Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 24, Issue 11, Pages 1891-1898Publisher
AMER CHEMICAL SOC
DOI: 10.1021/tx200237a
Keywords
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Funding
- JSTO-Defense Threat Reduction Agency [I2_X005_04_RC_C, CBM.SCAV.01.10.RC.017]
- National Institutes of Health through the National Institute of Neurological Disorders and Stroke [U01 NS058038]
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The LD50 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.
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