Synergistic induction of DNA strand breakage caused by nitric oxide together with catecholamine: implications for neurodegenerative disease.
Synergistic induction of DNA strand breakage caused by nitric oxide together with catecholamine: implications for neurodegenerative disease.
复制标题
一氧化氮与儿茶酚胺协同诱导 DNA 链断裂：对神经退行性疾病的影响。
DOI：
--
复制
发表时间：
1997
影响因子：
4.1
通讯作者：
H. Ohshima
中科院分区：
文献类型：
--
作者：
Y. Yoshie;H. Ohshima
神经元细胞和 DNA 的氧化损伤与各种神经退行性疾病的发病机制有关。我们已经证明，当质粒 DNA 在释放 NO 的化合物（二乙胺 NONOate、精胺 NONOate、硝普钠）和儿茶酚胺（例如 L-DOPA、多巴胺等）存在下孵育时，会协同诱导 DNA 链断裂。释放一氧化氮的化合物或单独的儿茶酚胺引起的链断裂要少得多。酪氨酸和酪胺以及多巴和多巴胺的O-甲基化衍生物在NO存在下不发挥这种协同作用。 NO 加多巴胺诱导的 DNA 链断裂受到羧基-PTIO（NO 和可能的其他自由基的捕获剂）、超氧化物歧化酶和抗氧化剂（如 N-乙酰半胱氨酸和抗坏血酸）的抑制，但不受 H2O 的抑制。清除剂，例如二甲亚砜、乙醇和D-甘露醇。这些结果表明游离 H2O。不参与；相反，NO 和儿茶酚胺之间反应形成的新氧化剂可能是导致 DNA 链断裂的原因。我们认为其中一个负责的化合物是过氧亚硝酸盐（ONOO-），它是一种强氧化剂和硝化剂，由 NO 和 O2.- 反应形成。 NO 已被证明可以氧化儿茶酚胺形成醌衍生物，从而通过醌/氢醌氧化还原系统产生 O2.-。 O2.- 然后与 NO 快速反应形成过氧亚硝酸盐。然而，其他化合物（例如儿茶酚胺和 NO 产生的 NOx）也可能导致 DNA 损伤。我们的研究结果表明，多巴胺能神经元中形成的儿茶酚胺与小胶质细胞或星形胶质细胞形成的NO或同一神经元细胞内产生的两种化合物之间存在协同相互作用，产生一种有效的氧化剂，可引起细胞和DNA损伤，从而在各种神经退行性疾病的发病机制中发挥重要作用。
Oxidative damage in neuronal cells and DNA has been implicated in the pathogenesis of various neurodegenerative diseases. We have demonstrated that DNA strand breakage is induced synergistically when plasmid DNA is incubated in the presence of both an NO-releasing compound (diethylamine NONOate, spermine NONOate, sodium nitroprusside) and a catecholamine (e.g., L-DOPA, dopamine, etc.). Either an NO-releasing compound or a catecholamine alone induced much fewer strand breaks. Tyrosine and tyramine as well as O-methylated derivatives of DOPA and dopamines did not exert this synergistic effect in the presence of NO. The DNA strand breakage induced by NO plus dopamine was inhibited by carboxy-PTIO (a trapping agent of NO and possibly other radicals), superoxide dismutase, and antioxidants such as N-acetylcysteine and ascorbate but not by HO. scavengers such as dimethyl sulfoxide, ethanol, and D-mannitol. These results suggest that the free HO. is not involved; rather a new oxidant(s) formed by the reaction between NO and catecholamine could be responsible for causing the DNA strand breakage. We propose that one of the responsible compounds is peroxynitrite (ONOO-), which is a strong oxidant and nitrating agent formed by the reaction between NO and O2.-. NO has been shown to oxidize catecholamines to form quinone derivatives, which lead to the generation of O2.- by the quinone/hydroquinone redox system. O2.- then reacts rapidly with NO to form peroxynitrite. However, it is also possible that other compounds such as NOx generated from catecholamines and NO may cause DNA damage. Our results implicate a synergistic interaction of catecholamines formed in dopaminergic neurons and NO formed by microglia or astrocytes or the two compounds produced within the same neuronal cells to produce a potent oxidant(s) which could cause damage in cells and DNA, thus playing an important role in the pathogenesis of various neurodegenerative diseases.