Title : Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes - Radic_2013_Biochem.J_450_231 |
Author(s) : Radic Z , Dale T , Kovarik Z , Zunec S , Garcia E , Zhang LM , Amitai G , Green C , Radic B , Duggan BM , Ajami D , Rebek J , Taylor P |
Ref : Biochemical Journal , 450 :231 , 2013 |
Abstract :
In the present paper we show a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide OPs (organophosphates) catalysed by purified hBChE (human butyrylcholinesterase) in combination with novel non-pyridinium oxime reactivators. We identified TAB2OH (2-trimethylammonio-6-hydroxybenzaldehyde oxime) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents VX and cyclosarin, and the pesticide paraoxon. It was also functional in reactivation of sarin- and tabun-inhibited hBChE. A 3-5-fold enhancement of in vitro reactivation of VX-, cyclosarin- and paraoxon-inhibited hBChE was observed when compared with the commonly used N-methylpyridinium aldoxime reactivator, 2PAM (2-pyridinealdoxime methiodide). Kinetic analysis showed that the enhancement resulted from improved molecular recognition of corresponding OP-hBChE conjugates by TAB2OH. The unique features of TAB2OH stem from an exocyclic quaternary nitrogen and a hydroxy group, both ortho to an oxime group on a benzene ring. pH-dependences reveal participation of the hydroxy group (pKa=7.6) forming an additional ionizing nucleophile to potentiate the oxime (pKa=10) at physiological pH. The TAB2OH protective indices in therapy of sarin- and paraoxon-exposed mice were enhanced by 30-60% when they were treated with a combination of TAB2OH and sub-stoichiometric hBChE. The results of the present study establish that oxime-assisted catalysis is feasible for OP bioscavenging. |
PubMedSearch : Radic_2013_Biochem.J_450_231 |
PubMedID: 23216060 |
Reactivator | TAB2OH |
Radic Z, Dale T, Kovarik Z, Zunec S, Garcia E, Zhang LM, Amitai G, Green C, Radic B, Duggan BM, Ajami D, Rebek J, Taylor P (2013)
Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes
Biochemical Journal
450 :231
Radic Z, Dale T, Kovarik Z, Zunec S, Garcia E, Zhang LM, Amitai G, Green C, Radic B, Duggan BM, Ajami D, Rebek J, Taylor P (2013)
Biochemical Journal
450 :231