NITRIC OXIDE TOXICITY--OXIDATIONS VIA PEROXYNITRITE

一氧化氮毒性——通过过氧亚硝酸盐进行氧化

• 批准号: 2155620
• 负责人: WILLIAM A PRYOR
• 金额: $ 15.35万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2155620
• 关键词: acidity /alkalinity; acrolein; alkenes; benzopyrenes; chemical kinetics; cis trans isomerization; cyclohexane /cyclohexene carboxylate; cyclohexanes; epoxides; heavy metals; high performance liquid chromatography; ionic strengths; methionine; nitrates; nitric oxide; oleate; oxidation; peroxides

Nitric oxide is an environmental toxin. Surprisingly NO is a ubiquitous biological messenger. Nitric oxide itself is a weak oxidant, but it reacts with O2-. in the lung to produce peroxynitrite and peroxynitrous acid. HOONO, potent oxidants and toxins. The three specific aims of this proposal concern the mechanisms that explain the toxicity of HOONO. (#1) Peroxynitrite undergoes a pH-dependent rearrangement reaction to form nitrate, an important pathway for detoxification of HOONO. The mechanism of this reaction has been reported to involve radicals: HOONO to HO. + .NO2 to HONO2. However, our preliminary data suggest the mechanism involves a molecular (non-radical) rearrangement. HOONO exists in both cisoid and transoid forms, which calculations predict have acid pK constants that differ by about 1.3 pH units. The published analysis of the rate of HOONO disappearance versus pH proposes just one HOONO species and a single wave with an inflection point at the reported pK of HOONO, 6.8. However, preliminary experimental data are fit better by a curve with two waves, involving two species (presumed to be cis and trans) with pK values that differ by about 1.5 units. By obtaining sufficient data at about pH 7, we will be able to establish whether this detoxification reaction involves one or two HOONO species and occurs via a molecular rearrangement or via the hydroxyl radical. (#2) HOONO can oxidize biomolecules via an SN2 reaction of nucleophilic species Y:to give Y=O and HNO2. This is involved, for example, in the inactivation of methionine-containing proteins. The SN2 reaction will be studied using the oxidation of methionine to methionine sulfoxide. Reactions of methionine amide and ester also will be studied. (#3) Most inorganic and organic peroxyacids that oxidize sulfides to sulfoxides also epoxidize olefins. We will test whether HOONO can epoxidize cyclohexene, methyl oleate and 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene. We also will ask if the ion -OO-N=O can epoxidize alpha,beta-unsaturated carbonyl compounds via a Michael addition-elimination mechanism. All three of the specific aims will be studied both in systems where trace transition metals have been removed and in systems to which chelates of redox-active transition metal ions have been added.

一氧化氮是一种环境毒素。 令人惊讶的是，NO 无处不在 生物信使。 一氧化氮本身是一种弱氧化剂，但它 与O2-反应。在肺中产生过氧亚硝酸盐和过氧亚硝基 酸。 HOONO，强效氧化剂和毒素。 三个具体目标 该提案涉及解释 HOONO 毒性的机制。 (#1) 过氧亚硝酸盐经历 pH 依赖性重排反应 形成硝酸盐，这是 HOONO 解毒的重要途径。 这 据报道，该反应的机制涉及自由基：HOONO 到何。 + .NO2 至 HONO2。 然而，我们的初步数据表明 机制涉及分子（非自由基）重排。 胡诺存在 顺式和反式形式，计算预测具有酸 pK 常数相差约 1.3 pH 单位。 已发表的分析 HOONO 消失率与 pH 值的关系表明只有一个 HOONO 物种和单波，其拐点为报告的 pK 胡诺，6.8。 然而，初步实验数据更适合 具有两个波的曲线，涉及两个物种（假定是顺式和 trans) 的 pK 值相差约 1.5 个单位。 通过获取 在 pH 7 左右有足够的数据，我们将能够确定这是否 解毒反应涉及一种或两种 HOONO 物种，并通过以下方式发生 分子重排或通过羟基自由基。 (#2) HOONO 可以 通过亲核物质 Y:to 的 SN2 反应氧化生物分子 给出 Y=O 和 HNO2。 例如，这涉及失活 含有蛋氨酸的蛋白质。 将研究SN2反应 利用甲硫氨酸氧化成甲硫氨酸亚砜。 的反应 蛋氨酸酰胺和酯也将被研究。 (#3) 大多数无机和 将硫化物氧化成亚砜的有机过氧酸也能环氧化 烯烃。 我们将测试HOONO是否可以环氧化环己烯、甲基 油酸酯和7,8-二羟基-7,8-二氢苯并[a]芘。 我们还会询问是否 离子-OO-N=O可以环氧化α,β-不饱和羰基化合物 通过迈克尔加成-消除机制。 所有三个具体目标都将在以下系统中进行研究： 痕量过渡金属已被去除，并且在系统中 添加了氧化还原活性过渡金属离子的螯合物。