Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Toxicol Lett. 2015 Feb 3;232(3):557-65. doi: 10.1016/j.toxlet.2014.12.009. Epub 2014 Dec 15.
Poisoning by organophosphorus compounds (OP) used as pesticides and nerve agents is due to irreversible inhibition of the enzyme acetylcholinesterase (AChE). Oximes have been widely recognized for their potency to reactivate the inhibited enzyme. The limited efficacy of currently available oximes against a broad spectrum of OP-compounds initiated novel research efforts to improve oxime-based treatment. Hereby, oxime-induced reactivation of OP-inhibited non-human AChE was reported to be accelerated by different AChE-ligands. To investigate this concept with AChE from human source, the inhibitory potency, binding properties and the potential enhancement of oxime-induced reactivation of OP-inhibited AChE by structurally different AChE-ligands was assessed. Several ligands competed with the oxime for the AChE binding-site impairing reactivation of OP-inhibited AChE whereas a markedly accelerated reactivation of sarin-inhibited enzyme by obidoxime was recorded in the presence of edrophonium, galanthamine and donepezil. Enhancement of oxime-induced reactivation with ligands was presumably subject to prevention of re-inhibition by the reaction product phosphonyloxime (POX). In the end, the results of the present study did not confirm that AChE-ligands directly accelerate the reactivation of OP-inhibited AChE by oximes, but indirectly by prevention of re-inhibition by the reaction product POX. This may be due to different experimental conditions and species differences between human and non-human AChE of previous experiments with non-human AChE.
有机磷化合物（OP）用作杀虫剂和神经毒剂导致的中毒，是由于酶乙酰胆碱酯酶（AChE）的不可逆抑制。肟类化合物因其能够重新激活被抑制的酶而被广泛认可。目前可用的肟类化合物对广谱 OP 化合物的疗效有限，这促使人们开展了新的研究工作，以改善基于肟的治疗方法。据报道，不同的 AChE 配体可以加速肟诱导的非人类 AChE 对 OP 抑制的重新激活。为了用人类来源的 AChE 研究这一概念，评估了结构不同的 AChE 配体对 OP 抑制的 AChE 的抑制效力、结合特性和肟诱导重新激活的潜在增强作用。一些配体与肟竞争 AChE 结合位点，从而损害 OP 抑制的 AChE 的重新激活，而在存在依酚氯铵、加兰他敏和多奈哌齐的情况下，沙林抑制的酶的重新激活明显加快。配体增强肟诱导的重新激活可能是由于反应产物磷酰肟（POX）的再抑制被阻止。最终，本研究的结果并未证实 AChE 配体直接加速肟对 OP 抑制的 AChE 的重新激活，而是通过阻止反应产物 POX 的再抑制间接加速。这可能是由于与之前使用非人类 AChE 的实验相比，人类和非人类 AChE 之间的实验条件和物种差异不同。
