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This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.077891v1 jpet.104.077891v2 314/1/363    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhao, X. Articles by Narahashi, T. Search for Related Content PubMed PubMed Citation Articles by Zhao, X. Articles by Narahashi, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB FIPRONIL GLUTAMIC ACID HYDROCHLORIDE

NEUROPHARMACOLOGY

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

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

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 (GluCls) 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 GluCls in the cockroach. Activation was required for block and unblock of desensitizing GluCls. In contrast, activation was not prerequisite for block and unblock of nondesensitizing channels. After repetitive activation of the receptors, the IC₅₀ of fipronil sulfone to block the desensitizing GluCls was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCls 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 IC₅₀ values ranging from 20 to 70 nM. In conclusion, although fipronil sulfone is a potent inhibitor of cockroach GABA receptors, desensitizing and nondesensitizing GluCls, 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 GluCls, which are lacking in mammals.

Address correspondence to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611. E-mail: narahashi{at}northwestern.edu