Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Toxicol Lett. 2018 Sep 1;293:216-221. doi: 10.1016/j.toxlet.2017.10.005. Epub 2017 Oct 6.
Acetylcholinesterase (AChE) inhibited by the organophosphorus nerve (OP) agent soman underlies a spontaneous and extremely rapid dealkylation ("aging") reaction which prevents reactivation by oximes. However, in vivo studies in various, soman poisoned animal species showed a therapeutic effect of oximes, with the exact mechanism of this effect remaining still unclear. In order to get more insight and a basis for the extrapolation of animal data to humans, we applied a dynamic in vitro model with continuous online determination of AChE activity. This model allows to simulate the in vivo toxico- and pharmacokinetics between human and guinea pig AChE with soman and the oximes HI-6 and MMB-4 in order to unravel the species dependent kinetic interactions. It turned out that only HI-6 was able to slow down the ongoing inhibition of human AChE by soman without preventing final complete inhibition of the enzyme. Continuous perfusion of AChE with soman and simultaneous or delayed (8, 15 or 40min) oxime perfusion did not result in a relevant reactivation of AChE (less than 2%). In conclusion, the results of the present study indicate a negligible reactivation of soman-inhibited AChE by oximes at conditions simulating the in vivo poisoning by soman. The observed therapeutic effect of oximes in soman poisoned animals in vivo must be attributed to alternative mechanisms which may not be relevant in humans.
乙酰胆碱酯酶（AChE）被有机磷神经（OP）剂梭曼抑制，这是一种自发且极快的脱烷基（“老化”）反应，可防止肟类化合物的重新激活。然而，在各种梭曼中毒的动物物种的体内研究表明肟类化合物具有治疗作用，但其确切机制仍不清楚。为了更深入地了解并为将动物数据外推到人类提供依据，我们应用了一种具有连续在线测定 AChE 活性的动态体外模型。该模型允许模拟人与豚鼠 AChE 之间的体内毒代动力学和药代动力学，用梭曼和肟类化合物 HI-6 和 MMB-4 来揭示物种相关的动力学相互作用。结果表明，只有 HI-6 能够减缓梭曼对人 AChE 的持续抑制，而不会阻止酶的最终完全抑制。连续灌注 AChE 与梭曼，并同时或延迟（8、15 或 40min）灌注肟类化合物，不会导致 AChE 的明显重新激活（小于 2%）。总之，本研究的结果表明，在模拟梭曼体内中毒的条件下，肟类化合物对梭曼抑制的 AChE 的重新激活作用可以忽略不计。肟类化合物在体内梭曼中毒动物中的治疗效果必须归因于替代机制，这些机制在人类中可能并不相关。
