Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase.
The reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) by oximes results inevitably in the formation of highly reactive phosphyloximes (POX), which may re-inhibit the enzyme. An impairment of net reactivation by stable POX was found with 4-pyridinium aldoximes, e.g. obidoxime, and a variety of OP compounds. In this study the effect of organophosphorus hydrolase (OPH), organophosphorus acid anhydrolase (OPAA) and diisopropylfluorophosphatase (DFPase) on obidoxime-induced reactivation of human acetylcholinesterase (AChE) inhibited by different OPs was investigated. Reactivation of paraoxon-, sarin-, soman- and VX-inhibited AChE by obidoxime was impaired by POX-induced re-inhibition whereas no deviation of pseudo first-order kinetics was observed with tabun, cyclosarin and VR. OPH prevented (paraoxon) or markedly reduced the POX-induced re-inhibition (VX, sarin, soman), whereas OPAA and DFPase were without effect. Additional experiments with sarin-inhibited AChE indicate that the POX hydrolysis by OPH was concentration-dependent. The activity of OP-inhibited AChE was not affected by OPH in the absence of obidoxime. In conclusion, OPH may be a valuable contribution to the therapeutic regimen against OP poisoning by accelerating the degradation of both the parent compound, OP, and the reaction product, POX.
Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstrasse 11, 80937 Munich, Germany.
S
S
Herkenhoff
L
L
Szinicz
V K
VK
Rastogi
T-C
TC
Cheng
J J
JJ
DeFrank
F
F
Worek
D000818:Animals; D043303:Aryldialkylphosphatase / Q000494:pharmacology*; D001419:Bacteria; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D049832:Decapodiformes; D004789:Enzyme Activation; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D009768:Obidoxime Chloride / Q000494:pharmacology*; D010755:Organophosphates / Q000633:toxicity*; D044345:Phosphoric Triester Hydrolases / Q000494:pharmacology*; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D009768:Obidoxime Chloride; D044345:Phosphoric Triester Hydrolases; D043303:Aryldialkylphosphatase; C020061:diisopropyl-fluorophosphatase