title: Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase.
abstract: Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates.
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: acoban@umc.edu.
authors.forename: Alper
authors.initials: A
authors.lastname: Coban
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: russell.carr@cvm.msstate.edu.
authors.forename: Russell L
authors.initials: RL
authors.lastname: Carr
authors.affiliation: Center for Environmental Health Sciences, Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, P.O. Box 9775, Mississippi State, MS 39762, USA. Electronic address: hwc2@msstate.edu.
authors.forename: Howard W
authors.initials: HW
authors.lastname: Chambers
authors.affiliation: Center for Environmental Health Sciences, Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, P.O. Box 9775, Mississippi State, MS 39762, USA. Electronic address: kwilleford@bch.msstate.edu.
authors.forename: Kenneth O
authors.initials: KO
authors.lastname: Willeford
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, P.O. Box 6100, Mississippi State, MS 39762, USA. Electronic address: chambers@cvm.msstate.edu.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Chambers
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D000067397:Nerve Agents / Q000737:chemistry / Q000633:toxicity*; D010755:Organophosphates / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D000067397:Nerve Agents; D010755:Organophosphates; D000110:Acetylcholinesterase
keywords: Anticholinesterase; Inhibition kinetics; Organophosphate