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Chem Res Toxicol. 2011 Nov 21;24(11):1891-8. doi: 10.1021/tx200237a. Epub 2011 Sep 7.

Production of ES1 plasma carboxylesterase knockout mice for toxicity studies.

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  • 1Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.

Abstract

The LD(50) for soman is 10-20-fold higher for a mouse than a human. The difference in susceptibility is attributed to the presence of carboxylesterase in mouse but not in human plasma. Our goal was to make a mouse lacking plasma carboxylesterase. We used homologous recombination to inactivate the carboxylesterase ES1 gene on mouse chromosome 8 by deleting exon 5 and by introducing a frame shift for amino acids translated from exons 6 to 13. ES1-/- mice have no detectable carboxylesterase activity in plasma but have normal carboxylesterase activity in tissues. Homozygous ES1-/- mice and wild-type littermates were tested for response to a nerve agent model compound (soman coumarin) at 3 mg/kg sc. This dose intoxicated both genotypes but was lethal only to ES1-/- mice. This demonstrated that plasma carboxylesterase protects against a relatively high toxicity organophosphorus compound. The ES1-/- mouse should be an appropriate model for testing highly toxic nerve agents and for evaluating protection strategies against the toxicity of nerve agents.

PMID:
21875074
[PubMed - indexed for MEDLINE]
PMCID:
PMC3221923
Free PMC Article

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