engleski

Development of new antidotes of organophosphate intoxications: Oxime-assisted reactivation of dimethoxy- and diethoxyphosphorylated human butyrylcholinesterase for construction of “pseudo catalytic” bioscavengers

Oxon forms of organophosphorus pesticides (e.g. chlorpyrifos) and nerve agents (e.g. sarin, VX) act as strong irreversible inhibitors of acetylcholinesterase (AChE) which is a key enzyme of human body involved in neurotransmission. For the recovery of inhibited AChE, pyridinium aldoximes (oximes) are used as antidotes. Relatively new approach in the treatment of organophosphate (OP) intoxications is a use of specific enzymes called bioscavengers. Bioscavengers neutralize the molecules of OPs in the bloodstream before they can reach their natural targets. Suitable enzyme for this purpose could be butyrylcholinesterase (BuChE), because it is under several clinical trials now. The antidotal efficacy of the enzyme could be further increased by combination with BuChE reactivator with sufficient reactivation ability. This combination can act as a “pseudo catalytic” bioscavenger where the catalytic activity of OP-inhibited cholinesterase could be continuously renewed in the presence of suitable oxime. For these purposes we have tested in vitro potency of 23 structurally different reactivators in concentration 100 and 10
M to reactivate human BuChE inhibited by dimethoxy- and diethoxy-OPs dichlorvos and paraoxon. The best reactivation ability for dichlorvos-inhibited BuChE was estimated for obidoxime, compound K033, K316. In the case of reactivation of paraoxon-inhibited BuChE, the best reactivators were K117, trimedoxime, K269. However, reactivation ability of tested oximes was low (less than 5% for dichlorvos and 20% for paraoxon) and therefore new and more potent reactivators of BuChE must be developed.

butyrylcholinesterase; bioscavenger; oximes; reactivation; pesticides

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