药学学报, 2016, 51(6): 886-891
引用本文:
王心怡, 张志荣. 美吡拉敏敏感的、逆质子有机阳离子转运体的研究进展[J]. 药学学报, 2016, 51(6): 886-891.
WANG Xin-yi, ZHANG Zhi-rong. Research progress of pyrilamine-sensitive H+/OC antiporter[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 886-891.

美吡拉敏敏感的、逆质子有机阳离子转运体的研究进展
王心怡, 张志荣
四川大学华西药学院, 四川 成都 610041
摘要:
近年来,一种新型的有机阳离子转运体被发现存在于脑毛细血管内皮细胞和Caco-2(人克隆结肠腺癌细胞)等细胞上,介导美吡拉敏、苯海拉明和氧可酮等有机阳离子药物的吸收和外排。其所介导的转运过程不能被典型的有机阳离子转运体底物或抑制剂所抑制,转运特性不同于已报道的有机阳离子转运体(OCTs)、有机阳离子/肉毒碱转运体(OCTNs)、多药及毒性化合物外排转运体(MATE)及细胞膜单胺转运体(PMAT)等,是一种新型的逆质子有机阳离子转运体,被称为美吡拉敏敏感的、逆质子有机阳离子转运体(pyrilamine-sensitive H+/OC antiporter)。本文将对其转运特性、底物结构特点、表达组织以及与其他有机阳离子转运体的区别等进行全面的归纳和阐述。
关键词:    美吡拉敏      有机阳离子转运体      转运特性      苯海拉明      氧可酮     
Research progress of pyrilamine-sensitive H+/OC antiporter
WANG Xin-yi, ZHANG Zhi-rong
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Abstract:
In recent years, a new type of organic cation transporter has been found to transport organic cation drugs like pyrilamine, diphenhydramine and oxycodone in brain capillary endothelial cells, Caco-2 cells and other cells. Its transport activity can not be inhibited by typical organic cation transporter substrates or inhibitors, and its transport characteristics are different from those reported for the organic cation transporters, such as organic cation transporters (OCTs), organic cation/carnitine transporters (OCTNs), multidrug and toxin extrusion transporters (MATE) and the plasma membrane monoamine transporter (PMAT). It is a novel organic cation transporter, called pyrilamine-sensitive H+/OC antiporter. This review will present a comprehensive summary to elaborate the transport characteristics, structure of the substrates, tissue expression and the differences with other organic cation transporters.
Key words:    pyrilamine    organic cation transporter    transport characteristy    diphenhydramine    oxycodone   
收稿日期: 2015-11-05
DOI: 10.16438/j.0513-4870.2015-1024
基金项目: 国家自然科学基金重点项目(81130060).
通讯作者: 张志荣,Tel:86-28-85501566,Fax:86-28-85501615,E-mail:zrzzl@vip.sina.com
Email: zrzzl@vip.sina.com
相关功能
PDF(551KB) Free
打印本文
0
作者相关文章
王心怡  在本刊中的所有文章
张志荣  在本刊中的所有文章

参考文献:
[1] Grundemann D, Gorboulev V, Gambaryan S, et al. Drug excretion mediated by a new prototype of polyspecific transporter[J]. Nature, 1994, 372:549-551.
[2] Li D, Sheng L, Li Y. Methods for the study of drug transporters[J]. Acta Pharm Sin (药学学报), 2014, 49:963-970.
[3] Tega Y, Akanuma SI, Kubo Y, et al. Blood-to-brain influx transport of nicotine at the rat blood-brain barrier:involvement of a pyrilamine-sensitive organic cation transport process[J]. Neurochem Int, 2013, 62:173-181.
[4] Ohashi R, Tamai I, Yabuuchi H, et al. Na+-dependent carnitine transport by organic cation transporter (OCTN2):its pharmacological and toxicological relevance[J]. J Pharmacol Exp Ther, 1999, 291:778-784.
[5] Yabuuchi H, Tamai I, Nezu JI, et al. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations[J]. J Pharmacol Exp Ther, 1999, 289:768-773.
[6] Yamazaki M, Terasaki T, Yoshioka K, et al. Carrier-mediated transport of H1-antagonist at the blood-brain barrier:a common transport system of H1-antagonists and lipophilic basic drugs[J]. Pharm Res, 1994, 11:1516-1518.
[7] Yamazaki M, Terasaki T, Yoshioka K, et al. Carrier-mediated transport of H1-antagonist at the blood-brain barrier:mepyramine uptake into bovine brain capillary endothelial cells in primary monolayer cultures[J]. Pharm Res, 1994, 11:975-978.
[8] Sadiq MW, Borgs A, Okura T, et al. Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo[J]. J Pharm Sci, 2011, 100:3912-3923.
[9] Engel K, Wang J. Interaction of organic cations with a newly identified plasma membrane monoamine transporter[J]. Mol Pharm, 2005, 68:1397-1407.
[10] Okura T, Ito R, Ishiguro N, et al. Blood-brain barrier transport of pramipexole, a dopamine D2 agonist[J]. Life Sci, 2007, 80:1564-1571.
[11] Kuwayama K, Inoue H, Kanamori T, et al. Uptake of 3,4-methylenedioxymethamphetamine and its related compounds by a proton-coupled transport system in Caco-2 cells[J]. Biochim Biophys Acta, 2008, 1778:42-50.
[12] André P, Debray M, Scherrmann JM, et al. Clonidine transport at the mouse blood-brain barrier by a new H+ antiporter that interacts with addictive drugs[J]. J Cereb Blood Flow Metab, 2009, 29:1293-1304.
[13] Kitamura A, Higuchi K, Okura T, et al. Transport characteristics of tramadol in the blood-brain barrier[J]. J Pharm Sci, 2014, 103:3335-3341.
[14] Mizuuchi H, Katsura T, Ashida K, et al. Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells[J]. Am J Physiol Gastrlointest Liver Physiol, 2000, 278:G563-G569.
[15] Kubo Y, Shimizu Y, Kusagawa Y, et al. Propranolol transport across the inner blood-retinal barrier:potential involvement of a novel organic cation transporter[J]. J Pharm Sci, 2013, 102:3332-3342.
[16] Zhu Y, Sun X, Gong T, et al. Antioxidant and antiapoptotic effects of 1,1'-(biphenyl-4,4'-diyl)-bis(3-(dimethylamino)-propan-1-one) on protecting PC12 cells from Aβ-induced injury[J]. Mol Pharm, 2014, 11:428-435.
[17] Zhang X, Liu X, Gong T, et al. In vitro and in vivo investigation of dexibuprofen derivatives for CNS delivery[J]. Acta Pharmacol Sin, 2012, 33:279-288.
[18] Li YP, Zhou YY, Qi BW, et al. Brain-specific delivery of dopamine mediated by N,N-dimethyl amino group for the treatment of Parkinson's disease[J]. Mol Pharm, 2014, 11:3174-3185.
[19] Wang XY, Li JB, Xu CQ, et al. Scopine as a novel braintargeting moiety enhances the brain uptake of chlorambucil[J]. Bioconjug Chem, 2014, 25:2046-2054.
[20] Li YP, Zhou YY, Jiang JY, et al. Mechanism of brain targeting by dexibuprofen prodrugs modified with ethanolamine-related structures[J]. J Cereb Blood Flow Metab, 2015, 35:1-10.
[21] Shimomura K, Okura T, Kato S, et al. Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model[J]. Fluids Barriers CNS, 2013. DOI:10.1186/2045-8118-10-8.
[22] Okura T, Hattori A, Takano Y, et al. Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone[J]. Drug Metab Dispos, 2008, 36:2005-2013.
[23] Mizuuchi H, Katsura T, Saito H, et al. Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells:contribution of pH-dependent transport system[J]. J Pharmacol Exp Ther, 1999, 290:388-392.
[24] Okura T, Higuchi K, Kitamura A, et al. Proton-coupled organic cation antiporter-mediated uptake of apomorphine enantiomers in human brain capillary endothelial cell line hCMEC/D3[J]. Biol Pharm Bull, 2014, 37:286-291.
[25] Higuchi K, Kitamura A, Okura T, et al. Memantine transport by a proton-coupled organic cation antiporter in hCMEC/D3 cells, an in vitro human blood-brain barrier model[J]. Drug Metab Pharmacokinet, 2015, 30:182-187.
[26] Han YH, Sweet DH, Hu DN, et al. Characterization of a novel cationic drug transporter in human retinal pigment epithelial cells[J]. J Pharmacol Exp Ther, 2001, 296:450-457.
[27] Fischer W, Bernhagen J, Neubert RH, et al. Uptake of codeine into intestinal epithelial (Caco-2) and brain endothelial (RBE4) cells[J]. Eur J Pharm Sci, 2010, 41:31-42.
[28] Tanaka Y, Hipolito CJ, Maturana AD, et al. Structural basis for the drug extrusion mechanism by a MATE multidrug transporter[J]. Nature, 2013, 496:247-251.
[29] Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease[J]. Nat Genet, 2004, 36:471-475.
[30] Koepsell H, Endou H. The SLC22 drug transporter family[J]. Pflügers Arch, 2004, 447:666-676.
[31] Zhang L, Wang JT, Zhang DW, et al. Molecular characterization of a HMG-CoA reductase gene from a rare and endangered medicinal plant, Dendrobium officinale[J]. Acta Pharm Sin (药学学报), 2014, 49:411-418.
[32] Tamai I, Yabuuchi H, Nezu JI, et al. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1[J]. FEBS Lett, 1997, 419:107-111.