TY - JOUR
T1 - Development and characterization of MDR1 (MDR1a/B) CRISPR/Cas9 knockout rat model
AU - Liang, Chenmeizi
AU - Zhao, Junfang
AU - Lu, Jian
AU - Zhang, Yuanjin
AU - Ma, Xinrun
AU - Shang, Xuyang
AU - Li, Yongmei
AU - Ma, Xueyun
AU - Liu, Mingyao
AU - Wang, Xin
N1 - Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2019/2
Y1 - 2019/2
N2 - 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 (2/2) 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 (2/2) 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.
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 (2/2) 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 (2/2) 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.
UR - https://www.scopus.com/pages/publications/85059499106
U2 - 10.1124/dmd.118.084277
DO - 10.1124/dmd.118.084277
M3 - 文章
C2 - 30478157
AN - SCOPUS:85059499106
SN - 0090-9556
VL - 47
SP - 71
EP - 79
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 2
ER -