title: Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes.
abstract: The wide-spread use of organophosphorus compounds (OP) as pesticides and the availability of highly toxic OP-type chemical warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents. The antidotal efficacy of new oximes is primarily tested in animals for ethical reasons. However, the various interactions between AChE, OP and oximes can be investigated with human AChE which enables the direct assessment of oxime potency, thus excluding species differences. The kinetics of inhibition, reactivation and aging were investigated with human erythrocyte AChE, various structurally different OP (organophosphates, -phosphonates and phosphoramidates) and oximes (obidoxime, pralidoxime, HI 6, HLö 7). The inhibitory potency of OPs, reactivating potency of oximes and spontaneous reactivation and aging were strongly affected by the structural characteristics of the OPs and of the phosphyl-AChE-complex. The kinetic data emphasize the superior inhibitory potency of organophosphonates. AChE inhibited by various phosphoramidates was mostly resistant towards reactivation by oximes while phosphonylated AChE was easily reactivated. HLö 7 was most potent with phosphonylated AChE and obidoxime with AChE inhibited by organophosphates and phosphoramidates. With the exception of soman, OP-inhibited AChE aged rather slowly (t(1/2) 3-231 h) and reactivated spontaneously with some compounds. These results indicate that there is obviously no direct structure-activity relationship for the various interactions of human AChE, OPs and oximes.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany. franzworek@bundeswehr.org
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Ladislaus
authors.initials: L
authors.lastname: Szinicz
authors.forename: Peter
authors.initials: P
authors.lastname: Eyer
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009943:Organophosphorus Compounds; D010091:Oximes; D000110:Acetylcholinesterase