Abstract
The possibility that organophosphate toxicity is due to inhibition of targets other than acetylcholinesterase (AChE, EC 3.1.1.7) was examined in AChE knockout mice. Mice (34–55 days old) were grouped for this study, after it was determined that AChE, butyrylcholinesterase (BChE), and carboxylesterase activities had reached stable values by this age. Mice with 0, 50, or 100% AChE activity were treated subcutaneously with the nerve agent VX. The LD50 for VX was 10 to 12 μg/kg in AChE−/−, 17 μg/kg in AChE+/−, and 24 μg/kg in AChE+/+ mice. The same cholinergic signs of toxicity were present in AChE−/− mice as in wild-type mice, even though AChE−/− mice have no AChE whose inhibition could lead to cholinergic signs. Wild-type mice, but not AChE−/− mice, were protected by pretreatment with atropine. Tissues were extracted from VX-treated and untreated animals and tested for AChE, BChE, and acylpeptide hydrolase activity. VX treatment inhibited 50% of the AChE activity in brain and muscle of AChE+/+ and +/− mice, 50% of the BChE activity in all three AChE genotypes, but did not significantly inhibit acylpeptide hydrolase activity. It was concluded that the toxicity of VX must be attributed to inhibition of nonacetylcholinesterase targets in the AChE−/− mouse. Organophosphorus ester toxicity in wild-type mice is probably due to inhibition or binding to several proteins, only one of which is AChE.
Footnotes
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This work was supported by U.S. Army Medical Research and Materiel Command Grant DAMD17-97-1-7349 (to O.L.), University of Nebraska Medical Center assistantship (to B.L.), and by a Center Grant to University of Nebraska Medical Center from the National Cancer Institute, Grant CA36727. The opinions or assertions contained herein belong to the authors and should not be construed as the official views of the U.S. Army or the Department of Defense.
- Abbreviations:
- OP
- organophosphorus pesticides and nerve agents
- AChE
- acetylcholinesterase
- DFP
- diisopropylfluorophosphate
- VX
- (O-ethylS-[2-(diisopropylamino)ethyl] methylphosphonothioate)
- BChE
- butyrylcholinesterase
- Received May 31, 2001.
- Accepted August 9, 2001.
- U.S. Government
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