Developmentally-regulated sodium channel subunits are differentially sensitive to α-cyano containing pyrethroids
Developmentally-regulated sodium channel subunits are differentially sensitive to α-cyano containing pyrethroids
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DOI：
10.1016/j.taap.2008.04.017
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发表时间：
2008-09-15
影响因子：
3.8
通讯作者：
Shafer, Timothy J.
中科院分区：
文献类型：
--
作者：
Meacham, Connie A.;Brodfuehrer, Peter D.;Shafer, Timothy J.
据报告，幼龄脂肪对拟除虫菊酯溴氰菊酯的急性神经毒性作用比成年脂肪更敏感。虽然记录了青少年和成年人之间的毒代动力学差异，但尚未检查毒代动力学差异。电压门控钠通道是拟除虫菊酯的主要靶点，由α和β亚基组成，每个亚基都有多种亚型，以发育调节的方式表达。为了开始测试毒代动力学差异是否可能导致年龄依赖性溴氰菊酯毒性，在注射大鼠α（Na（v）1.2或Na（v）1.3）和β（β（1）或β（3））亚基的不同组合的非洲爪蟾卵母细胞中检查了溴氰菊酯对钠电流的影响。溴氰菊酯在所有亚型组合中诱导尾电流，并以浓度依赖性方式增加修饰通道的百分比。溴氰菊酯的影响取决于亚基组合：含Na（v）1.3通道的修饰程度大于含Na（v）1.2通道。在存在β亚基的情况下，溴氰菊酯的作用显著更大，对Na（v）1.3通道的作用最明显：Na（v）1.3/β（3）通道比Na（v）1.2/β（1）通道对溴氰菊酯更敏感。Na（v）1.3/β（3）通道在胚胎中表达，而Na（v）1.2和β（1）亚基在成人中占主导地位，支持年龄依赖性毒力差异的假设。针对其他拟除虫菊酯，检查了这些亚基组合敏感性的构效关系。氯菊酯和胺菊酯没有修改电流介导的任一亚基组合。氯氰菊酯、β-氟氯氰菊酯、顺式氰戊菊酯和甲氰菊酯均改变钠通道功能;对Na（v）1.3/β（3）通道的影响显著大于对Na（v）1.2/β（1）通道的影响。这些数据表明Na（v）1.3通道与Na（v）1.2通道相比，对溴氰菊酯和其他含氰基拟除虫菊酯的敏感性更高，特别是在存在β亚基的情况下。爱思唯尔公司出版
Juvenile Fats 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. Published by Elsevier Inc.