Inhibition of gap junction currents by the abused solvent toluene
Inhibition of gap junction currents by the abused solvent toluene
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DOI：
10.1016/j.drugalcdep.2004.10.005
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发表时间：
2005-05-09
影响因子：
4.2
通讯作者：
Woodward, JJ
中科院分区：
文献类型：
--
作者：
Del Re, AM;Woodward, JJ
滥用吸入剂是一大类化合物，吸入后会产生醉人和改变情绪的效果。它们包括具有已知治疗用途的化学品，如麻醉剂气体，以及在油漆稀释剂和粘合剂中发现的甲苯等挥发性有机溶剂。由于其广泛的商业用途和可获得性，吸入剂往往是儿童最先接触到的药物之一，使用这些化合物往往与不良的急性和长期后果有关。滥用吸入剂的细胞和分子作用部位尚不清楚，尽管最近的研究报告甲苯和其他有机溶剂改变了调节细胞兴奋性的特定配体和电压门控离子通道的活性。作为确定滥用吸入剂的分子作用位点的持续努力的一部分，这项研究检测了甲苯对人胚胎肾脏(HEK 293)细胞内源性表达的缝隙连接蛋白功能的影响。缝隙连接允许细胞间的电子通信以及小分子物质的通过，对于某些组织中的细胞活动同步至关重要。用膜片钳电生理学方法测量HEK 293细胞的缝隙连接电流，并用已知的缝隙连接阻断剂阻断缝隙连接蛋白的表达。甲苯呈剂量依赖性地抑制这些电导，阈值效应出现在大约0.4 mM，在1 mM或更高的浓度下几乎完全抑制。甲苯抑制HEK 293细胞缝隙连接电流的EC50值估计为0.57 mm。这些研究结果表明，包括甲苯在内的挥发性溶剂可能通过干扰缝隙连接蛋白介导的细胞间通讯而产生一些影响。(C)2004爱思唯尔爱尔兰有限公司。保留所有权利。
Abused inhalants are a large class of compounds that are inhaled for their intoxicating and mood altering effects. They include chemicals with known therapeutic uses such as anesthetic gases as well as volatile organic solvents like toluene that are found in paint thinners and adhesives. Because of their widespread commercial use and availability, inhalants are often among the first drugs that children encounter and use of these compounds is often associated with adverse acute and long-term consequences. The cellular and molecular sites of action for abused inhalants is not well known although recent studies report that toluene and other organic solvents alter the activity of specific ligand-and voltage-gated ion channels that regulate cellular excitability. As part of an ongoing effort to define molecular sites of action for abused inhalants, this study examined the effect of toluene on the function of gap junction proteins endogenously expressed in human embryonic kidney (HEK 293) cells. Gap junctions allow cell-to-cell electrical communication as well as passage of small molecular weight substances and are critical for synchronizing cellular activity in certain tissues. Gap junction currents in HEK 293 cells were measured during brief voltage steps using patch-clamp electrophysiology and were blocked by known gap junction blockers confirming expression of connexin proteins in these cells. Toluene dose-dependently inhibited these conductances with threshold effects appearing at approximately 0.4 mM and near complete inhibition occurring at concentrations of I mM and higher. The estimated EC50 value for toluene inhibition of gap junction currents in HEK 293 cells was 0.57 mM. The results of these studies suggest that volatile solvents including toluene may produce some of their effects by disrupting inter-cellular communication mediated by gap junction proteins. (c) 2004 Elsevier Ireland Ltd. All rights reserved.