Interactions of lindane, toxaphene and cyclodienes with brain-specific [formula omitted]-butylbicyclophosphorothionate receptor

Abstract

Three major classes of chlorinated hydrocarbon insecticides, i . e ., the lindane/hexachlorocyclohexane, toxaphene and aldrin/dieldrin types, are potent, competitive, and stereospecific inhibitors of t -butylbicyclophosphorothionate (TBPS) binding to brain-specific sites, thereby indicating an action at the γ-aminobutyric acid (GABA)-regulated chloride channel. The most inhibitory and toxic of four isomers of hexachlorocyclohexane is lindane and of >188 components of toxaphene is 2,2,5- endo , 6- exo , 8,9,9,10-octachlorobornane. 12-Ketoendrin (IC 50 = 36 nM) is twice as active as the most potent previously known inhibitor of TBPS binding and it is also the most inhibitory and toxic of 22 cyclodienes examined. Within each of these three series of polychlorocycloalkanes the mammalian toxicity is closely related to the potency for inhibition of TBPS binding. A modified receptor assay incorporating liver microsomes and reduced nicotinamide-adenine dinucleotide phosphate compensates in part for oxidative detoxification and bioactivation. Specific TBPS binding is reduced in a dose-dependent manner in dieldrin-poisoned rats. DDT, mirex and kepone are not inhibitors of TBPS binding, even at 10 μM.