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.
Herkenhoff
S
S
Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstrasse 11, 80937 Munich, Germany.
Szinicz
L
L
Rastogi
V K
VK
Cheng
T-C
TC
DeFrank
J J
JJ
Worek
F
F
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