{"title":"-亚氨基二丙腈(IDPN)神经毒性:毒性激活的机制假说。","authors":"A R Jacobson, S H Coffin, C M Shearson, L M Sayre","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":77750,"journal":{"name":"Molecular toxicology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"1987-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"beta,beta'-Iminodipropionitrile (IDPN) neurotoxicity: a mechanistic hypothesis for toxic activation.\",\"authors\":\"A R Jacobson, S H Coffin, C M Shearson, L M Sayre\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":77750,\"journal\":{\"name\":\"Molecular toxicology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1987-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular toxicology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular toxicology","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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.