In vitro detoxification of cyclosarin in human blood pre-incubated ex vivo with recombinant serum paraoxonases

被引:16
作者
Ashani, Yacov [1 ,4 ]
Goldsmith, Moshe [2 ]
Leader, Haim [3 ]
Silman, Israel [4 ]
Sussman, Joel L. [1 ]
Tawfik, Dan S. [2 ]
机构
[1] Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel
[3] Weizmann Inst Sci, Dept Mat & Interfaces, IL-76100 Rehovot, Israel
[4] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel
关键词
Paraoxonase; Cholinesterase; Cyclosarin; Nerve agent; Detoxification; Protection; ACETYLCHOLINESTERASE ACTIVITY; TOXICITY; INHIBITION; PROTECTION; PON1;
D O I
10.1016/j.toxlet.2011.07.017
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 [卫生毒理学];
摘要
An ex vivo protocol was developed to assay the antidotal capacity of rePON1 variants to protect endogenous acetylcholinesterase and butyrylcholinesterase in human whole blood against OP nerve agents. This protocol permitted us to address the relationship between blood rePON1 concentrations, their kinetic parameters, and the level of protection conferred by rePON1 on the cholinesterases in human blood, following a challenge with cyclosarin (GF). The experimental data thus obtained were in good agreement with the predicted percent residual activities of blood cholinesterases calculated on the basis of the rate constants for inhibition of human acetylcholinesterase and butyrylcholinesterase by GF, the concentration of the particular rePON1 variant, and its k(cat)/K(m) value for GF. This protocol thus provides a rapid and reliable ex vivo screening tool for identification of rePON1 bioscavenger candidates suitable for protection of humans against organophosphorus-based toxicants. The results also permitted the refinement of a mathematical model for estimating the efficacious dose of rePON1s variants required for prophylaxis in humans. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:24 / 28
页数:5
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