Sulfone Metabolite of Fipronil Blocks gamma-Aminobutyric Acid-and Glutamate-Activated Chloride Channels in Mammalian and Insect Neurons

摘要

Fipronil sulfone,a major metabolite of fipronil in both insects and mammals,binds strongly to GABA receptors and is thought to play a significant role in poisoning by fipronil.To better understand the mechanism of selective insecticidal action of fipronil,we examined the effects of its sulfone metabolite on GABA-and glutamate-activated chloride channels(GluCIs)in cockroach thoracic ganglion neurons and on GABA_A receptors in rat dorsal root ganglion neurons using the whole-cell patch-clamp technique.Fipronil sulfone blocked both desensitizing and nondesensitizing GluCIs in the cockroach.Activation was required for block and unblock of desensitizing GluCIs.In contrast,activation was not prerequisite for block and unblock of nondesensitizing channels.After repetitive activation of the receptors,the IC_(50)of fipronil sulfone to block the desensitizing GluCIs was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCIs was reduced from 31.2 to 8.8 nM.This use-dependent block may be explained by its slow unbinding rate.In cockroach and rat neurons,fipronil sulfone blocked GABA receptors in both activated and resting states,with IC_(50)values ranging from 20 to 70 nM.In conclusion,although fipronil sulfone is a potent inhibitor of cockroach GABA receptors,desensitizing and nondesensitizing GluCIs,and rat GABA_A receptors,its selective toxicity in insects over mammals appears to be associated with its potent blocking action on both desensitizing and nondesensitizing GluCIs,which are lacking in mammals.