Developmentally-regulated sodium channel subunits are differentially sensitive to alpha-cyano containing pyrethroids.

Juvenile rats have been reported to be more sensitive to the acute neurotoxic effects of the pyrethroid deltamethrin than adults. While toxicokinetic differences between juveniles and adults are documented, toxicodynamic differences have not been examined. Voltage-gated sodium channels, the primary targets of pyrethroids, are comprised of alpha and beta subunits, each of which have multiple isoforms that are expressed in a developmentally-regulated manner. To begin to test whether toxicodynamic differences could contribute to age-dependent deltamethrin toxicity, deltamethrin effects were examined on sodium currents in Xenopus laevis oocytes injected with different combinations of rat alpha (Na(v)1.2 or Na(v)1.3) and beta (beta(1) or beta(3)) subunits. Deltamethrin induced tail currents in all isoform combinations and increased the percent of modified channels in a concentration-dependent manner. Effects of deltamethrin were dependent on subunit combination; Na(v)1.3-containing channels were modified to a greater extent than were Na(v)1.2-containing channels. In the presence of a beta subunit, deltamethrin effects were significantly greater, an effect most pronounced for Na(v)1.3 channels; Na(v)1.3/beta(3) channels were more sensitive to deltamethrin than Na(v)1.2/beta(1) channels. Na(v)1.3/beta(3) channels are expressed embryonically, while the Na(v)1.2 and beta(1) subunits predominate in adults, supporting the hypothesis for age-dependent toxicodynamic differences. Structure-activity relationships for sensitivity of these subunit combinations were examined for other pyrethroids. Permethrin and tetramethrin did not modify currents mediated by either subunit combination. Cypermethrin, beta-cyfluthrin, esfenvalerate and fenpropathrin all modified sodium channel function; effects were significantly greater on Na(v)1.3/beta(3) than on Na(v)1.2/beta(1) channels. These data demonstrate a greater sensitivity of Na(v)1.3 vs Na(v)1.2 channels to deltamethrin and other cyano-containing pyrethroids, particularly in the presence of a beta subunit.

Concentration-dependent accumulation of [3H]-deltamethrin in sodium channel Nav1.2/beta1 expressing Xenopus laevis oocytes.

Disruption of neuronal voltage-sensitive sodium channels (VSSCs) by pyrethroid insecticides such as deltamethrin (DLT) has been widely studied using Xenopus laevis oocytes transfected with VSSC. However, the extent of pyrethroid accumulation in VSSC-expressing oocytes is unknown. Therefore, accumulation of [(3)H]-DLT in non-transfected, sham (water)-transfected and VSSC (Na(v)1.2+beta(1))-transfected oocytes after a 1h exposure was measured using liquid scintillation counting. Successful transfection of Na(v)1.2+beta(1) VSSCs in X. laevis oocytes was confirmed by two-electrode voltage-clamp; inward, tetrodotoxin (TTX)-sensitive currents were obtained in 98% of all oocytes examined (n=60 in nine experiments). DLT (1.0 microM) induced tail currents in all VSSC-transfected oocytes; TTX also blocked these DLT-induced tail currents. In 0.1 microM DLT solution, non-transfected oocytes accumulated 0.098+/-0.01 ppm [(3)H]-DLT, sham-transfected oocytes accumulated 0.06+/-0.01 ppm DLT, and VSSC-transfected oocytes accumulated 0.050+/-0.009 ppm DLT. In 1.0 microM DLT solution, non-transfected oocytes accumulated 0.62+/-0.08 ppm DLT, sham-transfected oocytes accumulated 0.60+/-0.09 ppm DLT, and VSSC-transfected oocytes accumulated 0.51+/-0.07 ppm DLT. There was a significant difference in DLT accumulation between VSSC-transfected oocytes and non-transfected controls, where the transfected oocytes consistently had less accumulation.