The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency

Bin Li, Ellen G. Duysen, Michaela Carlson, Oksana Lockridge

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Abstract

Butyrylcholinesterase (BChE) is an important enzyme for metabolism of ester drugs. Many humans have partial or complete BChE deficiency due to genetic variation. Our goal was to create a mouse model of BChE deficiency to allow testing of drug toxicity. For this purpose, we created the BChE knockout mouse by gene-targeted deletion of a portion of the BCHE gene (accession number M99492). The BChE-/- mouse had no BChE activity in plasma, but it had low residual butyrylthiocholine hydrolase activity in all other tissues attributed to carboxylesterase ES-10. The BChE-/- mouse had a normal phenotype except when challenged with drugs. Nicotinic receptor function as indicated by response to nicotine seemed to be normal in BChE-/- mice, but muscarinic receptor function as measured by response to oxotremorine and pilocarpine was altered. Heart rate, blood pressure, and respiration, measured in a Vevo imager, were similar in BChE+/+ and BChE -/- mice. Like BChE-/- humans, the BChE-/- mouse responded to succinylcholine with prolonged respiratory arrest. Bambuterol was not toxic to BChE-/- mice, suggesting it is safe in BChE -/- humans. Challenge with 150 mg/kg pilocarpine i.p., a muscarinic agonist, or with 50 mg/kg butyrylcholine i.p., induced tonic-clonic convulsions and death in BChE-/- mice. This suggests that butyrylcholine, like pilocarpine, binds to muscarinic receptors. In conclusion, the BChE -/- mouse is a suitable model for human BChE deficiency.

Original languageEnglish (US)
Pages (from-to)1146-1154
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number3
DOIs
StatePublished - Mar 1 2008

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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