Production of ES1 plasma carboxylesterase knockout mice for toxicity studies

Ellen G. Duysen, Frank Koentgen, Gareth R. Williams, Christopher M. Timperley, Lawrence M Schopfer, Douglas M. Cerasoli, Oksana Lockridge

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27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1891-1898
Number of pages8
JournalChemical Research in Toxicology
Volume24
Issue number11
DOIs
Publication statusPublished - Nov 21 2011

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ASJC Scopus subject areas

  • Toxicology

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