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Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

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Abstract

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.

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstrasse 11, 80937, Munich, Germany

    S. Herkenhoff, L. Szinicz & F. Worek

  2. Edgewood Chemical Biological Center, Aberdeen Proving Ground, MD 21010-5424, USA

    V. K. Rastogi, T.-C. Cheng & J. J. DeFrank

Authors
  1. S. Herkenhoff
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  2. L. Szinicz
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  3. V. K. Rastogi
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  4. T.-C. Cheng
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  5. J. J. DeFrank
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  6. F. Worek
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Correspondence to F. Worek.

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Herkenhoff, S., Szinicz, L., Rastogi, V.K. et al. Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase. Arch Toxicol 78, 338–343 (2004). https://doi.org/10.1007/s00204-004-0547-2

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  • DOI: https://doi.org/10.1007/s00204-004-0547-2

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