Guidarelli A, Brambilla L, Rota C, Tomasi A, Cattabeni F, Cantoni O
Istituto di Farmacologia e Farmacognosia, Università di Urbino, Italy.
Biochem J. 1996 Jul 15;317 ( Pt 2)(Pt 2):371-5. doi: 10.1042/bj3170371.
Antimycin A at levels that abolish oxygen consumption had a slight, although statistically significant, inhibitory effect on the toxicity elicited by t-butylhydroperoxide in U937 cells. The protective effect was observed after 6 h of post-treatment incubation, but was no longer apparent after 24 h. Unexpectedly, these events were associated with a marked accumulation of DNA single-strand breaks produced by low levels of t-butylhydroperoxide. Both an oxygen- and a carbon-centred radical were found to arise during treatment with t-butylhydroperoxide, and their formation was significantly lowered by antimycin A. Thus inhibition of electron transport at the level of complex III appears (a) to decrease the formation of toxic species which mediate, at least partially, the lethal effects elicited by t-butylhydroperoxide, and (b) to enhance the formation of DNA-damaging species generated at low concentrations of t-butylhydroperoxide. Rotenone and cyanide, which respectively inhibit complexes I and IV, did not affect DNA damage elicited by t-butylhydroperoxide. These results suggest that DNA single-strand breaks do not mediate the toxicity of t-butylhydroperoxide, and that specific mitochondrial functions might modulate the formation of the toxic and of DNA-damaging species generated by organic hydroperoxides.
抗霉素A在消除氧气消耗的水平下，对叔丁基过氧化氢在U937细胞中引发的毒性具有轻微的抑制作用，尽管在统计学上具有显著意义。在处理后孵育6小时后观察到保护作用，但在24小时后不再明显。出乎意料的是，这些事件与低水平叔丁基过氧化氢产生的DNA单链断裂的显著积累有关。在叔丁基过氧化氢处理过程中发现同时产生了以氧为中心和以碳为中心的自由基，抗霉素A可显著降低它们的形成。因此，在复合体III水平上抑制电子传递似乎（a）减少了至少部分介导叔丁基过氧化氢致死效应的毒性物质的形成，（b）增强了低浓度叔丁基过氧化氢产生的DNA损伤物质的形成。分别抑制复合体I和复合体IV的鱼藤酮和氰化物，并不影响叔丁基过氧化氢引发的DNA损伤。这些结果表明，DNA单链断裂并不介导叔丁基过氧化氢的毒性，特定的线粒体功能可能会调节有机过氧化物产生的毒性物质和DNA损伤物质的形成。
