OXIME-INDUCED REACTIVATION OF CARBOXYLESTERASE INHIBITED BY ORGANOPHOSPHORUS COMPOUNDS

A structure-activity analysis of the ability of oximes to reactivate r at plasma carboxylesterase (CaE) that was inhibited by organophosphoru s (OP) compounds revealed that uncharged oximes, such as 2,3-butanedio ne monoxime (diacetylmonoxime) or monoisonitrosoacetone, were better r eactivators than cationic oximes. Cationic oximes that are excellent r eactivators of OP-inhibited acetylcholinesterase, such as pyridine-2-a ldoxime or the bis-pyridine aldoximes, HI-6 and TMB-4, produced poor r eactivation of OP-inhibited CaE. The best uncharged reactivator was 2, 3-butanedione monoxime, which produced complete reactivation at 0.3 mM in 2 h of CaE that was inhibited by phosphinates, alkoxy-containing p hosphates, and alkoxy-containing phosphonates. Complete reactivation o f CaE could be achieved even after inhibition by phosphonates with hig hly branched alkoxy groups, such as sarin and soman, that undergo rapi d aging with acetylcholinesterase. CaE that was inhibited by phosphona tes or phosphates that contained aryloxy groups were reactivated to a lesser extent. The cause of this decreased reactivation appears to be an oxime-induced aging reaction that competes with the reactivation re action. This oxime-induced aging reaction is accelerated by electron-w ithdrawing substituents on the aryloxy groups of phosphonates and by t he presence of multiple aryloxy groups on phosphates. Thus, reactivati on and aging of OP-inhibited CaE differ from the same processes for OP -inhibited acetylcholinesterase in both their oxime specificity and in hibitor specificity and, presumably, in their underlying mechanisms.