Differential actions of insecticides on target sites: basis for selective toxicity

Abstract

Whereas the selective toxicity of insecticides between insects and mammals has a long history of studies, it is now becoming abundantly clear that, in many cases, the differential action of insecticides on insects and mammalian target receptor sites is an important factor. In this paper, we first introduce the mechanism of action and the selective toxicity of pyrethroids as a prototype of study. Then, a more detailed account is given for fipronil, based primarily on our recent studies. Pyrethroids keep the sodium channels open for a prolonged period of time, causing elevation of the depolarizing after-potential. Once the after-potential reaches the threshold for excitation, repetitive after-discharges are produced, resulting in hyperexcitation of intoxicated animals. Only about 1% of sodium channels needs to be modified to produce hyperexcitation, indicating a high degree of toxicity amplification from sodium channels to animals. Pyrethroids were >1000-fold more potent on cockroach sodium channels than rat sodium channels, and this forms the most significant factor to explain the selective toxicity of pyrethroids in insects over mammals. Fipronil, a phenylpyrazole, is known to act on the gamma-aminobutyric acid receptor to block the chloride channel. It is effective against certain species of insects that have become resistant to most insecticides, including those acting on the gamma-aminobutyric acid receptor, and is much more toxic to insects than to mammals. Recently, fipronil has been found to block glutamate-activated chloride channels in cockroach neurons in a potent manner. Since mammals are devoid of this type of chloride channel, fipronil block of the glutamate-activated chloride channel is deemed responsible, at least partially, for the higher selective toxicity to insects over mammals and for the lack of cross-resistance.

Figure 1

Concentration-dependent modification of sodium channels by tetramethrin. The percentage of sodium channel modification was calculated from whole-cell tail current and peak current in rat Purkinje neurons (Song and Narahashi).

Figure 2

Allethrin modulates tetrodotoxin-sensitive sodium channels > 1000 times more potently in cockroach neurons than in rat dorsal roof ganglion neurons. Rat data from Ginsburg and Narahashi. Cockroach data from Narahashi.

Figure 3

Two components of glutamate-activated chloride currents in cockroach neurons.

Figure 4

Fipronil blocks slow non-desensitizing glutamate-induced current more potently than fast desensitizing current.