Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Na(v)1.6 sodium channels

• Published in: Toxicology and applied pharmacology 2010-09, Vol.247 (3), p.229
• Main Authors: Tan, Jianguo, Soderlund, David M
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALKALI METALS; Allethrin - chemistry; Allethrin - toxicity; ANIMALS; Cloning, Molecular; Cyclopropanes - chemistry; Cyclopropanes - toxicity; Dose-Response Relationship, Drug; ELEMENTS; GERM CELLS; Hydrocarbons, Fluorinated - chemistry; Hydrocarbons, Fluorinated - toxicity; In Vitro Techniques; INSECTICIDES; Insecticides - chemistry; Insecticides - toxicity; Ion Channel Gating - drug effects; MAMMALS; Membrane Potentials - drug effects; METALS; MODIFICATIONS; NAV1.6 Voltage-Gated Sodium Channel; Nitriles - chemistry; Nitriles - toxicity; OOCYTES; Oocytes - metabolism; Patch-Clamp Techniques; PESTICIDES; Protein Subunits; Pyrethrins - chemistry; Pyrethrins - toxicity; RATS; RODENTS; SODIUM; Sodium Channels - biosynthesis; Sodium Channels - physiology; Structure-Activity Relationship; Transfection; VERTEBRATES; Xenopus laevis
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2010.07.001

We expressed rat Na(v)1.6 sodium channels in combination with the rat beta(1) and beta(2) auxiliary subunits in Xenopus laevis oocytes and evaluated the effects of the pyrethroid insecticides S-bioallethrin, deltamethrin, and tefluthrin on expressed sodium currents using the two-electrode voltage clamp technique. S-Bioallethrin, a type I structure, produced transient modification evident in the induction of rapidly decaying sodium tail currents, weak resting modification (5.7% modification at 100 microM), and no further enhancement of modification upon repetitive activation by high-frequency trains of depolarizing pulses. By contrast deltamethrin, a type II structure, produced sodium tail currents that were ~9-fold more persistent than those caused by S-bioallethrin, barely detectable resting modification (2.5% modification at 100 microM), and 3.7-fold enhancement of modification upon repetitive activation. Tefluthrin, a type I structure with high mammalian toxicity, exhibited properties intermediate between S-bioallethrin and deltamethrin: intermediate tail current decay kinetics, much greater resting modification (14.1% at 100 microM), and 2.8-fold enhancement of resting modification upon repetitive activation. Comparison of concentration-effect data showed that repetitive depolarization increased the potency of tefluthrin approximately 15-fold and that tefluthrin was approximately 10-fold more potent than deltamethrin as a use-dependent modifier of Na(v)1.6 sodium channels. Concentration-effect data from parallel experiments with the rat Na(v)1.2 sodium channel coexpressed with the rat beta(1) and beta(2) subunits in oocytes showed that the Na(v)1.6 isoform was at least 15-fold more sensitive to tefluthrin and deltamethrin than the Na(v)1.2 isoform. These results implicate sodium channels containing the Na(v)1.6 isoform as potential targets for the central neurotoxic effects of pyrethroids.