Gant D B, Eldefrawi M E, Eldefrawi A T
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
Fundam Appl Toxicol. 1987 Nov;9(4):698-704. doi: 10.1016/0272-0590(87)90176-x.
The effects of several organophosphates were studied on the binding of t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) to rat brain GABAA receptor and receptor function as assayed by GABA-induced 36Cl-influx into membrane vesicles and on the binding of [35S]TBPS to a voltage-dependent Cl-channel in Torpedo californica electric organ. The organophosphate anticholinesterases diisopropylphosphorofluoridate, soman, sarin, tabun, and VX had little or no effect on GABA-regulated chloride channels. They also had no effect on [35S]TBPS binding to the voltage-dependent chloride channel, except for soman which inhibited it with an IC50 of 24 microM. Triphenyl phosphate was the only one of three organophosphate flame retardants tested that inhibited both GABA-regulated chloride channel and binding of [35S]TBPS to the voltage-dependent chloride channel with IC50s of 18 and 13 microM, respectively. The industrial organophosphate tri-o-cresyl phosphate and the anticholinesterase organophosphate insecticides leptophos, leptophos oxon, and O-ethyl O-4-nitrophenyl phenylphosphonothioate inhibited GABA-regulated chloride channels and bound with high affinity to the voltage-dependent chloride channels (IC50 = 0.3 to 8.7 microM). There was no apparent correlation between the affinities of the GABAA receptor chloride channel or the voltage-dependent chloride channel for the different organophosphates and their potencies in inhibiting acetylcholinesterase or in inducing delayed neurotoxicity. Nevertheless, although the voltage-dependent chloride channel and/or GABAA receptor are not primary targets for organophosphate anticholinesterases and flame retardants, it is suggested that the inhibition of these two proteins by certain organophosphates may contribute to their toxicities.
研究了几种有机磷酸酯对大鼠脑γ-氨基丁酸A型（GABAA）受体结合t-[35S]丁基-双环硫代磷酸酯（[35S]TBPS）的影响以及对受体功能的影响（通过γ-氨基丁酸诱导的36Cl流入膜囊泡来测定），还研究了其对加州电鳐电器官中电压依赖性氯离子通道结合[35S]TBPS的影响。有机磷酸酯类抗胆碱酯酶剂二异丙基氟磷酸酯、梭曼、沙林、塔崩和维埃克斯对γ-氨基丁酸调节的氯离子通道几乎没有影响或没有影响。它们对[35S]TBPS与电压依赖性氯离子通道的结合也没有影响，不过梭曼除外，它以24微摩尔/升的半数抑制浓度（IC50）抑制该结合。磷酸三苯酯是所测试的三种有机磷酸酯类阻燃剂中唯一一种抑制γ-氨基丁酸调节的氯离子通道以及[35S]TBPS与电压依赖性氯离子通道结合的物质，其IC50分别为18微摩尔/升和13微摩尔/升。工业用有机磷酸酯三邻甲苯基磷酸酯以及抗胆碱酯酶有机磷酸酯类杀虫剂倍硫磷、倍硫磷氧砜和O-乙基-O-4-硝基苯基苯硫代磷酸酯抑制γ-氨基丁酸调节的氯离子通道，并与电压依赖性氯离子通道高亲和力结合（IC50 = 0.3至8.7微摩尔/升）。GABAA受体氯离子通道或电压依赖性氯离子通道对不同有机磷酸酯的亲和力与其抑制乙酰胆碱酯酶或诱导迟发性神经毒性的效力之间没有明显的相关性。然而，尽管电压依赖性氯离子通道和/或GABAA受体不是有机磷酸酯类抗胆碱酯酶剂和阻燃剂的主要靶点，但有研究表明某些有机磷酸酯对这两种蛋白质的抑制作用可能会导致其毒性。
