PT  - JOURNAL ARTICLE
AU  - Chenmeizi Liang
AU  - Junfang Zhao
AU  - Jian Lu
AU  - Yuanjin Zhang
AU  - Xinrun Ma
AU  - Xuyang Shang
AU  - Yongmei Li
AU  - Xueyun Ma
AU  - Mingyao Liu
AU  - Xin Wang
TI  - Development and characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 knockout rat model
AID  - 10.1124/dmd.118.084277
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.084277
4099  - http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.084277.short
4100  - http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.084277.full
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 multidrug resistance. In this report, a novel MDR1 (Mdr1a/b) double knockout (KO) rat model was generated by CRISPR/Cas9 system without any off-target effect detected. Western blot results showed that MDR1 was completely absent in 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 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 multidrug resistance and drug target validation.