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. Issue 8 (22nd August 2022)

• Record Type: Journal Article
• Authors: Yamasaki, Yuki; Moriwaki, Takashi; Ogata, Seiryo; Ito, Shingo; Ohtsuki, Sumio; Minegishi, Genki; Abe, Satoshi; Ohta, Yumi; Kazuki, Kanako; Kobayashi, Kaoru; Kazuki, Yasuhiro
• Is Part Of: Pharmaocogenetics and genomics. Volume 32:Issue 8(2022)
• Page Start: 288
• Page End: 292
• Publication Date: 2022-08-22
• Subjects: blood-brain barrier -- brain distribution -- humanized -- mouse artificial chromosome -- mutant -- 2677G>T -- P-glycoprotein -- polymorphism; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000481
• Languages: English
• ISSNs: 1744-6872

Abstract

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.