Life without acetylcholinesterase: The implications of cholinesterase inhibitor toxicity in AChE-knockout mice

Oksana Lockridge, Ellen G. Duysen, Troy Voelker, Charles M. Thompson, Lawrence M Schopfer

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000 × g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP.

Original languageEnglish (US)
Pages (from-to)463-469
Number of pages7
JournalEnvironmental Toxicology and Pharmacology
Volume19
Issue number3
DOIs
StatePublished - May 2005

Fingerprint

Cholinesterase Inhibitors
Acetylcholinesterase
Knockout Mice
Toxicity
Proteins
Tetraisopropylpyrophosphamide
Dichlorvos
Isoflurophate
Cholinergic Agents
Acetylcholine
Labels
Brain

Keywords

  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Chlorpyrifos oxon
  • FP-biotin
  • Knockout mouse
  • Organophosphorus agent

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

Life without acetylcholinesterase : The implications of cholinesterase inhibitor toxicity in AChE-knockout mice. / Lockridge, Oksana; Duysen, Ellen G.; Voelker, Troy; Thompson, Charles M.; Schopfer, Lawrence M.

In: Environmental Toxicology and Pharmacology, Vol. 19, No. 3, 05.2005, p. 463-469.

Research output: Contribution to journalArticle

@article{9d07842767d94e7592870aea5e0ca4e2,
title = "Life without acetylcholinesterase: The implications of cholinesterase inhibitor toxicity in AChE-knockout mice",
abstract = "The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000 × g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP.",
keywords = "Acetylcholinesterase, Butyrylcholinesterase, Chlorpyrifos oxon, FP-biotin, Knockout mouse, Organophosphorus agent",
author = "Oksana Lockridge and Duysen, {Ellen G.} and Troy Voelker and Thompson, {Charles M.} and Schopfer, {Lawrence M}",
year = "2005",
month = "5",
doi = "10.1016/j.etap.2004.12.008",
language = "English (US)",
volume = "19",
pages = "463--469",
journal = "Environmental Toxicology and Pharmacology",
issn = "1382-6689",
publisher = "Elsevier",
number = "3",

}

TY - JOUR

T1 - Life without acetylcholinesterase

T2 - The implications of cholinesterase inhibitor toxicity in AChE-knockout mice

AU - Lockridge, Oksana

AU - Duysen, Ellen G.

AU - Voelker, Troy

AU - Thompson, Charles M.

AU - Schopfer, Lawrence M

PY - 2005/5

Y1 - 2005/5

N2 - The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000 × g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP.

AB - The acetylcholinesterase (AChE)-knockout mouse is a new tool for identifying physiologically relevant targets of organophosphorus toxicants (OP). If AChE were the only important target for OP toxicity, then mice with zero AChE would have been expected to be resistant to OP. The opposite was found. AChE-/- mice were more sensitive to the lethality of DFP, chlorpyrifos oxon, iso-OMPA, and the nerve agent VX. A lethal dose of OP caused the same cholinergic signs of toxicity in mice with zero AChE as in mice with normal amounts of AChE. This implied that the mechanism of toxicity of a lethal dose of OP in AChE-/- mice was the same as in mice that had AChE, namely accumulation of excess acetylcholine followed by overstimulation of receptors. OP lethality in AChE-/- mice could be due to inhibition of BChE, or to inhibition of a set of proteins. A search for additional targets used biotinylated-OP as a marker. In vitro experiments found that biotinylated-OP appeared to label as many as 55 proteins in the 100,000 × g supernatant of mouse brain. Chlorpyrifos oxon bound a set of proteins (bands 12, 41, 45) that did not completely overlap with the set of proteins bound by diazoxon (bands 9, 12, 41, 47) or dichlorvos (bands 12, 23, 24, 32, 44, 45, 51) or malaoxon (band 9). These results support the idea that a variety of proteins could be interacting with a given OP to give the neurotoxic symptoms characteristic of a particular OP.

KW - Acetylcholinesterase

KW - Butyrylcholinesterase

KW - Chlorpyrifos oxon

KW - FP-biotin

KW - Knockout mouse

KW - Organophosphorus agent

UR - http://www.scopus.com/inward/record.url?scp=17044399793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17044399793&partnerID=8YFLogxK

U2 - 10.1016/j.etap.2004.12.008

DO - 10.1016/j.etap.2004.12.008

M3 - Article

C2 - 21783513

AN - SCOPUS:17044399793

VL - 19

SP - 463

EP - 469

JO - Environmental Toxicology and Pharmacology

JF - Environmental Toxicology and Pharmacology

SN - 1382-6689

IS - 3

ER -