Quantitative Membrane Protein Expression at the Blood-Brain Barrier of Adult and Younger Cynomolgus Monkeys
Quantitative Membrane Protein Expression at the Blood-Brain Barrier of Adult and Younger Cynomolgus Monkeys
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DOI：
10.1002/jps.22487
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发表时间：
2011-09-01
影响因子：
3.8
通讯作者：
Terasaki, Tetsuya
中科院分区：
文献类型：
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作者：
Ito, Katsuaki;Uchida, Yasuo;Terasaki, Tetsuya
食蟹猴已被用作预测药物在人脑中分布的模型。本研究的目的是通过使用液相色谱串联质谱来阐明影响药物向脑分布的膜蛋白（如转运蛋白、受体和连接蛋白）在食蟹猴脑微血管中的蛋白表达水平。在成年猴中，三种ATP结合盒转运蛋白（多药耐药1（MDR 1）、乳腺癌耐药蛋白（BCRP）和多药耐药蛋白4（MRP 4）），六种溶质载体转运蛋白（葡萄糖转运蛋白1（GLUT 1）、GLUT 3/14、单羧酸转运蛋白1（MCT 1）、MCT 8、有机阴离子转运多肽1A 2和平衡型核苷转运蛋白1），检测到两种连接蛋白（紧密连接蛋白-5和血管内皮钙粘蛋白）和两种受体（胰岛素受体和低密度脂蛋白受体相关蛋白1）。与我们先前报道的小鼠中的表达水平的比较揭示了明显的种属差异。猴中BCRP的表达是小鼠的3.52倍，而猴中MDR 1和MRP 4的表达水平分别是小鼠的0.304倍和0.180倍。本研究还研究了新生猴和儿童猴膜蛋白表达的发育变化。MDR 1在新生猴和成年猴中的表达相似，而在大鼠中，据报道新生猴脑微血管中的P-糖蛋白表达显著低于成年大鼠。这些结果将有助于了解和预测不同物种和不同年龄灵长类动物脑内药物浓度。(C)2011 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 100：3939-3950，2011
Cynomolgus monkey has been used as a model for the prediction of drug disposition in human brain. The purpose of this study was to clarify protein expression levels of membrane proteins affecting drug distribution to brain, such as transporters, receptors, and junctional proteins, in cynomolgus monkey brain microvessels by using liquid chromatography tandem mass spectrometory. In adult monkeys, three ATP-binding cassette transporters (multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4)), six solute carrier transporters (glucose transporter 1 (GLUT1), GLUT3/14, monocarboxylate transporter 1 (MCT1), MCT8, organic anion transporting polypeptide 1A2, and equilibrative nucleoside tranporter 1), two junctional proteins (claudin-5 and vascular endothelial cadherin), and two receptors (insulin receptor and low-density lipoprotein receptor-related protein 1) were detected. Comparison of the expression levels with those in mouse, which we reported previously, revealed a pronounced species difference. BCRP expression in monkey was greater by 3.52-fold than that in mouse, whereas MDR1 and MRP4 expression levels in monkey were lower by 0.304- and 0.180-fold, respectively, than that in mouse. This study also investigated the developmental changes in expression of membrane proteins in neonate and child monkeys. Expression of MDR1 was similar in neonate and adult monkeys, whereas in rat, P-glycoprotein expression was reported to be significantly lower in brain microvessels of neonate as compared with adult rat. These results will be helpful to understand and predict brain concentrations of drugs in different species and at different ages of primates. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3939-3950, 2011