The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency

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

Research output: Contribution to journalArticle

59 Citations (Scopus)

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

Fingerprint

Butyrylcholinesterase
Knockout Mice
Pilocarpine
Muscarinic Receptors
Butyrylcholinesterase deficiency
Butyrylthiocholine
Tonic-Clonic Epilepsy
Oxotremorine
Muscarinic Agonists
Carboxylesterase
Succinylcholine
Poisons
Gene Deletion
Nicotinic Receptors
Hydrolases
Drug-Related Side Effects and Adverse Reactions
Nicotine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency. / Li, Bin; Duysen, Ellen G.; Carlson, Michaela; Lockridge, Oksana.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 3, 01.03.2008, p. 1146-1154.

Research output: Contribution to journalArticle

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