Bloomquist J R, Adams P M, Soderlund D M
Neurotoxicology. 1986 Fall;7(3):11-20.
Selected polychlorocycloalkane and pyrethroid insecticides were evaluated as inhibitors of gamma-aminobutyric acid (GABA)-dependent chloride flux into mouse brain vesicles. The inhibitory potencies of the polychlorocycloalkane insecticides, measured as concentrations producing 50% inhibition, spanned a 1200-fold concentration range in the following order of decreasing potency: 12-ketoendrin; isobenzan; endrin; dieldrin; heptachlor epoxide; aldrin; heptachlor; and lindane. For the cyclodienes, inhibition of chloride uptake was closely correlated with both mammalian toxicity and the ability to displace the binding of [35S]t-butylbicyclophosphorothionate (TBPS). However, lindane was much less potent as an inhibitor of GABA-dependent chloride uptake than would be expected from its acute toxicity or potency as an inhibitor of [35S]TBPS binding. Mirex and chlordecone were poor inhibitors of GABA-dependent chloride uptake, indicating that other sites are likely to be involved in their toxic action. The pyrethroid insecticide deltamethrin gave 50% inhibition of GABA-dependent chloride uptake at 25 microM, but the extent of inhibition was not increased at higher concentrations. In addition, the nontoxic enantiomer of deltamethrin produced dose-dependent inhibition in the chloride flux assay with a potency about 10-fold less than deltamethrin. These results demonstrate the utility of this functional assay to identify compounds that act at the GABAA receptor-ionophore complex and implicate this complex as the principal site of neurotoxic action for cyclodiene insecticides. Although lindane and deltamethrin also altered GABAA receptor-ionophore function, their low potencies and the incomplete stereospecificity of deltamethrin inhibition suggest that this complex is not involved in the neurotoxic action of lindane and alpha-cyano-substituted pyrethroids.
对选定的多氯环烷烃和拟除虫菊酯类杀虫剂进行了评估，以确定它们作为γ-氨基丁酸（GABA）依赖性氯离子流入小鼠脑囊泡的抑制剂的效果。多氯环烷烃类杀虫剂的抑制效力，以产生50%抑制作用的浓度来衡量，其浓度范围跨越1200倍，效力递减顺序如下：12-酮异狄氏剂；异艾氏剂；异狄氏剂；狄氏剂；七氯环氧化物；艾氏剂；七氯；以及林丹。对于环二烯类化合物，氯离子摄取的抑制作用与哺乳动物毒性以及取代[35S]叔丁基双环磷硫化物（TBPS）结合的能力密切相关。然而，林丹作为GABA依赖性氯离子摄取抑制剂的效力远低于根据其急性毒性或作为[35S]TBPS结合抑制剂的效力所预期的水平。灭蚁灵和十氯酮是GABA依赖性氯离子摄取的弱抑制剂，这表明它们的毒性作用可能涉及其他位点。拟除虫菊酯类杀虫剂溴氰菊酯在25微摩尔时对GABA依赖性氯离子摄取产生50%的抑制作用，但在更高浓度下抑制程度并未增加。此外，溴氰菊酯的无毒对映体在氯离子通量测定中产生剂量依赖性抑制，效力比溴氰菊酯低约10倍。这些结果证明了这种功能测定法在鉴定作用于GABAA受体-离子载体复合物的化合物方面的实用性，并表明该复合物是环二烯类杀虫剂神经毒性作用的主要位点。尽管林丹和溴氰菊酯也改变了GABAA受体-离子载体功能，但它们的低效力以及溴氰菊酯抑制作用的不完全立体特异性表明，该复合物不参与林丹和α-氰基取代拟除虫菊酯的神经毒性作用。
