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Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Radic, Z. Bosnjak Dale, Trevor Kovarik, Zrinka Berend, Suzana Garcia, E. Suarez Zhang, Limin Amitai, Gavriel Green, Carol Begay Radic, B. Velimir Duggan, Brendan M. Ajami, Dariush Rebek, Julius Taylor, Palmer |
| Copyright Year | 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. |
| Starting Page | 424 |
| Ending Page | 426 |
| Page Count | 3 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.biochemj.org/content/ppbiochemj/450/1/231.full.pdf |
| PubMed reference number | 23216060v1 |
| Alternate Webpage(s) | https://doi.org/10.1042/BJ20121612 |
| DOI | 10.1042/bj20121612 |
| Journal | The Biochemical journal |
| Volume Number | 450 |
| Issue Number | 1 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Butyrylcholinesterase Fluor-Op Immunostimulating conjugate (antigen) Nerve Agents Oximes Paraoxon Pesticides Phosphoric Acid Esters Pralidoxime Compounds Reactivation Technetium Tc 99m Exametazime cyclohexyl methylphosphonofluoridate deoxypyridinoline hydroxyl group insulin, N-methylpyridinium non-T, non-B childhood acute lymphoblastic leukemia pesticide poisoning tabun |
| Content Type | Text |
| Resource Type | Article |
