Reactions of desferrioxamine with peroxynitrite-derived carbonate and nitrogen dioxide radicals
Reactions of desferrioxamine with peroxynitrite-derived carbonate and nitrogen dioxide radicals
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DOI：
10.1016/j.freeradbiomed.2003.10.011
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发表时间：
2004-02-15
影响因子：
7.4
通讯作者：
Radi, R
中科院分区：
文献类型：
--
作者：
Bartesaghi, S;Trujillo, M;Radi, R
铁螯合剂去铁胺抑制过氧亚硝酸盐介导的氧化，并在体外和体内减弱一氧化氮和氧自由基依赖的氧化损伤。保护机制是独立的铁螯合作用，在过去的十年中仍然难以捉摸。在此，停流研究表明，去铁胺不直接与过氧亚硝酸盐反应。然而，在不存在和存在生理浓度的CO2的情况下以及在过量的亚硝酸盐下，将过氧亚硝酸盐添加到去铁胺导致形成单电子氧化产物，去铁胺氮氧自由基，这与去铁胺与过氧亚硝酸盐衍生的物质碳酸盐（CO 3.-）反应一致。和二氧化氮（（NO2）-N-.）根的去铁胺抑制过氧亚硝酸盐依赖的自由基介导的过程，包括酪氨酸二聚化和硝化，氧合血红蛋白氧化在CO2的存在下，和过氧亚硝酸盐加碳酸盐依赖的化学发光。谷胱甘肽的直接双电子氧化过氧亚硝酸盐是不受去铁胺。脱铁胺与CO 3.-的反应和（NO2）-N-。脉冲辐解研究明确证实了这一点，其二级速率常数分别为1.7 x 10（9）和7.6 x 10（6）M-1 s（-1）。去铁胺也与酪氨酰自由基反应，k= 6.3 x 10（6）M-1 s（-1）。然而，酪氨酰自由基之间或酪氨酰自由基与（NO2）-N-的自由基/自由基结合反应。胜过与去铁胺的反应，计算机辅助模拟表明，对酪氨酸氧化的抑制可以通过清除过氧亚硝酸盐衍生的自由基来完全解释。本文所示的结果提供了一种替代机制，以解释去铁胺通过与CO 3反应的一些生物化学和药理学作用。和（NO2）-N-。根的(C)2004年爱思唯尔公司All rights reserved.
The iron chelating agent desferrioxamine inhibits peroxynitrite-mediated oxidations and attenuates nitric oxide and oxygen radical-dependent oxidative damage both in vitro and in vivo. The mechanism of protection is independent of iron chelation and has remained elusive over the past decade. Herein, stopped-flow studies revealed that desferrioxamine does not react directly with peroxynitrite. However, addition of peroxynitrite to desferrioxamine in both the absence and the presence of physiological concentrations of CO2 and under excess nitrite led to the formation of a one-electron oxidation product, the desferrioxamine nitroxide radical, consistent with desferrioxamine reacting with the peroxynitrite-derived species carbonate (CO3.-) and nitrogen dioxide ((NO2)-N-.) radicals. Desferrioxamine inhibited peroxynitrite-dependent free radical-mediated processes, including tyrosine dimerization and nitration, oxyhemoglobin oxidation in the presence of CO2, and peroxynitrite plus carbonate-dependent chemiluminescence. The direct two-electron oxidation of glutathione by peroxynitrite was unaffected by desferrioxamine. The reactions of desferrioxamine with CO3.- and (NO2)-N-. were unambiguously confirmed by pulse radiolysis studies, which yielded second-order rate constants of 1.7 x 10(9) and 7.6 x 10(6) M-1 s(-1), respectively. Desferrioxamine also reacts with tyrosyl radicals with k= 6.3 x 10(6) M-1 s(-1). However, radical/radical combination reactions between tyrosyl radicals or of tyrosyl radical with (NO2)-N-. outcompete the reaction with desferrioxamine and computer-assisted simulations indicate that the inhibition of tyrosine oxidation can be fully explained by scavenging of the peroxynitrite-derived radicals. The results shown herein provide an alternative mechanism to account for some of the biochemical and pharmacological actions of desferrioxamine via reactions with CO3.- and (NO2)-N-. radicals. (C) 2004 Elsevier Inc. All rights reserved.