Article

Production of ES1 Plasma Carboxylesterase Knockout Mice for Toxicity Studies

Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
Chemical Research in Toxicology (Impact Factor: 3.53). 09/2011; 24(11):1891-8. DOI: 10.1021/tx200237a
Source: PubMed

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.

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Available from: Christopher M. Timperley, Jun 11, 2014
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    • "In general, carboxylesterase activity in sheep revelations greater sensitivity to organophosphorus compounds than other esterases (del Loandos et al., 2012) and its assessable activity is higher (Hatfield et al., 2011; Wang et al., 2011). Therefore, possible that the joint biochemical biomarker of carboxylesterase activities will provide an additional valuable indication of organophosphorus compounds exposure in sheep species than the measurement of other esterases alone (Duysen et al., 2011; Lee et al., 2011). Toward use enzyme activities, for example carboxylesterase as accurate and sensitive biomarkers of organophosphorus poisoning, it is significant not only that the enzymes are adequately characterised in the species in query, but also that the assays themselves are adequately healthy and accessible to permit their use to make measurements of activity of adequate accuracy and precision to detect delicate changes in activity. "

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