Title : The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency - Li_2008_J.Pharmacol.Exp.Ther_324_1146 |
Author(s) : Li B , Duysen EG , Carlson M , Lockridge O |
Ref : Journal of Pharmacology & Experimental Therapeutics , 324 :1146 , 2008 |
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 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. |
PubMedSearch : Li_2008_J.Pharmacol.Exp.Ther_324_1146 |
PubMedID: 18056867 |
Li B, Duysen EG, Carlson M, Lockridge O (2008)
The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency
Journal of Pharmacology & Experimental Therapeutics
324 :1146
Li B, Duysen EG, Carlson M, Lockridge O (2008)
Journal of Pharmacology & Experimental Therapeutics
324 :1146