...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Digestive Diseases and Sciences >Differential Effects of Nucleoside Analogs on Oxidative Phosphorylation in Human Pancreatic Cells
【24h】

Differential Effects of Nucleoside Analogs on Oxidative Phosphorylation in Human Pancreatic Cells

机译：核苷类似物对人胰腺细胞氧化磷酸化的差异作用

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Although nucleoside analogs as a group inhibit mtDNA replication, individually they target specific organs for toxicity. For example, dideoxyinosine(ddI) is most closely associated with clinical pancreatitis and dideoxycytosine (ddC) with peripheral neuropathy. Comparison of the differential effects of these analogs on mitochondrial function in relevant human cell lines could provide general clues as to the mechanisms of their differential toxicity. We compared the effects of ddI [and its intracellular metabolite dideoxyadenosine (ddA)], with other nucleoside analogs ddC, Azidothymidine (AZT) and didehydrodeoxythymidine(d4T) on mtDNA elongation, cytotoxicity, oxidative phosphorylation, and cellular ATP concentration in a human pancreatic cell line, Capan-1 cells. AZT, like all the other analogs tested, altered mtDNA elongation, but had no other effect on these cells. Both ddC and d4T, but not ddI (20 μm and 50 μM), reduced total dish protein (a measure of cell numbers) in cells grown to confluence. The effect of ddA was intermediate. All (except AZT) increased lactate concentration in the cell culture medium. Dideoxycytosine (ddC) and d4T did not significantly affect cell oxygen consumption, expressed as a fraction of total dish protein. By contrast, ddI and ddA reduced basal and/or FCCP-stimulated oxygen consumption. %Dideoxycytosine (ddC) but not ddI or ddA (50 μM) was cytotoxic to cells after six days of growth. Nevertheless, the ATP content (expressed as a fraction of surviving cells) for ddC-, ddI-, and ddA-treated cells was similar to control cells. Cytotoxicity was apparent for ddI, ddA, as well as ddC after seven days. Paradoxically, cell ATP content was now significantly higher than control cells. Electron microscopy of cells treated with ddI confirmed significant ultrastructural changes affecting the inner mitochondria membrane and cristae. In conclusion, these data suggest that nucleoside analogs uniformly induce damage to mtDNA. However, the mitochondrial phenotypic damage induced by ddI and ddA appear to result in less Capan-1 cytotoxicity than ddC and d4T. The link between these differential effects and ddI pancreatitis is unclear.
机译：尽管核苷类似物作为一个整体抑制mtDNA复制，但它们各自针对特定器官具有毒性。例如，双脱氧肌苷（ddI）与临床胰腺炎关系最密切，而双脱氧胞嘧啶（ddC）与周围神经病密切相关。比较这些类似物对相关人类细胞系中线粒体功能的差异作用，可以提供有关其差异毒性机理的一般线索。我们比较了ddI [及其细胞内代谢产物双脱氧腺苷（ddA）]与其他核苷类似物ddC，叠氮胸苷（AZT）和双脱氢胸苷（d4T）对人胰腺细胞中mtDNA延伸，细胞毒性，氧化磷酸化和细胞ATP浓度的影响线，Capan-1细胞。像测试的所有其他类似物一样，AZT改变了mtDNA的延伸，但对这些细胞没有其他影响。 ddC和d4T都降低了培养到汇合的细胞中的总碟状蛋白（一种细胞数量的度量值），但ddI（20μm和50μM）却没有降低。 ddA的作用中等。所有细胞因子（AZT除外）均增加了细胞培养基中的乳酸浓度。脱氧胞嘧啶（ddC）和d4T并未显着影响细胞耗氧量，表示为总培养皿蛋白的一部分。相反，ddI和ddA减少了基础和/或FCCP刺激的耗氧量。生长六天后，％Dideoxycytosine（ddC）而非ddI或ddA（50μM）对细胞具有细胞毒性。但是，ddC-，ddI-和ddA处理的细胞的ATP含量（表示为存活细胞的分数）与对照细胞相似。七天后，ddI，ddA和ddC的细胞毒性明显。矛盾的是，现在细胞中的ATP含量明显高于对照细胞。用ddI处理的细胞的电子显微镜检查证实，明显的超微结构变化会影响线粒体内膜和cr。总之，这些数据表明核苷类似物均一地诱导对mtDNA的破坏。但是，由ddI和ddA诱导的线粒体表型损伤似乎比ddC和d4T导致的Capan-1细胞毒性更小。这些差异作用与ddI胰腺炎之间的联系尚不清楚。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号