MECHANISMS OF NEUROTOXIC ACTION AND METABOLIC ACTIVATION

这是一项合作努力的延续，旨在阐明分子 几种类型的化学诱导神经毒性的相关机制 类似于自然发生的神经紊乱的症状。使用 正在进行的这一计划的开发，主要推力是更多地关注 毒素激活机制的具体方面和潜在的 生化方面的考虑。在项目I中，一个主要问题是 大鼠外周神经轴突中神经细丝的堆积 神经毒性化学物质，如伽马双酮，β，β‘-亚氨基- 二丙腈(IDPN)和CS2是(I)简单共价的结果 改性氮肥或(Ii)随后的氮肥交联剂。研究：关于 允许这两个因子解离的伽马二酮类似物 提出了一些建议，还有一些化学研究，这些研究解决了 潜在的蛋白质交联反应。另一个关注的领域是 IDPN的代谢激活，这是一种诱导Tourette样痛的神经毒素 除外周轴索病变外的行为异常，以及 相关膀胱神经毒素β-(二甲氨基)丙腈(DMAP)。 项目II的第一部分旨在澄清某些细节 关于多巴胺能神经毒性激活的机制 1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)。研究 建议(I)进一步深入了解和 线粒体抑制的结构依赖性 神经毒性MPTP代谢物1-- 甲基-4-苯基吡啶(MPP+)，(Ii)，以获得更好的定义 什么样的MPTP-或MPP+样结构可以作为内源性或外源性 神经毒素，(Iii)阐明产生自由基的倾向 和MPTP代谢中的反应中间产物，以及(Iv)到 正电子发射断层扫描用18F-MPTP类似物的研制 (PET)研究MPTP在灵长类动物脑中的生物分布。第二部分 项目II的重点是代谢的基本生化机制 与MPTP相关的有毒叔胺的激活，它们与 代谢酶自杀性失活和共价结合 蛋白质。模型化学氧化、酶学和In的组合 建议进行体外代谢研究。

This is a continuation of a collaborative effort to elucidate molecular mechanisms associated with several types of chemically-induced neurotoxic syndromes that resemble naturally-occurring neurological disorders. With ongoing development of this program, the major thrust is focusing more on specific aspects of the toxic activation mechanisms and on underlying biochemical considerations. In Project I, a major issue is whether accumulation of neurofilaments (NF) in peripheral axons induced by neurotoxic chemicals such as gamma-diketones, beta, beta'-imino- dipropionitrile (IDPN), and CS2, is a consequence of (i) simple covalent modification of NF or (ii) a subsequent NF cross-linking. Studies on gamma-diketone analogs which permit a dissociation of these two factors are proposed, as are chemical studies which address the nature of potential protein cross-linking reactions. Another area of focus is the metabolic activation of IDPN, a neurotoxin which induces a Tourette-like behavioral abnormality in addition to a peripheral axonopathy, and the related bladder neurotoxin beta-(dimethylamino)propionitrile (DMAP). The first part of Project II is directed at clarifying certain details regarding the mechanism of toxic activation of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Studies are proposed (i) to gain further insight into the mechanism of and structural dependence governing the inhibition of mitochondrial respiration by the neurotoxic MPTP metabolite, 1-- methyl-4-phenylpyridinium (MPP+), (ii) to obtain a better definition of what MPTP- or MPP+-like structures could act as endogenous or exogenous neurotoxins, (iii) to clarify the propensity for free-radical production and reactive intermediate generation in MPTP metabolism, and (iv) to develop 18F-containing MPTP analogs for positron emission tomography (PET) studies on MPTP biodistribution in primate brain. The second part of Project II focuses on basic biochemical mechanisms of metabolic activation of toxic tertiary amines related to MPTP, which are associated with suicide inactivation of metabolizing enzymes and covalent binding to proteins. A combination of model chemical oxidation, enzymologic, and in vitro metabolism studies is proposed.