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ToxSci Advance Access published online on August 13, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm215
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aging pathways for organophosphate inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry

He Li{ddagger}, Lawrence M. Schopfer{ddagger}, Florian Nachon§, Marie-Thérèse Froment§, Patrick Masson§ and Oksana Lockridge{ddagger},*

{ddagger} Eppley Institute and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-6805 § Centre de Recherches du Service de Santé des Armées, Département de Toxicologie-Unité d'Enzymologie, 24 avenue des Maquis du Grésivaudan-BP87, 38702 La Tronche cedex, France

* To whom correspondence should be addressed. Tel: (402) 559-6032. Fax: (402) 559-4651. E-mail: olockrid{at}unmc.edu

Received June 27, 2007; revision received July 23, 2007; accepted July 24, 2007


  Abstract

Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N or S; and Y can be methyl, OR or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a non-reactivatable enzyme. Aging mechanisms have been studied primarily using acetylcholinesterase. However, some recent studies have indicated that organophosphate inhibited butyrylcholinesterase may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to study the aging mechanism of human butyrylcholinesterase inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate, isomalathion, soman, sarin, cyclohexyl-sarin, VX and VR. Inhibited butyrylcholinesterase was aged in the presence of H2O18 to allow incorporation of 18O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate-conjugates were identified through peptide mass mapping. Our results showed no aging of VX and VR treated butyrylcholinesterase at 25°C, pH 7.0. However, butyrylcholinesterase inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate, soman, sarin and cyclohexyl-sarin aged exclusively through O-C bond cleavage, i.e. the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage.

Key Words: butyrylcholinesterase; organophosphate; aging; mass spectrometry.


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