title: An unexpected plasma cholinesterase activity rebound after challenge with a high dose of the nerve agent VX.
abstract: Organophosphorus chemical warfare agents (nerve agents) are to be feared in military operations as well as in terrorist attacks. Among them, VX (O-ethyl-S-[2-(diisopropylamino)ethyl] methylphosphonothioate) is a low volatility liquid that represents a percutaneous as well as an inhalation hazard if aerosolized. It is a potent irreversible cholinesterase (ChE) inhibitor that causes severe signs and symptoms, including respiratory dysfunction that stems from different mechanisms. VX-induced pulmonary oedema was previously reported in dogs but mechanisms involved are not well understood, and its clinical significance remains to be assessed. An experimental model was thus developed to study VX-induced cardiovascular changes and pulmonary oedema in isoflurane-anaesthetized swine. In the course of this study, we observed a fast and unexpected rebound of plasma ChE activity following inhibition provoked by the intravenous injection of 6 and 12 microg kg(-1) of VX. In whole blood ChE activity, the rebound could stay unnoticed. Further investigations showed that the rebound of plasma esterase activity was neither related to spontaneous reactivation of ChE nor to VX-induced increase in paraoxonase/carboxylesterase activities. A bias in Ellman assay, haemoconcentration or severe liver cytolysis were also ruled out. All in all, these results suggest that the rebound was likely due to the release of butyrylcholinesterase into the blood stream from ChE producing organs. Nature of the organ(s) and mechanisms involved in enzyme release will need further investigations as it may represent a mechanism of defence, i.e. VX scavenging, that could advantageously be exploited.
authors.affiliation: Département de Toxicologie, Centre de Recherches du Service de Santé des Armées, 24 avenue des Maquis du Grésivaudan, BP 87, F-38702 La Tronche Cedex, France. fdorandeu@crssa.net <fdorandeu@crssa.net>
authors.forename: F
authors.initials: F
authors.lastname: Dorandeu
authors.forename: A
authors.initials: A
authors.lastname: Foquin
authors.forename: R
authors.initials: R
authors.lastname: Briot
authors.forename: C
authors.initials: C
authors.lastname: Delacour
authors.forename: J
authors.initials: J
authors.lastname: Denis
authors.forename: A
authors.initials: A
authors.lastname: Alonso
authors.forename: M T
authors.initials: MT
authors.lastname: Froment
authors.forename: F
authors.initials: F
authors.lastname: Renault
authors.forename: G
authors.initials: G
authors.lastname: Lallement
authors.forename: P
authors.initials: P
authors.lastname: Masson
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D008297:Male; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013552:Swine
chemical_list: D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002802:Cholinesterases; D009946:Organothiophosphorus Compounds; C009680:VX-agent