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.
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Research Article|
January 24 2013
Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes
Zoran Radić;
Zoran Radić
1
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, U.S.A.
1To whom correspondence should be addressed (email [email protected]).
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Trevor Dale;
Trevor Dale
†Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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Zrinka Kovarik;
Zrinka Kovarik
‡Institute for Medical Research and Occupational Health, HR-10001 Zagreb, Croatia
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Suzana Berend;
Suzana Berend
‡Institute for Medical Research and Occupational Health, HR-10001 Zagreb, Croatia
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Edzna Garcia;
Edzna Garcia
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, U.S.A.
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Limin Zhang;
Limin Zhang
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, U.S.A.
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Gabriel Amitai;
Gabriel Amitai
§Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona 74100, Israel
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Carol Green;
Carol Green
∥SRI International, Menlo Park, CA 94025-3493, U.S.A.
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Božica Radić;
Božica Radić
‡Institute for Medical Research and Occupational Health, HR-10001 Zagreb, Croatia
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Brendan M. Duggan;
Brendan M. Duggan
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, U.S.A.
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Dariush Ajami;
Dariush Ajami
†Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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Julius Rebek, Jr;
Julius Rebek, Jr
†Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, U.S.A.
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Palmer Taylor
Palmer Taylor
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, U.S.A.
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Publisher: Portland Press Ltd
Received:
October 22 2012
Revision Received:
December 04 2012
Accepted:
December 06 2012
Accepted Manuscript online:
December 06 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 450 (1): 231–242.
Article history
Received:
October 22 2012
Revision Received:
December 04 2012
Accepted:
December 06 2012
Accepted Manuscript online:
December 06 2012
Citation
Zoran Radić, Trevor Dale, Zrinka Kovarik, Suzana Berend, Edzna Garcia, Limin Zhang, Gabriel Amitai, Carol Green, Božica Radić, Brendan M. Duggan, Dariush Ajami, Julius Rebek, Palmer Taylor; Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes. Biochem J 15 February 2013; 450 (1): 231–242. doi: https://doi.org/10.1042/BJ20121612
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