title: 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.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA. narahashi@northwestern.edu
authors.forename: T
authors.initials: T
authors.lastname: Narahashi
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: J Z
authors.initials: JZ
authors.lastname: Yeh
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D006801:Humans; D007313:Insecta; D007306:Insecticides / Q000633:toxicity*; D007473:Ion Channels / Q000187:drug effects*; D008322:Mammals; D011720:Pyrazoles / Q000633:toxicity; D011722:Pyrethrins / Q000633:toxicity; D011955:Receptors, Drug / Q000187:drug effects*; D018079:Receptors, GABA / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013045:Species Specificity
chemical_list: D018118:Chloride Channels; D007306:Insecticides; D007473:Ion Channels; D011720:Pyrazoles; D011722:Pyrethrins; D011955:Receptors, Drug; D018079:Receptors, GABA; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C082360:fipronil