RT Journal Article
SR Electronic
T1 Development and Characterization of MDR1 (<em>Mdr1a/b</em>) CRISPR/Cas9 Knockout Rat Model
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 71
OP 79
DO 10.1124/dmd.118.084277
VO 47
IS 2
A1 Chenmeizi Liang
A1 Junfang Zhao
A1 Jian Lu
A1 Yuanjin Zhang
A1 Xinrun Ma
A1 Xuyang Shang
A1 Yongmei Li
A1 Xueyun Ma
A1 Mingyao Liu
A1 Xin Wang
YR 2019
UL http://dmd.aspetjournals.org/content/47/2/71.abstract
AB 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.