxyguanosine (dG) was converted to be 8-hydroxy-deoxyguanosine (8-OH-dG). 38% of the total dG was converted to 8-OH-dG with AZT 5 mg/kg/day. In vitro, the conversion of dG to 8-OH-dG was demonstrated by incubating mtDNA in the oxygen radical producing system containing NADH and KCN treated mitochondrial inner membrane. Thus it is concluded that, by lack of repairing system, damaged mtDNA with AZT results in impaired mitochondrial respiratory chain causing oxygen radicals which are responsible for 8-OH-dG formation. These results suggest that the oxygen damage of mtDNA is the primary cause of mitochondrial myopathy with AZT therapy.