Acute Cyanide Toxicity, Complex IV, NO & Nitrite

急性氰化物毒性,复合物 IV,NO

基本信息

  • 批准号:
    7915539
  • 负责人:
  • 金额:
    $ 52.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-15 至 2012-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The surprise use of either hydrogen cyanide gas (HCN) as a weapon directed against individuals deceived into becoming confined in enclosed spaces is likely to rapidly result in mass casualties. Nitric oxide (NO) is presently the only agent known that is able to displace cyanide (CN) from the active site of cytochrome c oxidase - the critical site of inhibition during acute intoxication. Enthusiasm for the use of traditional antidotes, nitrites (amyl and/or sodium nitrite), has decreased, in part, because of the uncertain assumption that its mechanism of action is the induction of methemoglobin (MetHb). Coincidently, extraordinary recent efforts have been redirected towards the role of nitrite in human physiology (as a source of NO). We now suggest that reversal of CN toxicity by nitrite is less dependent on production of MetHb but rather is secondary to formation of NO. Since nitrites and nitric oxide are already approved for human use and may provide an inexpensive antidote that is easy to administer (via inhalation) and can be readily stockpiled for public health use, we suggest that further understanding of their molecular mechanisms of action and a preclinical trial of their efficacy represent rational advances in chemical countermeasures. We propose that vaporized nitrite solution, to be administered by inhalation, will lead to the in situ production of NO which will ameliorate the acute toxic effects of CN. Our Specific Aims are to: 1) establish the biochemical mechanism through which NO counteracts the inhibition of isolated cytochrome c oxidase by HCN; 2) elucidate the mechanisms that account for the interactions between cytochrome c oxidase, HCN, molecular oxygen (O2) and NO, or sodium nitrite in mitochondria; 3) demonstrate in animals the efficacy, of NO and NO-releasing compounds, including sodium nitrite, in the treatment of acute cyanide intoxication.
描述(由申请人提供): 突然使用氰化氢气体(HCN)作为武器,直接针对被骗进入封闭空间的个人,可能会迅速造成大规模伤亡。一氧化氮(NO)是目前已知的唯一能够从细胞色素c氧化酶的活性位点(急性中毒期间抑制的关键位点)置换氰化物(CN)的试剂。使用传统解毒剂亚硝酸盐(戊基和/或亚硝酸钠)的热情有所下降,部分原因是不确定的假设,即其作用机制是诱导高铁血红蛋白(MetHb)。巧合的是,最近的努力已经转向亚硝酸盐在人体生理学中的作用(作为NO的来源)。我们现在认为,亚硝酸盐对CN毒性的逆转不太依赖于MetHb的产生,而是继发于NO的形成。由于亚硝酸盐和一氧化氮已被批准用于人类使用,并可能提供一种易于管理的廉价解毒剂(通过吸入)并且可以随时储存用于公共卫生用途,我们认为,进一步了解它们的分子作用机制和临床前试验的效力代表了合理的进展,在化学对策。我们建议,蒸发的亚硝酸盐溶液,通过吸入给药,将导致在原位产生NO,这将改善CN的急性毒性作用。我们的具体目标是:(1)建立了NO对抗HCN对细胞色素c氧化酶抑制的生化机制,(2)阐明了线粒体中细胞色素c氧化酶、HCN、分子氧(O_2)与NO或亚硝酸钠相互作用的机制; 3)在动物中证明NO和NO释放化合物(包括亚硝酸钠)在治疗急性氰化物中毒中的功效。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Metalloporphyrin Co(III)TMPyP ameliorates acute, sublethal cyanide toxicity in mice.
Metalloporphyrin Co(III)TMPyP 可改善小鼠的急性亚致死氰化物毒性。
  • DOI:
    10.1021/tx300327v
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Benz,OscarS;Yuan,Quan;Amoscato,AndrewA;Pearce,LindaL;Peterson,Jim
  • 通讯作者:
    Peterson,Jim
Relative Propensities of Cytochrome c Oxidase and Cobalt Corrins for Reaction with Cyanide and Oxygen: Implications for Amelioration of Cyanide Toxicity.
细胞色素 c 氧化酶和钴 Corrin 与氰化物和氧气反应的相对倾向:对改善氰化物毒性的影响。
  • DOI:
    10.1021/acs.chemrestox.7b00275
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Yuan,Quan;Pearce,LindaL;Peterson,Jim
  • 通讯作者:
    Peterson,Jim
Effect of Ascorbate on the Cyanide-Scavenging Capability of Cobalt(III) meso-Tetra(4-N-methylpyridyl)porphine Pentaiodide: Deactivation by Reduction?
抗坏血酸对钴(III)内消旋四(4-N-甲基吡啶基)卟啉五碘化物清除氰化物能力的影响:还原失活?
  • DOI:
    10.1021/acs.chemrestox.5b00447
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Benz,OscarS;Yuan,Quan;Cronican,AndreaA;Peterson,Jim;Pearce,LindaL
  • 通讯作者:
    Pearce,LindaL
Comparison of the relative propensities of isoamyl nitrite and sodium nitrite to ameliorate acute cyanide poisoning in mice and a novel antidotal effect arising from anesthetics.
  • DOI:
    10.1021/tx400103k
  • 发表时间:
    2013-05-20
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Cambal LK;Weitz AC;Li HH;Zhang Y;Zheng X;Pearce LL;Peterson J
  • 通讯作者:
    Peterson J
Covalent modifications of hemoglobin by nitrite anion: formation kinetics and properties of nitrihemoglobin.
亚硝酸根阴离子对血红蛋白的共价修饰:硝基血红蛋白的形成动力学和特性。
  • DOI:
    10.1021/tx100242w
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Otsuka,Mai;Marks,SarahA;Winnica,DanielE;Amoscato,AndrewA;Pearce,LindaL;Peterson,Jim
  • 通讯作者:
    Peterson,Jim
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JAMES PETERSON其他文献

JAMES PETERSON的其他文献

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{{ truncateString('JAMES PETERSON', 18)}}的其他基金

Acute Cyanide Toxicity, Complex IV, NO & Nitrite
急性氰化物毒性,复合物 IV,NO
  • 批准号:
    7547329
  • 财政年份:
    2008
  • 资助金额:
    $ 52.34万
  • 项目类别:
Acute Cyanide Toxicity, Complex IV, NO, & Nitrite
急性氰化物毒性,复合物 IV,NO,
  • 批准号:
    7696176
  • 财政年份:
    2008
  • 资助金额:
    $ 52.34万
  • 项目类别:
Acute Cyanide Toxicity, Complex IV, NO & Nitrite
急性氰化物毒性,复合物 IV,NO
  • 批准号:
    7684760
  • 财政年份:
    2008
  • 资助金额:
    $ 52.34万
  • 项目类别:
New small molecule targets for radiation protection
用于辐射防护的新小分子靶标
  • 批准号:
    7055203
  • 财政年份:
    2005
  • 资助金额:
    $ 52.34万
  • 项目类别:
MITOCHONDRIA AND PULMONARY ENDOTHELIAL CELL DEATH
线粒体和肺内皮细胞死亡
  • 批准号:
    6390108
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:
Mitochondria and Pulmonary Endothelial Cell Death
线粒体和肺内皮细胞死亡
  • 批准号:
    6776070
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:
Mitochondria and Pulmonary Endothelial Cell Death
线粒体和肺内皮细胞死亡
  • 批准号:
    7198050
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:
MITOCHONDRIA AND PULMONARY ENDOTHELIAL CELL DEATH
线粒体和肺内皮细胞死亡
  • 批准号:
    6537482
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:
Mitochondria and Pulmonary Endothelial Cell Death
线粒体和肺内皮细胞死亡
  • 批准号:
    6871327
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:
Mitochondria and Pulmonary Endothelial Cell Death
线粒体和肺内皮细胞死亡
  • 批准号:
    7035875
  • 财政年份:
    2000
  • 资助金额:
    $ 52.34万
  • 项目类别:

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氧化还原平衡在氰化物毒性和线粒体疾病中的作用
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Acute Cyanide Toxicity, Complex IV, NO & Nitrite
急性氰化物毒性,复合物 IV,NO
  • 批准号:
    7547329
  • 财政年份:
    2008
  • 资助金额:
    $ 52.34万
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急性氰化物毒性,复合物 IV,NO,
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    2008
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    $ 52.34万
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急性氰化物毒性,复合物 IV,NO
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