title: Reactions of methylphosphonic difluoride with human acetylcholinesterase and oximes--Possible therapeutic implications.
abstract: Highly toxic organophosphorus (OP) nerve agents are well characterized regarding chemical, biological and toxicological properties and the effectiveness of standard atropine and oxime therapy. Open literature data on the key nerve agent precursor methylphosphonic difluoride (DF) are scarce. To fill this gap the reactions of DF and its main degradation product methylphosphonofluoridic acid (MF) with human acetylcholinesterase (AChE) and the oximes obidoxime, HI-6 and 2-PAM were investigated in vitro. DF and MF were found to be weak inhibitors of human AChE being at least five orders less potent compared to the nerve agent sarin. Incubation of human AChE with millimolar DF and MF and subsequent addition of obidoxime and HI-6 resulted in a concentration-dependent decrease of AChE activity. This effect was not observed when incubating highly diluted AChE with oximes. The most likely explanation for this phenomenon is an inhibitory effect of phosphonyloximes formed by direct reaction of DF or MF with obidoxime and HI-6. These data indicate that high DF doses, resulting in millimolar blood and tissue DF/MF concentrations, are necessary to induce cholinergic signs and that under these conditions treatment with obidoxime and HI-6 may even worsen the poisoning.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany. Electronic address: franzworek@bundeswehr.org.
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Elsinghorst
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Koller
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D009768:Obidoxime Chloride / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000633:toxicity; D011726:Pyridinium Compounds / Q000633:toxicity; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; D009943:Organophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; C046675:methylphosphonic difluoride; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime
keywords: Acetylcholinesterase; Methylphosphonic difluoride; Organophosphorus compounds; Oxime; Phosphonyloxime; Reactivation