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

被引：24

作者：

Liang, Chenmeizi ^{[1
,2
]}

Zhao, Junfang ^{[1
,2
]}

Lu, Jian ^{[1
,2
]}

Zhang, Yuanjin ^{[1
,2
]}

Ma, Xinrun ^{[1
,2
]}

Shang, Xuyang ^{[1
,2
]}

Li, Yongmei ^{[1
,2
]}

Ma, Xueyun ^{[1
,2
]}

Liu, Mingyao ^{[1
,2
,3
]}

Wang, Xin ^{[1
,2
]}

机构：

[1] East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China

[2] East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China

[3] Texas A&M Univ, Hlth Sci Ctr, Inst Biosci & Technol, Ctr Canc & Stem Cell Biol, Houston, TX USA

来源：

DRUG METABOLISM AND DISPOSITION | 2019年 / 47卷 / 02期

基金：

中国国家自然科学基金;

关键词：

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

D O I：

10.1124/dmd.118.084277

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：71 / 79

页数：9

共 45 条

[1] The Role of ABC Transporters in Protecting Cells from Bilirubin Toxicity [J].