TY - JOUR T1 - The Butyrylcholinesterase Knockout Mouse as a Model for Human Butyrylcholinesterase Deficiency JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1146 LP - 1154 DO - 10.1124/jpet.107.133330 VL - 324 IS - 3 AU - Bin Li AU - Ellen G. Duysen AU - Michaela Carlson AU - Oksana Lockridge Y1 - 2008/03/01 UR - http://jpet.aspetjournals.org/content/324/3/1146.abstract N2 - 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 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. The American Society for Pharmacology and Experimental Therapeutics ER -