engleski

Interaction of the pyridinium oximes K027, K033 and K048 with native and tabun-inhibited human acetylcholinesterase

The mechanism of nerve agent tabun poisoning involves phosphorylation of a serine hydroxyl group in the active site of human acetylcholinesterase (AChE ; EC 3.1.1.7), leading to inactivation of this essential enzyme. The therapeutic approach to organophosphate poisoning is to reactivate AChE with a site-directed nucleophile such as an oxime. The ability of three bispyridinium oximes K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] and K033 [1, 4-bis(2-hydroxyiminomethylpyridinium) butane dibromide] to reactivate tabun-inhibited human erythrocyte AChE was evaluated. Reversible inhibition of native AChE by these oximes and their protective index from inactivation by tabun were determined as well. Tabun-inhibited AChE was completely reactivated by micromolar concentrations of K027 and K048 within two hours with the overall reactivation rate constants 303 min-1M-1 and 640 min-1M-1, respectively. The reactivation by K033 reached 60 % after 26 hours. The enzyme-oxime dissociation constants for K027, K048 and K033 binding to native AChE were 130 μ M, 130 μ M and 15 μ M, respectively. Although K033 did not show significant reactivation ability, this oxime might be of interest as a pretreatment drug due to its high affinity for the native AChE. The theoretically calculated protective index of oxime against AChE phosphorylation by tabun was as high as 7.6 for 0.1 mM K033, and only 1.8 for 0.1 mM K027 and K048. Our experiments pointed out K048 and K027 as promising reactivators in tabun poisoning and K033 as a promising protective agent.

antidotes; acetylcholinesterase; tabun; reactivation; oxime

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