PEROXYNITRITE-INDUCED MEMBRANE LIPID-PEROXIDATION - THE CYTOTOXIC POTENTIAL OF SUPEROXIDE AND NITRIC-OXIDE
PEROXYNITRITE-INDUCED MEMBRANE LIPID-PEROXIDATION - THE CYTOTOXIC POTENTIAL OF SUPEROXIDE AND NITRIC-OXIDE
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DOI：
10.1016/0003-9861(91)90224-7
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发表时间：
1991-08-01
影响因子：
3.9
通讯作者：
FREEMAN, BA
中科院分区：
文献类型：
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作者：
RADI, R;BECKMAN, JS;FREEMAN, BA
内皮细胞、巨噬细胞、嗜中性粒细胞和神经元细胞产生超氧化物（O2−）和一氧化氮（·NO），它们可以联合收割机形成过氧亚硝酸根阴离子（ONOO−）。已知过氧亚硝酸盐氧化巯基并产生指示羟基自由基（·OH）与脱氧核糖和二甲亚砜反应的产物，本文显示其诱导膜脂质过氧化。过氧亚硝酸盐添加到大豆磷脂酰胆碱脂质体导致丙二醛和共轭二烯的形成，以及氧消耗。脂质过氧化作用在酸性和中性pH值更大，没有显着的脂质过氧化作用发生在pH值9.5以上。添加亚铁（Fe+2）或三价铁（Fe+3）铁并没有增强脂质过氧化物的形成，可归因于单独的过氧亚硝酸盐。二乙烯四胺五乙酸（DTPA）或通过离子交换色谱法从溶液中去除铁可使共轭二烯的形成减少25- 50%。铁没有发挥重要作用，在启动脂质过氧化反应，因为DTPA和铁耗尽的反应系统，只有部分抑制。相比之下，去铁胺具有更大的浓度依赖性抑制作用，在200 μm处完全消除脂质过氧化作用。去铁胺对脂质过氧化的强烈抑制作用是由于它除了与铁螯合作用外，还与过氧亚硝酸直接反应。我们得出结论，过氧亚硝酸盐的共轭酸，过氧亚硝酸（ONOOH），和/或其分解产物，即，·OH和二氧化氮（·NO2），在不需要铁的情况下启动脂质过氧化。这些观察结果证明了O2−和·NO介导的细胞毒性的潜在机制。
Endothelial cells, macrophages, neutrophils, and neuronal cells generate superoxide (O2−) and nitric oxide (·NO) which can combine to form peroxynitrite anion (ONOO−). Peroxynitrite, known to oxidize sulfhydryls and to yield products indicative of hydroxyl radical (·OH) reaction with deoxyribose and dimethyl sulfoxide, is shown herein to induce membrane lipid peroxidation. Peroxynitrite addition to soybean phosphatidylcholine liposomes resulted in malondialdehyde and conjugated diene formation, as well as oxygen consumption. Lipid peroxidation was greater at acidic and neutral pH, with no significant lipid peroxidation occurring above pH 9.5. Addition of ferrous (Fe+2) or ferric (Fe+3) iron did not enhance lipid peroxide formation over that attributable to peroxynitrite alone. Diethylenetetraminepentacetic acid (DTPA) or iron removal from solutions by ion-exchange chromatography decreased conjugated diene formation by 25–50%. Iron did not play an essential role in initiating lipid peroxidation, since DTPA and iron depletion of reaction systems were only partially inhibitory. In contrast, desferrioxamine had an even greater concentration-dependent inhibitory effect, completely abolishing lipid peroxidation at 200 μm. The strong inhibitory effect of desferrioxamine on lipid peroxidation was due to direct reaction with peroxynitrous acid in addition to iron chelation. We conclude that the conjugate acid of peroxynitrite, peroxynitrous acid (ONOOH), and/or its decomposition products, i.e., ·OH and nitrogen dioxide (·NO2), initiate lipid peroxidation without the requirement of iron. These observations demonstrate a potential mechanism contributing to O2−- and ·NO-mediated cytotoxicity.