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Paradox findings may challenge orthodox reasoning in acute organophosphate poisoning.

Abstract
It is generally accepted that inhibition of acetylcholinesterase (AChE) is the most important acute toxic action of organophosphorus compounds, leading to accumulation of acetylcholine followed by a dysfunction of cholinergic signaling. However, the degree of AChE inhibition is not uniformly correlated with cholinergic dysfunction, probably because the excess of essential AChE varies among tissues. Moreover, the cholinergic system shows remarkable plasticity, allowing modulations to compensate for dysfunctions of the canonical pathway. A prominent example is the living (-/-) AChE knockout mouse. Clinical experience indicates that precipitous inhibition of AChE leads to more severe poisoning than more protracted yet finally complete inhibition. The former situation is seen in parathion, the latter in oxydemeton methyl poisoning. At first glance, this dichotomy is surprising since parathion is a pro-poison and has to be activated to the oxon, while the latter is still the ultimate inhibitor. Also oxime therapy in organophosphorus poisoning apparently gives perplexing results: Oximes are usually able to reactivate diethylphosphorylated AChE, but the efficiency may be occasionally markedly smaller than expected from kinetic data. Dimethylphosphorylated AChE is in general less amenable to oxime therapy, which largely fails in some cases of dimethoate poisoning where aging was much faster than expected from a dimethylphosphorylated enzyme. Similarly, poisoning by profenofos, an O,S-dialkyl phosphate, leads to a rapidly aged enzyme. Most surprisingly, these patients were usually well on admission, yet their erythrocyte AChE was completely inhibited. Analysis of the kinetic constants of the most important reaction pathways, determination of the reactant concentrations in vivo and comparison with computer simulations may reveal unexpected toxic reactions. Pertinent examples will be presented and the potentially underlying phenomena discussed.
AuthorsPeter Eyer, Franz Worek, Horst Thiermann, Michael Eddleston
JournalChemico-biological interactions (Chem Biol Interact) Vol. 187 Issue 1-3 Pg. 270-8 (Sep 06 2010) ISSN: 1872-7786 [Electronic] Ireland
PMID19883634 (Publication Type: Journal Article, Review)
CopyrightCopyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Cholinesterase Inhibitors
  • Oximes
  • Cholinesterases
Topics
  • Animals
  • Cholinesterase Inhibitors (poisoning)
  • Cholinesterases (blood, metabolism)
  • Humans
  • Hypotension (etiology)
  • Kinetics
  • Organophosphate Poisoning
  • Oximes (pharmacology)

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