Comparative kinetics of organophosphates and oximes with erythrocyte, muscle and brain acetylcholinesterase.
There is an ongoing debate whether oximes can effectively counteract the effects of organophosphorus compounds (OP) on brain acetylcholinesterase (AChE) activity and whether there are differences in the kinetic properties of brain and erythrocyte AChE. In order to investigate the kinetics of AChE from different tissues and species the well established dynamically working in vitro model with real-time determination of membrane-bound AChE activity was adapted for use with brain AChE. The enzyme reactor, that was loaded with brain, erythrocyte or muscle AChE, was continuously perfused with substrate and chromogen while AChE activity was on-line analyzed in a flow-through detector. It was possible to determine the Michaelis-Menten constants of human erythrocyte, muscle and brain AChE which were almost identical. In addition, the inhibition kinetics of sarin and paraoxon as well as the reactivation kinetics of obidoxime and HI 6 were determined with human, swine and guinea pig brain and erythrocyte AChE. It was found that the inhibition and reactivation kinetics of brain and erythrocyte AChE were highly comparable in all tested species. These data support the view that AChE from different tissue has similar kinetic properties and that brain AChE is comparably susceptible toward reactivation by oximes.
Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Nadja M
NM
Herkert
Gregor
G
Freude
Ulrich
U
Kunz
Horst
H
Thiermann
Franz
F
Worek
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D010755:Organophosphates / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D010091:Oximes / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013552:Swine
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase