The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency
The butyrylcholinesterase knockout mouse as a model for human butyrylcholinesterase deficiency
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DOI：
10.1124/jpet.107.133330
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Lockridge, Oksana
中科院分区：
文献类型：
--
作者：
Li, Bin;Duysen, Ellen G.;Lockridge, Oksana
丁酰胆碱酯酶（BChE）是酯类药物代谢的重要酶。许多人由于遗传变异而部分或完全缺乏BChE。我们的目标是建立一个BChE缺乏的小鼠模型，以测试药物毒性。为此，我们通过基因靶向缺失BCHE基因的一部分（登录号M99492）来创建BChE敲除小鼠。BChE（-/-）小鼠在血浆中没有BChE活性，但在所有其他组织中具有归因于羧酸酯酶ES-10的低残留丁酰硫代胆碱水解酶活性。BChE（-/-）小鼠具有正常表型，除非用药物攻击。尼古丁受体功能表明，尼古丁的反应似乎是正常的BChE（-/-）小鼠，但毒蕈碱受体功能测定的反应oxotremorine和毛果芸香碱改变。在Vevo成像仪中测量的心率、血压和呼吸在BChE（-/-）和BChE（-/-）小鼠中是相似的。与BChE（-/-）人类一样，BChE（-/-）小鼠对琥珀胆碱的反应是长时间的呼吸停止。班布特罗对BChE（-/-）小鼠没有毒性，表明它对BChE（-/-）人类是安全的。腹腔注射150 mg/kg毛果芸香碱激发，毒蕈碱激动剂，或与50 mg/kg丁酰胆碱腹腔注射，在BChE（-/-）小鼠中诱导强直-阵挛性惊厥和死亡。这表明，丁酰胆碱，像毛果芸香碱，结合毒蕈碱受体。总之，BChE（-/-）小鼠是一个合适的模型，为人类BChE缺乏症。
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.