Comparative study of oxime-induced reactivation of erythrocyte and muscle AChE from different animal species following inhibition by sarin or paraoxon.
Standard treatment of acute poisoning by organophosphorus compounds (OP) includes administration of an antimuscarinic (e.g. atropine) and of an oxime-based reactivator of OP-inhibited acetylcholinesterase (AChE). A recently introduced dynamically working in vitro model with real-time determination of membrane-bound AChE activity was shown to be a very versatile and promising model to investigate oxime-induced reactivation kinetics of OP-inhibited enzyme. In this assay, human AChE from erythrocytes or muscle tissue was immobilized on a particle filter. This bioreactor was continuously perfused with substrate and chromogen and AChE activity was analyzed on-line in a flow-through detector. The model has been successfully adopted to Rhesus monkey, swine and guinea pig erythrocytes and intercostal muscle AChE. In addition, the basic kinetic constants of inhibition, aging, spontaneous- and oxime-induced-reactivation of erythrocyte AChE from these species were determined with a standard static model. The major findings were, in part substantial species differences in the inhibition (sarin, paraoxon) and reactivation kinetics (obidoxime, HI 6) of erythrocyte AChE, but comparable kinetics of inhibition and reactivation between erythrocyte and muscle AChE. Hence, these data provide further support of the assumption that erythrocyte AChE is an adequate surrogate of muscle (synaptic) AChE and admonish that major species differences have to be considered for the design and evaluation of therapeutic animal models.
Bundeswehr Institute of Pharmacology and Toxicology, 80937 Munich, Germany.
Nadja M
NM
Herkert
Nadine
N
Aurbek
Peter
P
Eyer
Horst
H
Thiermann
Franz
F
Worek
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D006168:Guinea Pigs; D008253:Macaca mulatta; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D010261:Paraoxon / Q000633:toxicity; D012524:Sarin / Q000633:toxicity; D013552:Swine
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D012524:Sarin; D000110:Acetylcholinesterase; D010261:Paraoxon