engleski

Oxime-assisted Reactivation of Phosphorylated Butyrylcholinesterase

A new approach to reduce the in vivo toxicity of chemical warfare nerve agents includes the use of bioscavengers – enzymes that could react with nerve agent before it inhibits acetylcholinesterase (AChE ; EC 3.1.1.7) at the physiologically important target sites. Butyrylcholinesterase (BChE ; EC 3.1.1.8), naturally present in plasma, liver, small intestine, smooth muscle, hearth, adipose tissue and in the brain, is considered an endogenous stochiometric bioscavenger of anticholinesterase compounds. Due to a limited concentration of BChE in organism, a stochiometric reduction of nerve agents is not always sufficient. This can be improved by creating a pseudo-catalytic scavenger adding oxime as a reactivator of inhibited BChE. In order to discuss BChE endogenous bioscavenging function in tabun and paraoxon poisoning, we tested in vitro reactivation of phosphorylated human plasma BChE by several bispyridinium oximes. In the case of tabun-inhibited BChE, the most potent reactivators were K117 [1, 1'-(2, 2'-oxybis(ethane-2, 1-diyl))bis(4-hydroxyiminomethyl pyridinium) bromide] and K127 [4-carbamoyl-1-(2-(2-(4-(hydroxyiminomethyl) pyridinium-1-yl)ethoxy)ethyl)pyridinium bromide]. The reactivation by these oximes (1 mM) reached about 50 % after only 20 min, but reactivation stopped at 70 %. Observed first order reactivation rate constants (kobs) were 0.05 min-1 for K117 and 0.03 min-1 for K127. On the other hand, reactivation of paraoxon-inhibited BChE, was much slower by all of the selected oximes. The maximum of 70-95 % was obtained in 8 h with kobs ranging from 0.004-0.006 min-1. Nevertheless, reactivation results obtained for K117 and K127, pointed out these oximes as promising leads in the search and development of new BChE reactivators.

reactivators; oximes; tabun; inhibition; butylcholinesterase

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