Nace C G, Genter M B, Sayre L M, Crofton K M
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US EPA, Research Triangle Park, NC 27711, USA.
Fundam Appl Toxicol. 1997 Jun;37(2):131-40. doi: 10.1006/faat.1997.2307.
This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite N-hydroxy3,3'-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long-Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMO-mediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotoxicities.
本研究旨在使用含黄素单加氧酶（FMO）的底物和竞争性抑制剂甲巯咪唑（MMI），研究FMO在3,3'-亚氨基二丙腈（IDPN）的听觉和前庭神经毒性中的作用。具体而言，目的是阻断FMO介导的IDPN向假定的神经毒性代谢物N-羟基-3,3'-亚氨基二丙腈（HOIDPN）的转化。在三个独立的实验中，成年雄性Long-Evans带帽大鼠分别腹腔注射生理盐水（溶剂）、MMI、IDPN或HOIDPN，或IDPN与MMI或HOIDPN与MMI的组合。每天观察动物10天，观察ECC综合征（伴有舞蹈样动作和转圈运动的兴奋）的体征。暴露后1至2周，使用一系列行为测试来检查前庭和听觉功能。MMI完全阻断了与600mg/kg剂量IDPN相关的神经毒性，并部分阻断了1000mg/kg剂量IDPN的作用。相比之下，MMI未能阻断与HOIDPN相关的神经毒性，反而增强了这种神经毒性。这些数据表明，IDPN的FMO介导的代谢对于产生负责前庭和听觉神经毒性的代谢物是必要的。
