Suitability of human butyrylcholinesterase as therapeutic marker and pseudo catalytic scavenger in organophosphate poisoning: a kinetic analysis.
The widespread use of organophosphorus compounds (OPs) as pesticides and the frequent misuse of OP nerve agents in military conflicts or terrorist attacks emphasize the high clinical relevance of OP poisoning. The toxic symptomatology is caused by inhibition of acetylcholinesterase (AChE). A mainstay of standard antidotal treatment is atropine for antagonizing effects mediated by over stimulation of muscarinic ACh-receptors and oxime to reactivate OP-inhibited AChE. For therapeutic monitoring of oxime treatment in OP poisoning, measurement of erythrocyte AChE is suitable because erythrocyte AChE is an easily accessible surrogate for synaptic AChE. However, measurement of erythrocyte AChE is not standard practice. In contrast, determination of plasma butyrylcholinesterase (BChE) activity is in routine use for monitoring the benefit of oxime therapy. As oxime efficacy is limited with certain OPs (e.g. dimethoate, tabun, soman) alternative therapeutic approaches, e.g. the application of scavengers (BChE) which may sequester OPs before they reach their physiological target, are under investigation. To assess the eligibility of BChE as laboratory parameter and (pseudo catalytic or stoichiometric) scavenger in OP poisoning we initiated an in vitro study under standardized experimental conditions with the objective of determination of kinetic constants for inhibition, reactivation and aging of plasma BChE. It could be shown that, due to limited efficacy of obidoxime, pralidoxime, HI 6 and MMB4 with OP-inhibited BChE, plasma BChE activity is an inappropriate parameter for therapeutic monitoring of oxime treatment in OP poisoning. Furthermore, oxime-induced reactivation is too slow to accomplish a pseudo catalytic function, so that administered BChE may be merely effective as a stoichiometric scavenger.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
N
N
Aurbek
H
H
Thiermann
F
F
Eyer
P
P
Eyer
F
F
Worek
D000110:Acetylcholinesterase / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000506:poisoning; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000493:pharmacokinetics*; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009768:Obidoxime Chloride / Q000737:chemistry / Q000493:pharmacokinetics; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D010575:Pesticides / Q000493:pharmacokinetics / Q000506:poisoning; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D011726:Pyridinium Compounds / Q000494:pharmacology / Q000627:therapeutic use
D015415:Biomarkers; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D010575:Pesticides; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; C005514:N,N'-monomethylenebis(pyridiniumaldoxime); D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime