title: Reactions of isodimethoate with human red cell acetylcholinesterase.
abstract: Isodimethoate is a thermal decomposition product that is present in usual pesticide formulations of dimethoate. Owing to its PO structure the compound is a direct anticholinesterase agent whose properties, to the best of our knowledge, are presented here for the first time. Isodimethoate shows an inhibition rate constant towards human red blood cell acetylcholinesterase (AChE) of 2.3x10(3) M(-1) min(-1) (pH 7.4, 37 degrees C), indicating a somewhat higher potency than found with omethoate, the CYP450-mediated active metabolite of pure dimethoate. Isodimethoate-inhibited AChE shows fast spontaneous reactivation and aging kinetics (half-life 2.3 and 25 min, respectively). The inhibited, non-aged enzyme is readily reactivated by obidoxime (k(r)=9 min(-1); K(D)=0.1 mM) but hardly by pralidoxime at therapeutic concentrations. Interestingly, isodimethoate hydrolyzes readily in buffered solutions at pH 7.4 and 37 degrees C with liberation of methylmercaptan (half-life 16 min). Liberation of N-(methyl)mercaptoacetamide, the expected leaving group, was not observed. These properties make isodimethoate a hit-and-run agent that renders part of AChE non-reactivatable within a short period of time. The clinical consequences of exposure to or intentional ingestion of isodimethoate-containing dimethoate formulations are a partly untractable AChE shortly after incorporation. In fact, aging of AChE in dimethoate-poisoned patients on admission was much more advanced than expected from the reaction with omethoate. Manufacturers, researching scientists and clinical toxicologists should be aware of this problem.
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University of Munich, Goethestrasse 33, 80336 Munich, Germany. peter.eyer@lrz.uni-muenchen.de
authors.forename: Peter
authors.initials: P
authors.lastname: Eyer
authors.forename: Maria
authors.initials: M
authors.lastname: Radtke
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D004117:Dimethoate / Q000031:analogs & derivatives* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009768:Obidoxime Chloride / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; C002302:dimethoxon; D009768:Obidoxime Chloride; D000110:Acetylcholinesterase; D004117:Dimethoate