Inhibition of gamma-aminobutyric acid-stimulated chloride flux in mouse brain vesicles by polychlorocycloalkane and pyrethroid insecticides.
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.
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D001556:Hexachlorocyclohexane / Q000494:pharmacology; D007306:Insecticides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009570:Nitriles; D011722:Pyrethrins / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002712:Chlorides; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane