Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent

Supersensitivity of acetylcholinesterase knockout mouse to VX lethality

Ellen G. Duysen, Bin Li, Weihua Xie, Lawrence M Schopfer, Robert S. Anderson, Clarence A. Broomfield, Oksana Lockridge

Research output: Contribution to journalArticle

118 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)528-535
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number2
StatePublished - Oct 30 2001

Fingerprint

Acetylcholinesterase
Knockout Mice
Butyrylcholinesterase
Cholinergic Agents
Nerve Agents
VX
Carboxylesterase
Organophosphates
Lethal Dose 50
Atropine
Esters
Genotype
Muscles

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent : Supersensitivity of acetylcholinesterase knockout mouse to VX lethality. / Duysen, Ellen G.; Li, Bin; Xie, Weihua; Schopfer, Lawrence M; Anderson, Robert S.; Broomfield, Clarence A.; Lockridge, Oksana.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 299, No. 2, 30.10.2001, p. 528-535.

Research output: Contribution to journalArticle

@article{42edb40a82bf4b55af51e206742e7514,
title = "Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: Supersensitivity of acetylcholinesterase knockout mouse to VX lethality",
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.",
author = "Duysen, {Ellen G.} and Bin Li and Weihua Xie and Schopfer, {Lawrence M} and Anderson, {Robert S.} and Broomfield, {Clarence A.} and Oksana Lockridge",
year = "2001",
month = "10",
day = "30",
language = "English (US)",
volume = "299",
pages = "528--535",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent

T2 - Supersensitivity of acetylcholinesterase knockout mouse to VX lethality

AU - Duysen, Ellen G.

AU - Li, Bin

AU - Xie, Weihua

AU - Schopfer, Lawrence M

AU - Anderson, Robert S.

AU - Broomfield, Clarence A.

AU - Lockridge, Oksana

PY - 2001/10/30

Y1 - 2001/10/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034760772&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034760772&partnerID=8YFLogxK

M3 - Article

VL - 299

SP - 528

EP - 535

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -