engleski

In vitro interactions between pyridinium aldoximes and endogenous bio-scavenger butyrylcholinesterase in tabun poisoning

Kinetic parameters were evaluated for inhibition and reactivation of tabun-inhibited human plasma butyrylcholinesterase (BChE ; EC 3.1.1.8) by five pyridinium aldoximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], K033 [1, 4-bis(2-hydroxyiminomethylpyridinium) butane dibromide], HI-6 [(1-(2’ -hydroxyimi-nomethyl-1'-pyridinium)-3-(4''-carbamoyl-1''-pyridinium)-2-oxapropane dichloride)] and TMB-4 [1, 3-bis(4-hydroxyiminomethylpyridinium) propane dibromide]. Selected aldoximes have been recently evaluated as protectors/reactivators of tabun-inhibited human erythrocyte AChE [1]. Since BChE can be considered an endogenous bio-scavenger of anticholinesterase compounds, in order to discuss the possible use of BChE as scavenging agent, and BChE prophylactic properties, we examined aldoxime interactions with BChE. Progressive inhibition by tabun was faster for BChE than for AChE, indicating that BChE would scavenge tabun prior to AChE inhibition [1]. The reactivation of tabun-inhibited BChE by selected aldoximes was very slow, reaching maximum of 70%, which means that BChE in combination with the aldoximes investigated cannot be considered as catalytic scavenger of tabun. The overall reactivation rate constants were between 2.2 and 53.6 min-1M-1. Interestingly, the fastest reactivation was achieved by K033, aldoxime with the lowest efficacy for reactivation of tabun-inhibited AChE. The phosphorylated BChE had lower affinities for two potent AChE reactivators, K027 and K048, than phosphorylated AChE, indicating that fast AChE reactivation by these aldoximes would not be obstructed by interactions between BChE and aldoxime [1]. All aldoximes reversibly inhibited BChE and the enzyme-aldoxime dissociation constants ranged between 0.04 and 0.70 mM. However, BChE had lower affinities for aldoximes than AChE (except for TMB-4 for which both enzymes had similar affinity) indicating aldoxime preference for binding to the native AChE [1]. These results imply possible use of the aldoximes as protectors of AChE against phosphorylation by tabun. [1] Čalić, M. et al (2006) Toxicology 219, 85-96.

antidotes; nerve agent; tabun; butyrylcholinesterase

nije evidentirano