Zhao Xilong, Yeh Jay Z, Salgado Vincent L, Narahashi Toshio
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
J Pharmacol Exp Ther. 2005 Jul;314(1):363-73. doi: 10.1124/jpet.104.077891. Epub 2005 Feb 8.
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.
氟虫腈砜是氟虫腈在昆虫和哺乳动物体内的主要代谢产物，它与γ-氨基丁酸（GABA）受体紧密结合，被认为在氟虫腈中毒过程中起重要作用。为了更好地理解氟虫腈的选择性杀虫作用机制，我们采用全细胞膜片钳技术，研究了其砜代谢产物对蟑螂胸神经节神经元中GABA和谷氨酸激活的氯离子通道（GluCls）以及大鼠背根神经节神经元中GABA(A)受体的影响。氟虫腈砜可阻断蟑螂体内脱敏和非脱敏的GluCls。阻断和解除脱敏GluCls的阻断需要激活。相比之下，阻断和解除非脱敏通道的阻断并不需要激活。受体重复激活后，氟虫腈砜阻断脱敏GluCls的半数抑制浓度（IC50）从350 nM降至25 nM，阻断非脱敏GluCls的IC50从31.2 nM降至8.8 nM。这种使用依赖性阻断可能是由于其缓慢的解离速率所致。在蟑螂和大鼠神经元中，氟虫腈砜可阻断激活状态和静息状态下的GABA受体，IC50值在20至70 nM之间。总之，尽管氟虫腈砜是蟑螂GABA受体、脱敏和非脱敏GluCls以及大鼠GABA(A)受体的强效抑制剂，但其对昆虫的选择性毒性高于哺乳动物，这似乎与其对脱敏和非脱敏GluCls的强效阻断作用有关，而哺乳动物缺乏这些通道。
