Abstract
Several quaternary oxime reactivators of phosphorylated cholinesterases (ChE) are effective antidotes in organophosphates (OP) toxicity. Reactivation of OP-inhibited ChEs probably proceeds via nucleophilic displacement which causes the accumulation of a phosphorylated oxime (POX) intermediate. Several POXs that were generated in situ over the last 4 decades from a variety of oxime antidotes and OPs, have been demonstrated to be more potent inhibitors of acetylcholinesterase (AChE) than the parent OPs (1, 2). Their rapid removal is expected to improve therapeutic management of OP toxicity by oxime antidotes (1). In order to examine the possibility of augmenting the endogenous detoxification of POXs by exogenous stoichoimetric (e. g., ChE) or a catalytic (e. g., phosphotriesterase; PTE) scavenger, the diethylphosphoric acid esters of 1-methyl-4 pyridinium carboxaldehyde oxime (DEP-4PAM) and of 1-methyl-2-pyridinium carboxaldehyde oxime (DEP-2PAM) were synthesized and their structure and homogeneity was determined by 1H, 31P, MS, and UV spectroscopies. DEP-4PAM was fully characterized as inhibitor of butyrylcholinesterases (BChE) and AChEs, and as a substrate of a PTE purified from Pseudomonas sp. In addition, the stability of the POXs and their decomposition pathways in aqueous solutions were studied by product identification. DEP-4PAM has t1/2 of 11 min in phosphate buffer pH 8.0, and was found to inhibit ChEs with the following ranking order: human BChE (7.1×108 M−1 min−1) »equine BChE > mouse AChE > fetal bovine serum AChE. PTE-induced hydrolysis of DEP-4PAM was recorded at kcat/Km = 3.6×107 M−1 min−1 with Km = 0.78 mM.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call