血脑脊液屏障上P- 糖蛋白的研究进展

doi:10.3969/j.issn.2095-1396.2016.02.009

摘要/Abstract

摘要： 血脑脊液屏障是由脑微血管内皮细胞、星形胶质细胞和周皮细胞等组成的动态生理结构，对中枢神经系统内环境稳态的维持发挥至关重要的作用。P- 糖蛋白作为血脑脊液屏障上一种常见膜蛋白，它在脑微血管内皮细胞中大量表达，限制毒性物质和大量治疗中枢神经系统的药物进入脑内。因此对P- 糖蛋白在血脑脊液屏障中的外排转运机制的了解是神经系统疾病治疗的一个突破点。该文主要对P- 糖蛋白的基本结构、转运途径、在生理与病理情况下P- 糖蛋白的调节机制以及P- 糖蛋白抑制剂研究进展等进行综述，对中枢神经系统药物研发以及提高血脑脊液屏障对治疗药物通透性研究提供参考。

关键词: P- 糖蛋白, 基本结构, 转运机制, 调节机制, 抑制剂

Abstract: Blood-cerebrospinal fluid barrier（blood-CSF barrier） is a dynamic physiological structure，which is composed of brain microvascular endothelial cells，astrocytes and pericytes，playing an important role in maintaining homeostasis in the central nervous system（CNS）. P-glycoprotein（P-gp） is a common membrane protein in the blood cerebrospinal fluid barrier，which is expressed in the brain microvascular endothelial cells，and it limits the toxic substances and a large number of drugs for the treatment of the central nervous system into the brain. Therefore the efflux transport mechanism of P-gp in the blood-CSF barrier is a break though point for the treatment of nervous system disease. This article mainly reviews research progress on the basic structure and trans-port mechanism of P-gp，it’s regulation mechanism in the physiological and pathological conditions and inhibitors，to provide references for drug development and blood-CSF barrier transport mechanism of CNS.

Key words: P-glycoprotein, basic structure, transport mechanism, regulation mechanism, inhibitor

中图分类号:

R964

张海威，张力. 血脑脊液屏障上P- 糖蛋白的研究进展[J]. 神经药理学报, 2016, 6(2): 53-64.

ZHANG Hai-wei，ZHANG Li. Review of P-Glycoprotein on the Blood-Cerebrospinal Fluid Barrier[J]. Acta Neuropharmacologica, 2016, 6(2): 53-64.

参考文献

[1] 马金柱, 王化磊, 郑学星, 等. 天然免疫屏障-血脑屏障调节的研究进展[J]. 细胞与分子免疫学杂志, 2013, 29(8): 885-888.

[2] 周曼, 杨万超, 刘翔, 等. 血脑屏障结构功能及体外模型的研究进展[J]. 疑难病杂志, 2014, 13(6): 647-649.

[3] 张珉, 张俊钰, 钟武. 血脑屏障开放方法研究进展[J]. 国际药学研究杂志, 2016, 43(1): 126-133.

[4] 王玉璘，王少峡，郭虹，胡利民.血脑屏障中P-糖蛋白的调节机制[J]. 中国药理学通报, 2011, 27(9): 1196-2000.

[5] David S Miller. Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier[J]. Trend Pharmacol Sci, 2010, 31(6): 246-254.

[6] Remi-Martin Laberge, Raghuram Ambadipudi, Elias Georges. P-glycoprotein mediates thecollateral sensitivity of multidrug resistant cells to steroidhormones[J]. Biochem Biophys Res Commun, 2014, 447(4): 574-579．

[7] Juliano R L, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants[J]. Biochim Biophys Acta, 1976, 455(1): 152-162.

[8] Munekazu Nakaichi, Yoko Takeshita, Masaru Okuda, et al. Expression of the MDR1 gene and P-glycoprotein in canine mast cell tumor cell lines[J]. J Veterinary Medical Science, 2007, 69: 111-115.

[9] 牛芳，周芳，吴晓兰，等. 血脑屏障上ABC转运体与中枢神经系统疾病相关性的研究进展[J]. 中国临床药理学与治疗学, 2012, 17(2): 225-233.

[10] 涂春华，杨冬梓. P-糖蛋白结构及作用机制[J]. 中国生物化学与分子生物学, 2009, 25(1): 7-11.

[11] 吴松笛，万琪. 血脑屏障ATP结合盒超家族转运蛋白和药物转运[J]. 国外医学：脑血管疾病手术分册, 2005, 13(5): 386-389.

[12] Annie Frelet, Markus Klein. Insight in eukaryotic ABC transporter function by mutation analysis[J]. Febs Letters, 2006, 580(4): 1064-1084.

[13] Lin Jiunn H, Masayo Yamazaki. Role of P-glycoprotein in pharmacokinetics-clinical implications[J]. Clin Pharmacokinet, 2003, 42(1): 59-98.

[14] Michael Hohl, Christophe Briand, Markus G Grütter, et al. Crystal structure of a hete-rodimeric ABC transporter in its inward-facing conformation[J]. Nature Str-uctural&Molecular Biology, 2012, 19(4): 395-402.

[15] Chitra A Shintre, Ashley C W Pike, Li Qiu-hong, et al. Structures of ABCB10 a human ATP-binding cassette transporter in apo- and nucleotide-bound states[J]. Proc Natl Acad Sciences USA, 2013, 110(24): 9710-9715.

[16] Suresh V Ambudkar, Saibal Dey, Christine A Hrycyna. Biochemical, cellular, and pharmacolo-gical aspects of the multidrug transporter[J]. Annual Review of Pharmacology and Toxicology, 1999, 39, 361-398.

[17] 袁洪雨. 喹喔啉酮类P-糖蛋白抑制剂的设计、合成及逆转肿瘤多药耐药活性研究[D].济南：山东大学, 2009.

[18] Karin Pleban, Stephan Kopp, Edina Csaszar, et al. P-glycoprotein substratebinding domains are located at the transmembrane domain transmembrane domain interfaces:a combined photoaffinity labeling-protein homology modeling approach[J]. Mol Pharmacol, 2005, 67(2): 365-374.

[19] Miguel R Lugo, Frances Jane Sharom. Interaction of LDS-751 and rhodamine 123 with P-glycoprotein: evidence for simultaneous binding of both drugs[J]. Biochemistry, 2005, 44(42): 14020-14029.

[20] Christopher F Higgins, Kenneth J Linton. The ATP switch model for ABC transporters[J]. Nat StructMol Biol, 2004, 11(10): 918-926.

[21] Suresh V Ambudkar, In-Wha Kim, Zuben E Sauna. The power of the pump:mechanisms of action of P-glycoprotein(ABCB1) [J]. Eur J Pharm Sci, 2006, 27: 392-400.

[22] Gabriel E Jara, D Mariano A Vera, Adriana B Pierini. Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study[J]. J Molecular Graphics Modelling, 2013, 46: 10-21.

[23] Freya Klepsch, Poongavanam Vasanthanathan, Gerhard F Ecker. Ligand and structure-based classi-fication models for prediction of P-glycoprotein inhibitors[J]. J Chem Inf Model, 2014, 54(1): 218-229.

[24] Wen Po-chan, Brandy Verhalen, Stephan Wilkens, et al. On the origin of large flexibility of P-glycoprotein in the inward-facing state[J]. J Biological Chemistry, 2013, 288: 19211-19220.

[25] Jessica H van Wonderen, Roisin M McMahon, Megan L O'Mara, et al. The central cavity of ABCB1 undergoes alternating access during ATP hydrolysis[J]. FEBS J, 2014, 281(9): 2190–2201.

[26] Ricardo J Ferreira, Maria-Jose U Ferreira, Daniel J V A dos Santos, et al. Insights on P-glycoprotein’s efflux mechanism obtained by molecular dynamics simulations[J]. J Chemical Theory and Computation, 2012, 8(6): 1853-1864.

[27] Justin Charles Jagodinsky, Ugur Akgun. Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates[J]. Pharmacology Research & Perspectives, 2015, 3: e00114.

[28] Nandhitha Subramanian, Karmen Condic-Jurkic, Alan Edward Mark, et al. Identification of possi-ble binding sites for morphine and nicardipine on the multidrug transporter P-glycoprotein using umbrella sampling techniques[J]. J Chemical Information Modeling, 2015, 55(6): 1202-1217.

[29] Nandhitha Subramanian, Alexandra Schumann-Gillett, Alan E Mark, et al. Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning[J]. Biochimica et Biophysica Acta (BBA) Bi-omembranes, 2016, 1858(4): 776-782.

[30] Suresh V Ambudkar, In-Wha Kim, Zuben E Sauna, et al. The Aloop,a novel c-onserved aromatic acid subdomain upstream of the Walker A motif in AB-C transporters,is critical for ATP binding[J]. FEBS Lett, 2006, 580(4): 1049-1055.

[31] Yurika Watanabe, Wei-lin Hsu, Shuntaro Chiba, et al. Dynamics and structural changes induced by ATP and/or substrate binding in the inward-facing conformation state of P-glycoprotein[J]. Chemical Physics Letters, 2013, 557: 145-149.

[32] Megan L O’Mara, Alan E Mark. Structural characterization of two metastable ATP-bound states of P-glycoprotein[J]. PLoS ONE, 2014, 9(3): e91916.

[33] Zuben E Sauna, In-Wha Kim, Suresh V Ambudkar. Genomics and the mechanis-m of P-glycoprotein(ABCB1)[J]. J Bioenerg Biomembr, 2007, 39(5): 481-487.

[34] Catherine Vigano, Michel Julien, Isabelle Carrier, et al. Structural and functional asymmetry of the nucleotide-binding domains of P-glycoprotein investigated by attenua-ted total reflection Fourier transform infrared spectroscopy[J]. J Biological Chemistry, 2002, 277(7): 5008-5016.

[35] Suresh V Ambudkar, In-War Kim, Zuben E Sauna. The power of the pump: mechanisms of action of action of P-glycoprotein(ABCB1) [J]. Eur J Pharm Sci, 2006, 279(5): 392-400.

[36] Michael Hohl, Christopher Briand, Markus G Grütter, et al. Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation[J]. Nature Structural & Molecular Biology, 2012, 19(4): 395-402.

[37] Chitra A Shintre, Ashley C W Pike, Li Qiu-hong. Structures of ABCB10, a human ATP-bi-nding cassette transporter in apo- and nucleotide-bound states[J]. Proceedings of the National Academy of Sciences USA, 2013, 110: 9710-9715.

[38] Roger J P Dawson, Kaspar P Locher. Structure of a bacterial multidrug ABC transporter[J]. Nature, 2006, 443: 180-185.

[39] Hassanul G Choudhury, Zhen Tong, Indran Mathavan, et al. Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state[J]. Proceedings of the National Academy of Sciences USA, 2014, 111(25): 9145-9150.

[40] Aller S G, Yu J, Ward A, et al. Structure of P-glycoprotein reveals a molecular basis for polyspecific drug binding[J]. Science, 2009, 323: 1718-1722.

[41] 聂昊，王晖. P糖蛋白在不同组织中的分布与功能研究进展[J]. 广东药学学报, 2012, 28(4): 456-460.

[42] Luscher A, Harry P de Koning, Master P. Chemotherapeeutic strategies against Trypanosoma brucei: Drug targets vs. drug targeting[J]. Current Pharmaceutical Design, 2007, 13(6): 555-567.

[43] Nandhitha Subramanian, Karmen Condic-Jurkic, Megan L O Mara. Structural and dynamic perspectives on the promiscuous transport activity of P-glycoprotein[J]. Neurochemistry International, 2016, 10: 1016.

[44] 韩嘉华，朱斯琦，谢燕. 黄酮类化合物抵抗P-糖蛋白介导肿瘤多药耐药特性机制研究进展[J]. 国际药学研究杂志, 2016, 43(5): 818-823.

[45] Zhu Li-tao, Zhao Li, Wang Hu, et al. Oroxylin A reverses P-glycoprotein mediated multidrug resistance of MCF7/ADR cells by G2/M arrest[J]. Toxicol Lett, 2013, 219(2): 107-115.

[46] Zhao Bo-xin, Sun Ya-bin, Wang Sheng-qi, et al. Grape seed procyanidin reversal of P-glycoprotein associated multidrug resistance viadown-regulation of NF-κB and MAPK/ERK mediated YB-1 activity in A2780/T cells[J]. PLoS One, 2013, 8(8): e71071.

[47] Xia Yuan-zheng, Ni Kai, Guo Chao, et al. Alopecurone B reverses doxorubicin-resistant human osteosarcoma cell line by inhibiting P-glycoprotein and NF-κB sig-naling[J]. Phytomedicine, 2015, 22(3): 344-351.

[48] 赵博欣. 原花青素通过抑制P-糖蛋白功能与表达从而逆转肿瘤多药耐药作用的机制研究[D]. 深圳：南方科技大学, 2014.

[49] 董会月. 丹皮酚逆转人白血病耐药细胞系K562/ADM细胞多药耐药的作用研究[D]. 福建：福建中医药大学, 2010.

[50] 周勇，钟文彬，陈凯,等. Disulfiram联合Cu通过上调TNF-α表达及蓄积ROS诱导白血病干细胞凋亡[J]. 第三军医大学学报, 2015, 37(10): 984-989.

[51] 何海兰，季丽娟，李琦智, 等. 槲皮素对阿霉素诱导HL-60细胞MDR1基因表达的影响[J]. 中国实验血液学杂志, 2015, 23(1): 70-76.

[52] 刘小微，王慧君，梁伟, 等. 从Akt/COX-2/P-gp信号通路研究丹参酚酸B逆转HCT-8/VCR细胞多药耐药的作用及机制[J]. 中国中西医结合消化杂志, 2016, 2(5): 338-344.

[53] Anika M S Hartz, Bjorn Bauer, Gert Fricker, et al. Rapid regulation of P-glycoprotein at the blood-brain barrier by endothelin-1[J]. Molecular Pharmacology, 2004, 66(3): 387-394.

[54] Robert R Rigor, Brian T Hawkins, David S Miller. Activation of PKC isoform beta(I) atthe blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drugdelivery to the brain[J]. J Cerebral Blood Flow and Metabolism, 2010, 30(7): 1373-1383.

[55] Wang Xue-qian, Brian T Hawkins, David S Miller. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier[J]. FASEB J, 2011, 25(2): 644-652.

[56] Brian T Hawkins, Robert R Rigor, David S Miller. Rapid loss of blood-brain barrier P-glycoprotein activity through transporter internalization demonstrated usin-g a novel in situ proteolysis protection assay[J]. J Cerebral Blood Flow and Metabolism, 2010, 30(9): 1593–1597.

[57] Brian T Hawkins, Destiny B Sykes, David S Miller. Rapid, reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor[J]. J Neurosci, 2010, 30(4): 1417-1425.

[58] David S Miller. ABC transporter regulation by signaling at the blood-brain barrier: relevance to pharmacology[J]. Advances in Pharmacology, 2014, 71:1-24.

[59] Rashid Deane, Wu Zhen-hua, Berislav V Zlokovic. RAGE(yin) versus LRP(yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier[J]. Stroke, 2004, 35(11 suppl 1): 2628-2631.

[60] Fred C Lam, Liu Rong-hua, Lu Pei-hua, et al. β-Amyloid efflux mediated by p-glycoprotein[J]. J Neurochem, 2001, 76(4): 1121-1128.

[61] Anika M S Hartz, David S Miller, Bjorn Bauer. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease[J].Mol Pharmacol, 2010, 77(5): 715-723.

[62] Silke Vogelgesang, Ingolf Cascorbi, Eike Schroeder, et al. Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans[J]. Pharmacogenetics, 2002, 12(7): 283-296.

[63] Silke Vogelgesang, Rolf W Warzok, Ingolf Cascorbi, et al. The role of P-glycoprotein in cerebral amyloid angiopathy: Implications for the early pathogenesis of Alzheimer’s disease[J]. Curr Alzheimer Res, 2004, 1(2): 121-125.

[64] Anja Brenn, Markus Grube, Michele Peters, et al. Beta-amyloid downregulates MDR1 P-Glycoprotein(ABCB1) expression at the blood-brain barrier in mice[J]. Int J Alzheimers Dis, 2011, 2011: 690121.

[65] Diana Kuhnke, Gabriele Jedlitschky, Markus Grube, et al. MDR1-P-Glycoprotein(ABCB1) mediates transport of Alzheimer’s amyloid-beta peptides-implications for the mechanisms of Aβ clearance at the blood-brain barrier[J]. Brain Pathol, 2007, 17(4): 347-353.

[66] 张觅，张啟智，楼江, 等. P-糖蛋白在退行性疾病中的作用[J]. 中国临床药理学与治理学, 2012, 17(7): 835-840.

[67] Bartels A L, Willemsen A T, Kortekaas R, et al. Decreased blood-brain barri-er P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA[J]. J Neural Transm, 2008, 115(7): 1001-1009.

[68] Terry P Brown, Paul C Rumsby, Alexander C Capleton, et al. Pesticides and Parkinson’s di-sease is there a link[J]. Environ Health Perspect, 2006, 114(2): 156-164.

[69] Sreeramulu K, Liu Rong-hua, Frances J Sharom. Interaction of insecticides with mammalian P-glycopertein and their effects on its transport function[J]. Biochim Biophys Acta, 2007, 1768(7): 1750-1757.

[70] Marie Westerlund, Andrea Carmine Belin, Lars Olson, et al. Expression of muti-drug resistan-ce1 mRNA in human and rodent tissue: reduced levels in Parkinson patients[J]. Cell Tissue Res, 2008, 334(2): 179-185.

[71] 牛芳，周芳，吴晓兰，王广基. 血脑屏障上ABC转运体与中枢神经系统疾病相关性的研究进展[J]. 中国临床药理学和治疗学, 2012, 17(2): 225-233.

[72] Zhang Chun-bo, Patrick Kwan, Zuo Zhong, et al. The transport of antiepileptic drugsby P-glycoprotein[J]. Adv Drug Delivery Rev, 2012, 64(10): 930-942.

[73] Bjorn Bauer, Anika M Hartz, Antom Pekcec, et al. Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling [J]. Mol Pharmacol, 2008, 73(5): 1444-1453.

[74] Maria Feldmann, Matthias Koepp. P-glycoprotein imaging in temporal lobeepilepsy: in vivo PET experiments with the Pgp substrate[(11)C]-verapamil[J]. Epilepsia, 2012, 53(6): 60-63.

[75] 高敏，张敬军. P糖蛋白与难治性癫痫关系的研究进展[J]. 中国脑科疾病与康复杂志：电子版, 2016, 6(2): 120-123.

[76] Hiram Luna-Munguia, Heidrun Potschka. CNS transporters and drug delivery inepilepsy[J]. Curr Pharm Des, 2014, 20(10): 1534-1542.

[77] Andrew Owen, Becky Chandler, David J Back. The implications of P-glycoprotein in HI-V: friend or foe[J]? Fundam Clin Pharmacol, 2005, 19(3): 283-296.

[78] Kentaro Hayashi, Pu Hong, Ibolya E Andras, et al. HIV-Tat protein upregulates expression of multidrug resistance protein 1 in blood-brain barrier[J]. J Cereb Blood Flow Metab, 2006, 26(8): 1052-1065.

[79] Zhong Yu, Bernhard Hennig, Michal Toborek. Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregula-tion of P-glycoprotein in brain endothelial cells[J]. J Cereb BloodFlow Metab, 2010, 30(3):522-33.

[80] 雷燕,张建华,张明,等. P-糖蛋白抑制剂研究进展[J].广州化工, 2016, 44(6): 27-30.

[81] Hilary Thomas, Helen M Coley. Overcoming multidrug resistance in cancer: anupdate on the clinical strategy of inhibiting p-glycoprotein[J]. Cancercontrol, 2003, 10(2): 159-159.

[82] Nicola Antonio Colabufo, Francesco Berardi, Mariangela Cantore, et al. Perspectives of P-glycoprotein modulating agents in oncology and neuro-degenerative diseases: pharmace-utical, biological, and diagnostic potentials[J]. J Med Chem, 2010, 53(5): 1883-1897.

[83] 刘念，耿小平，熊茂明. P－糖蛋白抑制剂的研究进展[J]. 国外医学: 药学分册, 2006, 33(2): 107-110.

[84] Andreia Palmeira, Emilia Sousa, Vasconcelos M H, et al. Threedecades of P-gp inhi-bitors: skimming through severalgenerations and scaffolds[J]. Curr Med Che-m, 2012, 19(13): 1946-2025.

[85] 朱宝英,黄静,王永林,等. P-糖蛋白及肿瘤多药耐药的逆转[J]. 中国药房, 2011, 22(6): 550-552.

[86] Christopher A McDevitt, Richard Callaghan. How can we best usestructural information on P-glycoprotein to designinhibitors[J]? Pharm Ther, 2007, 113(2): 429-441.

[87] Lajos Pusztai, Peter Wagner, Nuhad Ibrahim, et al. Phase II study oftariquidar, a selective P-glycoprotein inhibitor, in patientswith chemotherapy-resistant, advanced breast carcinoma[J]. Cancer, 2005, 104(4): 682-691.

[88] Christine Y Malati, Sarah M Robertson, Jennifer D Hunt, et al. Influence of panaxginsengon cytochrome P450(CYP) 3A and P-glycoprotein(P-gp) activity in healthy subjects[J]. J Clin Pharmacol, 2012, 52(6): 932-939.

[89] Li Xue, Hu Jin-ping, Wang Bao-lian, et al. Inhibitory effects of herbal constituents on P-glycoprotein in vitro and in vivo: herbdrug interactions mediated via P-gp[J]. Toxicol Appl Pharm, 2014, 275(2): 163-175.

[90] Sun Yan-fang, Wink Michael. Tetrandrine and fangchinoline, bisbenzylisoquinoline alkaloids from stephania tetrandra can reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells[J]. Phytomedicine, 2014, 21(8-9): 1110-1119.

[91] Ye Ling, Wang Tao, Tang Lan, et al. Poor oral bioavailability of apromising anticancer agent andrographolide is due to extensivemetabolism and efflux by P-glycoprotein[J]. J Pharm Sci, 2011, 100(11): 5007-5017.

[92] Jiunn H Lin, Masayo Yamazaki. Role of P-glycoprotein in pharmacokinetics clinical implications[J]. Clin Pharmacokinet, 2003, 42(1): 59-98.