In vitro oxime-assisted reactivation of paraoxon-inhibited human acetylcholinesterase and butyrylcholinesterase.
BACKGROUND
Organophosphorus pesticides and nerve agents are highly toxic to humans and other living organisms, primarily because of their interaction with enzyme acetylcholinesterase. The aim of our study was to find suitable reactivators of acetylcholinesterase and butyrylcholinesterase and to recommend the most efficacious compounds for the next evaluation as antidotes for intoxication by pesticides.


METHODS
Eighteen structurally different oxime reactivators were tested for their in vitro ability to reactivate paraoxon-inhibited human erythrocyte acetylcholinesterase and human plasma butyrylcholinesterase to find out structure-activity relationship within this set of compounds. Their reactivation ability was compared with commercially available acetylcholinesterase reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, and HI-6).


CONCLUSIONS
The best reactivation ability was achieved with obidoxime, trimedoxime, compounds K027, K075, K203, and K048. We have also tested reactivation of butyrylcholinesterase with the aim to recommend an efficient reactivator, able to perform a "pseudo catalytic" bioscavenger with butyrylcholinesterase, which is developed as new antidote of organophosphate poisonings. Such combination could allow an enhancement of prophylactic and therapeutic efficiency of administered enzyme. Compounds K117, K269, K075, and trimedoxime were found to be the most potent reactivators of inhibited butyrylcholinesterase.


CONCLUSIONS
In this work, we have evaluated only reactivation of paraoxon-inhibited cholinesterases. To get better understanding of this problem, a larger number of organophosphorus inhibitors should be used.
Musilova
Lucie
L
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic. lucie.musil@centrum.cz
Kuca
Kamil
K
Jung
Young-Sik
YS
Jun
Daniel
D
D000110:Acetylcholinesterase / Q000378:metabolism*; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D015394:Molecular Structure; D010261:Paraoxon / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D000110:Acetylcholinesterase; D010261:Paraoxon