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TOXICOLOGY

The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency

Eppley Institute (B.L., E.G.D., O.L.) and Department of Cellular and Integrative Physiology (M.C.), University of Nebraska Medical Center, Omaha, Nebraska

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 [GenBank] ). 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 tonicclonic 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.

Address correspondence to: Dr. Oksana Lockridge, Eppley Institute, 986805, Nebraska Medical Center, Omaha, NE 68198-6805. E-mail: olockrid{at}unmc.edu

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