Inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds: pig versus minipig acetylcholinesterase.
Organophosphorus compound-based (OP) chemical warfare agents (nerve agents) represent a continuing threat to military forces and the civilian population. OPs act primarily by inhibiting acetylcholinesterase (AChE), the standard treatment for which includes AChE reactivators (oximes) in combination with antimuscarinic drugs. In the last decades, the efficacy of oximes has been investigated mostly in small animal models. In order to increase the predictive value of animal studies it is desirable to measure numerous physiological and biochemical parameters. This is difficult in small animals. Large animal models fulfil these requirements and swine are increasingly being used in toxicology studies. Swine breeds generally show considerable variability in different characteristics which may be minimised by the use of specially bred minipigs which have a known genetic background and health status. A comparative study was, therefore, initiated to investigate the kinetic properties of the White Landrace pig and Göttingen minipig AChE in respect of inhibition by the pesticide paraoxon; the nerve agents cyclosarin, VX and VR; the reactivation of inhibited AChE by oximes (obidoxime, pralidoxime and HI 6); and the aging and spontaneous reactivation of inhibited AChE. The determination of the respective kinetic constants found similarities between pig and minipig AChE which showed marked differences in comparison with human AChE values. This has to be considered in designing meaningful models for the investigation of oxime efficacy in pig or minipig experiments. The generated data indicate comparable kinetic properties of pig and minipig AChE and may provide a kinetic basis for extrapolation of data from pig studies to humans.
Worek
F
F
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. FranzWorek@Bundeswehr.org
Aurbek
N
N
Wetherell
J
J
Pearce
P
P
Mann
T
T
Thiermann
H
H
D000110:Acetylcholinesterase / Q000097:blood* / Q000378:metabolism; D000375:Aging; D000465:Algorithms; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood* / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D023421:Models, Animal; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000633:toxicity*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D010261:Paraoxon / Q000737:chemistry / Q000633:toxicity; D013552:Swine; D013556:Swine, Miniature
D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D010091:Oximes; D010261:Paraoxon; C009680:VX-agent; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate; C053914:cyclohexyl methylphosphonofluoridate