Hypochlorite-induced damage to DNA, RNA, and polynucleotides: Formation of chloramines and nitrogen-centered radicals
Hypochlorite-induced damage to DNA, RNA, and polynucleotides: Formation of chloramines and nitrogen-centered radicals
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DOI：
10.1021/tx015548d
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发表时间：
2002-01-01
影响因子：
4.1
通讯作者：
Davies, MJ
中科院分区：
文献类型：
--
作者：
Hawkins, CL;Davies, MJ
刺激的单核细胞和中性粒细胞通过释放酶髓过氧化物酶和过氧化氢产生次氯酸盐（HOCl）。HOCl是一种关键的杀菌剂，但也会损害宿主组织。由于慢性炎症和某些癌症之间存在密切联系，我们研究了HOCl对DNA、RNA和多核苷酸的损伤。HOCl与这些物质的反应显示出产生多个半稳定的氯胺（RNHCl/RR`NCl），它们是主要的初始产物，并且占所加入的HOCl的50-95%。这些氯胺通过热和金属离子催化过程衰变，产生核苷衍生的、氮中心的自由基。后者的特征在于EPR自旋捕获：与多核苷酸形成自由基的倾向是胞苷>腺苷=鸟苷>尿苷=胸苷。衰变速率和形成的自由基的产率取决于它们形成的核碱基的性质，由环杂环胺基团形成的氯胺比在环外胺（RNH 2基团）上形成的氯胺更不稳定。有证据表明，氯转移从前者，动力学上有利的，网站的更cubically有利的环外胺。EPR实验也提供了嘧啶衍生的氮中心自由基与其他核碱基快速加成以产生二聚体和DNA被来自预先形成的核苷氯胺的自由基氧化的证据。HOCl与质粒DNA的直接反应通过氯胺介导的反应引起单链和双链断裂。预先形成的核苷氯胺也诱导质粒裂解，虽然这只发生在不稳定的胸苷和尿苷衍生的氯胺，其中自由基的形成是快速的显着程度。总的来说，这些数据合理化了DNA中优先形成氯化的2 '-脱氧胞苷和2'-脱氧腺苷，并表明HOCl和预先形成的氯胺诱导的DNA损伤发生在序列特异性位点。
Stimulated monocytes and neutrophils generate hypochlorite (HOCl) via the release of the enzyme myeloperoxidase and hydrogen peroxide. HOCl is a key bactericidal agent, but can also damage host tissue. As there is a strong link between chronic inflammation and some cancers, we have investigated HOCl damage to DNA, RNA, and polynucleotides. Reaction of HOCl with these materials is shown to yield multiple semistable chloramines (RNHCl/RR`NCl), which are the major initial products, and account for 50-95% of the added HOCl These chloramines decay by thermal and metal-ion catalyzed processes, to give nucleoside-derived, nitrogen-centered, radicals. The latter have been characterized by EPR spin trapping: The propensity for radical formation with polynucleotides is cytidine > adenosine = guanosine > uridine = thymidine. The rates of decay, and yield of radicals formed, are dependent on the nature of the nucleobase on which they are formed, with chloramines formed from ring heterocyclic amine groups being less stable than those formed on exocyclic amines (RNH2 groups). Evidence is presented for chlorine transfer from the former, kinetically favored, sites to the more thermodynamically favored exocyclic amines. EPR experiments have also provided evidence for the rapid addition of pyrimidine-derived nitrogen-centered radicals to other nucleobases to give dimers and the oxidation of DNA by radicals derived from preformed nucleoside chloramines. Direct reaction of HOCl with plasmid DNA gives rise to single- and double-strand breaks via chloramine-mediated reactions. Preformed nucleoside chloramines also induce plasmid cleavage, though this only occurs to a significant extent with unstable thymidine- and uridine-derived chloramines, where radical formation is rapid. Overall the data rationalize the preferential formation of chlorinated 2'-deoxycytidine and 2'-deoxyadenosine in DNA and suggest that DNA damage induced by HOCl, and preformed chloramines, occurs at sequence-specific sites.