Reactivation by oximes

The reactivation by oximes and hydroxamic acids of cholinesterase Inhibited by organophosphorus compounds. Brit. J. Pharmacol. Chemotherap. 10 462-465. 

Michel, H.O., 1958 Development of resistance to allqfl phosphorylated cholinesterase to reactivation by oximes (Abstract) Fed. Proc. 17 275. 

Shih, T.M., Kan, R.K. and McDonough, J.H. In vivo reactivation by oximes of nerve agent-inhibited cholinesterase activity in guinea pigs, presented at the Bioscience Review, Hunt Valley, Maryland, 2004. 

The ageing process consists of the monodealkylation of the AChE-nerve agent complex. The loss of an alkyl group produces a conformational change that results in the formation of a very stable agent-enzyme complex which is then resistant to spontaneous hydrolysis and reactivation by oximes. The rate of ageing is dependent... 

Davies DR and Green AL (1956). The kinetics of reactivation, by oximes, of cholinesterase inhibited by organophosphorus compounds. Biochem J, 63, 529-535. 

Typical inhibited cholinesterases produced by dimethoxy and dicthoxy OPs can be reactivated by oximes. 

The differences in oxime efficacy against various nerve agents are mainly due to the various aging rates at which inhibited AChE is converted to a form that can no longer be reactivated by oximes (E5, B32, C7). The reactivation of VX, sarin, or GF-inhibited AChE is still possible hours after the intoxication, while soman-inhibited AChE becomes unreactivatable within minutes and, therefore, renders the treatment of soman poisoning much more difficult (Bll, B16, B17, Cl). Some results were achieved with HI-6 (G8). 

Davies, D.R., Green, A.L., 1956. The kinetics of reactivation, by oximes, of cholinesterase inhibited by organophosphorus compounds. Biochem. J. 63,529-535. Dorandeu, R, Carpentier, P., Baubichon, D., et al., 2005. Efficacy of the ketamine-atropine combination in the delayed treatment of soman-induced status epi-lepticus. Brain Res. 1051 (1-2), 164-175. 

Shih, T.-M., Skovira, J.W., O Donnell, J.C., et al., 2010. In vivo reactivation by oximes of inhibited blood, brain and peripheral tissue cholinesterase activity following exposure to nerve agents in guinea pigs. Chem. Biol. Interact. 187,207-214. 

Figure 3.2 Schematic representation of the reactions between sarin and AChE. (a) Sarin and the active site of AChE combine to form an inhibitor-enzyme intermediate, (b) The fluoride has been lost, leaving a complex of sarin and AChE. From this state, either (c) spontaneous hydrolysis and restoration of function or (d) dealkylation can occur, (c) The ester link in the phosphonylated AChE has been hydrolysed, the enzyme has reactivated and alkyl methyl phosphonic acid has been formed, (d) The link between the alkyl group and the phosphorus has been cleaved. This produces a conformational change that results in the formation of a very stable agent-enzyme complex that is then resistant to spontaneous hydrolysis and reactivation by oximes. This is known as ageing . The rate of ageing is dependent on the nature of the alkyl group and is fairly slow (hours) in the case of sarin and VX, but is very rapid (minutes) in the case of soman. Figure adapted from Vale et aL ...

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