Hypochlorite-induced damage to nucleosides: Formation of chloramines and nitrogen-centered radicals
Hypochlorite-induced damage to nucleosides: Formation of chloramines and nitrogen-centered radicals
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DOI：
10.1021/tx010071r
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发表时间：
2001-08-01
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
受刺激的单核细胞和中性粒细胞通过释放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。由于慢性炎症和一些癌症之间有很强的联系，我们研究了HOCl2对DNA碱基的损伤。我们发现HOCl与胞苷、腺苷和鸟苷的外环-NH2基团以及所有碱的环NH基团反应生成氯胺(RNHCl/RR‘NCL)。这些是最初的主要产品。紫外线和金属离子可以加速氯胺的衰变，这些反应与热分解一起产生核苷衍生的以氮为中心的自由基。有证据表明，在另一种母体分子上，可以快速地将嘧啶衍生的氮心自由基加成，从而得到二聚体。核苷混合物的实验表明，形成自由基的倾向是胞苷和GT；腺苷=鸟苷和GT；尿苷=胸苷。这些数据与HOCl攻击的选择性和生成的氯胺的稳定性不一致，但如果碱之间的氯转移迅速并产生最稳定的氯胺，并且这种转移先于自由基的形成，则这些数据是合理的。因此，尽管胸腺嘧啶核苷是氯胺形成的主要起始部位，但快速的氯原子转移会产生胞苷和腺苷氯胺。这些反应使DNA中氯化胞苷和腺苷的优先形成合理化。
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 bases. We show that reaction of HOCl with the exocyclic -NH2 groups of cytidine, adenosine, and guanosine, and the ring NH groups of all bases, yields chloramines (RNHCl/RR ' NCl). These are the major initial products. Chloramine decay can be accelerated by UV light and metal ions, and these reactions, together with thermal decomposition, give rise to nucleoside-derived nitrogen-centered radicals. Evidence is presented for the rapid addition of pyrimidine-derived nitrogen-centered radicals to another parent molecule to give dimers. Experiments with nucleoside mixtures show that the propensity for radical formation is cytidine > adenosine = guanosine > uridine = thymidine. These data are inconsistent with the selectivity of HOCl attack and the stability of the resulting chloramines, but can be rationalized if chlorine transfer between bases is rapid and yields the most stable chloramine, with such transfer preceding radical formation. Thus, though thymidine is the major initial site of chloramine formation, rapid chlorine atom transfer generates cytidine and adenosine chloramines. These reactions rationalize the preferential formation of chlorinated cytidine and adenosine in DNA.