Interindividual and Regional Variability in Drug Transporter Abundance at the Human Blood-Brain Barrier Measured by Quantitative Targeted Proteomics
Interindividual and Regional Variability in Drug Transporter Abundance at the Human Blood-Brain Barrier Measured by Quantitative Targeted Proteomics
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DOI：
10.1002/cpt.1373
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发表时间：
2019-07-01
影响因子：
6.7
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
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作者：
Billington, Sarah;Salphati, Laurent;Unadkat, Jashvant D.
对于在人血脑屏障（BBB）处转运的药物的脑分布的体外到体内外推（IVIVE），重要的是量化该屏障处药物转运蛋白丰度的个体间和区域变异性。因此，使用定量靶向蛋白质组学，我们比较了丰富的三磷酸腺苷结合盒和溶质载体转运体在脑微血管内皮细胞（BMEC）分离的两个匹配的脑区，枕叶（布罗德曼区（BA）17）和顶叶（BA 39），从30名成年人的尸检标本。在可定量转运蛋白中，丰度排序为：葡萄糖转运蛋白（GLUT）1 >乳腺癌耐药蛋白> P-糖蛋白（P-gp）>平衡型核苷转运蛋白（ENT）1 >有机阴离子转运多肽（OATP）2B 1。多药耐药蛋白1/2/3/4、OATP 1A 2、有机阴离子转运蛋白（OAT）3、有机阳离子转运蛋白（OCT）1/2、OCTN 1/2或ENT 2的丰度低于定量限。BA 17中每克组织的转运蛋白丰度（使用BMEC与脑匀浆中的GLUT 1丰度缩放）比BA 39高30-42%。转运蛋白丰度的个体间变异性（变异系数百分比（%CV））为35-57%（BA 17）和27-46%（BA 39）。这些数据可以用于蛋白质组学信息自下而上的IVIVE来预测人脑药物分布。
For in vitro to in vivo extrapolation (IVIVE) of brain distribution of drugs that are transported at the human blood-brain barrier (BBB), it is important to quantify the interindividual and regional variability of drug transporter abundance at this barrier. Therefore, using quantitative targeted proteomics, we compared the abundance of adenosine triphosphate-binding cassette and solute carrier transporters in brain microvascular endothelial cells (BMECs) isolated from postmortem specimens of two matched brain regions, the occipital (Brodmann Area (BA)17) and parietal (BA39) lobe, from 30 adults. Of the quantifiable transporters, the abundance ranked: glucose transporter (GLUT)1 > breast cancer resistance protein > P-glycoprotein (P-gp) > equilibrative nucleoside transporter (ENT)1 > organic anion-transporting polypeptide (OATP)2B1. The abundance of multidrug resistance protein 1/2/3/4, OATP1A2, organic anion transporter (OAT)3, organic cation transporter (OCT)1/2, OCTN1/2, or ENT2 was below the limit of quantification. Transporter abundance per gram of tissue (scaled using GLUT1 abundance in BMEC vs. brain homogenate) in BA17 was 30-42% higher than BA39. The interindividual variability in transporter abundance (percentage of coefficient of variation (%CV)) was 35-57% (BA17) and 27-46% (BA39). These data can be used in proteomics-informed bottom-up IVIVE to predict human brain drug distribution.