title: Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes.
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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA. zradic@ucsd.edu
authors.forename: Zoran
authors.initials: Z
authors.lastname: Radić
authors.forename: Trevor
authors.initials: T
authors.lastname: Dale
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Suzana
authors.initials: S
authors.lastname: Berend
authors.forename: Edzna
authors.initials: E
authors.lastname: Garcia
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Amitai
authors.forename: Carol
authors.initials: C
authors.lastname: Green
authors.forename: Božica
authors.initials: B
authors.lastname: Radić
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Duggan
authors.forename: Dariush
authors.initials: D
authors.lastname: Ajami
authors.forename: Julius
authors.initials: J
authors.lastname: Rebek
authors.forename: Palmer
authors.initials: P
authors.lastname: Taylor
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002384:Catalysis; D002619:Chemical Warfare Agents / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D010755:Organophosphates / Q000378:metabolism* / Q000633:toxicity; D010091:Oximes / Q000737:chemistry* / Q000378:metabolism; D010261:Paraoxon / Q000378:metabolism* / Q000633:toxicity; D012524:Sarin / Q000378:metabolism* / Q000633:toxicity
chemical_list: D002619:Chemical Warfare Agents; D010755:Organophosphates; D010091:Oximes; D012524:Sarin; D002091:Butyrylcholinesterase; D010261:Paraoxon