title: Safety of administration of human butyrylcholinesterase and its conjugates with soman or VX in rats.
abstract: We evaluated the effects of conjugated enzyme-nerve agent product resulting from the inhibition of bioscavenger human serum butyrylcholinesterase (Hu BChE) by nerve agents soman or VX. Rats were trained on a multiple Fixed-Ratio 32, Extinction 30 sec. (FR32, Ext30) schedule of food reinforcement and then injected (i.m.) with Hu BChE (30 mg/kg), equivalent amounts of Hu BChE-soman conjugate (GDC), Hu BChE-VX conjugate, oxotremorine (OXO) (0.316 mg/kg) or vehicle (n = 8, each group). On the day of injection and on 10 subsequent daily sessions, performance was evaluated on the FR32, Ext30 schedule. Neither conjugates nor Hu BChE produced a performance deficit under the schedule. OXO produced a substantial decrease in responding on the day of administration, with complete recovery observed on subsequent sessions. None of the treatments affected circulating acetylcholinesterase (AChE) activity when evaluated 24-72 hr after injection. The dose of Hu BChE produced a 20,000-fold increase above baseline in circulating BChE activity. Pathological evaluation of organ systems approximately 2 weeks following administration of conjugates or Hu BChE alone did not show toxicity. Taken together, these results suggest that Hu BChE - nerve agent conjugates produced following bioscavenger protection against nerve agents soman and VX do not appear to be particularly toxic. These results add to the safety assessment of Hu BChE as a bioscavenger countermeasure against nerve agent exposure.
authors.affiliation: Divisions of Psychiatry and Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. raymond.genovese@us.army.mil
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Genovese
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Christina C
authors.initials: CC
authors.lastname: Johnson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Ditargiani
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010095:Oxotremorine / Q000633:toxicity; D051381:Rats; D012999:Soman / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D010095:Oxotremorine; D012999:Soman; C009680:VX-agent