Myeloperoxidase-induced Genomic DNA-centered Radicals
Myeloperoxidase-induced Genomic DNA-centered Radicals
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DOI：
10.1074/jbc.m109.086579
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发表时间：
2010-06-25
影响因子：
4.8
通讯作者：
Ramirez, Dario C.
中科院分区：
文献类型：
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作者：
Gomez-Mejiba, Sandra E.;Zhai, Zili;Ramirez, Dario C.
髓过氧化物酶（MPO）由活化的中性粒细胞释放，可以启动和促进肿瘤的发生。MPO产生次氯酸（HOCl），其氧化炎性细胞以及周围上皮细胞中的基因组DNA。以DNA为中心的自由基是DNA氧化过程中形成的早期中间体。一旦形成，以DNA为中心的自由基通过尚不完全了解的机制衰变，产生许多氧化产物，这些产物被研究为DNA氧化的标志物。在这项研究中，我们采用了5，5-二甲基-1-吡咯啉N-氧化物为基础的免疫自旋捕获技术，以调查MPO触发的DNA为中心的自由基在炎症和上皮细胞的形成，并测试是否白藜芦醇块HOCl诱导的DNA为中心的自由基在这些细胞中的形成。我们发现，外源性加入的HOCl或由已被细胞摄取的MPO或由新合成的MPO在细胞内产生的HOCl在细胞内产生以DNA为中心的自由基。我们还发现，白藜芦醇通过细胞膜和清除HOCl之前，它与基因组DNA反应，从而阻止DNA为中心的自由基的形成。总之，我们的研究结果表明，细胞内MPO形成的DNA为中心的自由基可能是一个有用的点，治疗干预炎症诱导的癌变。
Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis.