-亚氨基二丙腈(IDPN)神经毒性:毒性激活的机制假说。

Molecular toxicology Pub Date : 1987-01-01
A R Jacobson, S H Coffin, C M Shearson, L M Sayre
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引用次数: 0

摘要

β, β′-亚氨基二丙腈(IDPN)在实验动物中引起神经行为异常和轴突近端神经丝的大量局灶性积累。提出了一种假说来解释IDPN在氧化胺代谢方面的神经毒性活性,其中可以产生共振稳定的氰胺3-(2-氰乙基氨基)丙烯腈(脱氢-IDPN, 5)。进行了化学研究以验证所提出的酶转化的可能性及其与已知排泄代谢物的一致性。脱氢idpn在pH值为7时引起氰乙醛的缓慢水解释放,这可以将蛋白质基氨基转化为氰胺,尽管后者衍生物可以通过与脱氢idpn在pH值为7时相对快速的转氨化反应直接形成。动力学研究评估了氰胺的竞争性水解(伪一级)和转氨化(二级)之间的平衡,作为ph的功能。神经丝(NF)亚基蛋白“尾部”区域关键赖氨酸残基的ε -氨基的氰乙基化可能破坏被认为有助于维持细胞骨架直径的超分子库仑相互作用。这可能导致NF的缓慢轴突运输缺陷,随后导致近端轴突增大的形成。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
beta,beta'-Iminodipropionitrile (IDPN) neurotoxicity: a mechanistic hypothesis for toxic activation.

beta,beta'-Iminodipropionitrile (IDPN) induces neurobehavioral aberrations in experimental animals and massive focal accumulations of neurofilaments in proximal regions of axons. A hypothesis is presented to explain the neurotoxic activity of IDPN in terms of oxidative amine metabolism, wherein a resonance-stabilized cyanoenamine 3-(2-cyanoethylamino)acrylonitrile (dehydro-IDPN, 5) could be generated. Chemical studies were conducted to verify the likelihood of the proposed enzymatic transformations and their consistency with the known excreted metabolites. Dehydro-IDPN gives rise to a slow hydrolytic release of cyanoacetaldehyde at pH 7, which can transform protein-based amino groups to cyanoenamines, though the latter derivatives could be formed directly through a relatively rapid transamination reaction with dehydro-IDPN at pH 7. Kinetic studies were conducted to assess the balance between competing hydrolysis (pseudo-first order) and transamination (second order) of cyanoenamines as a function of pH. Cyanoethenylation of the epsilon-amino groups of critical lysine residues in the "tail-piece" domains of neurofilament (NF) subunit proteins could disrupt the supramolecular coulombic interactions thought to contribute to maintenance of cytoskeletal caliber. This could result in a defect in the slow axonal transport of NF, and subsequently in the formation of proximal axonal enlargements.

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