Development and Characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 Knockout Rat Model

作者：Liang, Chenmeizi; Zhao, Junfang; Lu, Jian; Zhang, Yuanjin; Ma, Xinrun; Shang, Xuyang; Li, Yongmei; Ma, Xueyun; Liu, Mingyao; Wang, Xin^*

来源：Drug Metabolism and Disposition, 2019, 47(2): 71-79.

DOI：10.1124/dmd.118.084277

• MEDIATED MULTIDRUG-RESISTANCE
• BLOOD-BRAIN-BARRIER
• P-GLYCOPROTEIN
• CLINICAL-RELEVANCE
• ABC TRANSPORTERS
• DRUG-RESISTANCE
• RECENT INSIGHTS
• MICE LACKING
• IN-VITRO
• CHOLESTEROL

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 [MDR1 (also known as P-glycoprotein)] is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor MDR. In this report, a novel MDR1 (Mdr1a/b) double-knockout (KO) rat model was generated by the CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in the liver, small intestine, brain, and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (-/-) rats, the mRNA levels of the CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney, and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor MDR, and drug target validation.

• 出版日期2019-2-1
• 单位华东师范大学