Influence of MDR1 gene polymorphism (2677G>T) on expression and function of P-glycoprotein at the blood-brain barrier: utilizing novel P-glycoprotein humanized mice with mutation.

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Pharmacogenetics and genomics Pub Date : 2022-10-01 DOI:10.1097/FPC.0000000000000481
Yuki Yamasaki, Takashi Moriwaki, Seiryo Ogata, Shingo Ito, Sumio Ohtsuki, Genki Minegishi, Satoshi Abe, Yumi Ohta, Kanako Kazuki, Kaoru Kobayashi, Yasuhiro Kazuki
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引用次数: 1

Abstract

P-glycoprotein, the encoded product of the MDR1 / ABCB1 gene in humans, is expressed in numerous tissues including brain capillary endothelial cells and restricts the distribution of xenobiotics into the brain as an efflux pump. Although a large number of single nucleotide polymorphisms in the MDR1 gene have been identified, the influence of the nonsynonymous 2677G>T/A single nucleotide polymorphism on P-glycoprotein at the blood-brain barrier has remained unclear. In the present study, we developed a novel P-glycoprotein humanized mouse line carrying the 2677G>T mutation by utilizing a mouse artificial chromosome vector constructed by genetic engineering technology and we evaluated the influence of 2677G>T on the expression and function of P-glycoprotein at the blood-brain barrier in vivo . The results of this study showed that the introduction of the 2677G>T mutation does not alter the expression levels of P-glycoprotein protein in the brain capillary fraction. On the other hand, the brain penetration of verapamil, a representative substrate of P-glycoprotein, was increased by the introduction of the 2677G>T mutation. These results suggested that the 2677G>T single nucleotide polymorphism may attenuate the function of P-glycoprotein, resulting in increased brain penetration of P-glycoprotein substrates, without altering the expression levels of P-glycoprotein protein in the blood-brain barrier. This mutant mouse line is a useful model for elucidating the influence of an MDR1 gene single nucleotide polymorphism on the expression and function of P-glycoprotein at the blood-brain barrier.

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MDR1基因多态性(2677G>T)对血脑屏障p -糖蛋白表达和功能的影响——以新型p -糖蛋白突变人源化小鼠为例
p -糖蛋白是人类MDR1 / ABCB1基因的编码产物,在包括脑毛细血管内皮细胞在内的许多组织中表达,并作为外排泵限制外源药物在脑内的分布。尽管MDR1基因的大量单核苷酸多态性已经被发现,但非同义的2677G>T/ a单核苷酸多态性对血脑屏障p -糖蛋白的影响尚不清楚。本研究利用基因工程技术构建的小鼠人工染色体载体,构建了携带2677G>T突变的新型p -糖蛋白人源化小鼠系,并在体内研究了2677G>T对p -糖蛋白血脑屏障表达和功能的影响。本研究结果表明,引入2677G>T突变不会改变p -糖蛋白蛋白在脑毛细血管中的表达水平。另一方面,引入2677G>T突变增加了p -糖蛋白的代表性底物维拉帕米的脑渗透。这些结果表明,2677G>T单核苷酸多态性可能减弱p -糖蛋白的功能,导致p -糖蛋白底物的脑渗透增加,而不改变p -糖蛋白在血脑屏障中的表达水平。该突变小鼠系为阐明MDR1基因单核苷酸多态性对血脑屏障p -糖蛋白表达和功能的影响提供了一个有用的模型。
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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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