权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MECHANISMS FOR ALTERING PARAQUAT TOXICITY

改变百草枯毒性的机制

基本信息

批准号：
3438176
负责人：
STEVEN D MERCURIO
金额：
$ 8.64万
依托单位：
MINNESOTA STATE UNIVERSITY, MANKATO
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-07 至 1992-03-31
项目状态：
已结题

项目摘要

The purpose of the proposed study is to investigate the mechanisms by which paraquat's prooxidant toxicity can be prevented through prophylactic treatment with novel chemical agents. Although the use of superoxide dismutase has been widely reviewed in the literature, few other interactions have been examined except for diet modification or nutritional deficiencies. Although extensive publications on paraquat exist, no antidotal therapies short of hemodialysis or blood replacement appear to be effective. Experiments in the chicken and the mouse have indicated negative interactions between arthritis medications and prooxidant chemicals, such as paraquat. Prevention of paraquat toxicity is accomplished through dietary addition of Ebselen, a novel anti- inflammatory agent with glutathione peroxidase activity or simultaneously administered penicillamine. Preliminary experiments in the mouse indicate 1) Low dose prevention of paraquat toxicity by penicillamine and high dose enhanced lethality, 2) an unexpected substantial protection of intramuscularly injected corn oil against oral paraquat, and 3) reversal of corn oil's protective effect by high intramuscular doses of Ebselen in corn oil. The present study will concentrate on the last two factors to determine the role of injected oils and injected versus oral Ebselen on paraquat toxicity in the mouse to understand the mechanisms which define their antidotal versus toxic interactions with paraquat. Expected experiments are 1) effects of corn oil and other linoleic- polyunsaturated oils on paraquat toxicity, 2) influence of oral versus injected Ebselen on paraquat toxicity, 3) alterations in paraquat pharmacokinetics by Ebselen and corn oil, especially in intestine/plasm and plasma/lung, and 4) modification of paraquat toxicity by cyclooxygenase and lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inactivation effects of Ebselen and possible effects of injected corn oil on lung prostaglandins and leukotrienes.

拟议研究的目的是调查其机制可以通过以下方式预防百草枯的促氧化毒性：使用新型化学制剂进行预防性治疗。虽然超氧化物歧化酶的使用已被广泛审查文献中，除了饮食调整或营养缺乏。虽然广泛已有关于百草枯的出版物，没有任何解毒疗法血液透析或血液替代似乎是有效的。鸡和小鼠实验结果显示阴性关节炎药物和促氧化剂之间的相互作用化学品，例如百草枯。预防百草枯毒性的方法是通过在饮食中添加依布硒啉（Ebselen）来实现，依布硒啉是一种新型抗- 具有谷胱甘肽过氧化物酶活性的炎症剂或同时给予青霉胺。初步实验小鼠体内表明 1) 低剂量预防百草枯毒性通过青霉胺和高剂量增强致死率，2）意想不到的肌内注射玉米油可有效防止口服百草枯，以及 3) 逆转玉米油的保护作用玉米油中高剂量的依布硒啉肌肉注射。目前的研究将集中于最后两个因素来确定注射油和注射与口服依布硒啉对百草枯毒性的影响在小鼠中了解定义其的机制与百草枯的解毒与毒性相互作用。预期的实验是1）玉米油和其他亚油酸的影响多不饱和油对百草枯毒性的影响，2) 口服的影响与注射依布硒啉相比，百草枯毒性的变化，3) 依布硒啉和玉米油的百草枯药代动力学，特别是在肠/血浆和血浆/肺，以及 4) 百草枯的修饰环加氧酶和脂氧合酶抑制的毒性不含玉米油作为脂氧合酶抑制的对照有和没有玉米油均作为脂氧合酶的对照 Ebselen 的灭活作用和注射的可能影响玉米油对肺前列腺素和白三烯的影响。