芳香开窍化合物对MDCK-MDR1单层细胞透过性的影响

doi:10.5246/jcps.2011.06.075

芳香开窍化合物对MDCK-MDR1单层细胞透过性的影响

张承悦, 赵攀, 施喆, 杨晓达^*

北京大学医学部天然药物及仿生药物国家重点实验室; 药学院化学生物学系, 北京 100191

收稿日期:2011-05-10 修回日期:2011-09-28 出版日期:2011-11-15 发布日期:2011-11-15
通讯作者: 杨晓达*

Effects of herbal aromatics on the permeability of MDCK-MDR1 monolayers

Cheng-Yue Zhang, Pan Zhao, Zhe Shi, Xiao-Da Yang^*

State Key Laboratories of Natural and Biomimetic Drugs; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2011-05-10 Revised:2011-09-28 Online:2011-11-15 Published:2011-11-15
Contact: Xiao-Da Yang*

摘要/Abstract

摘要：

在中医理论体系中, 芳香开窍类药物对于调节脑部的药物摄取具有重要的作用。对于此作用的分子机制研究目前仍然有限。MDCK-MDR1细胞是研究药物透过血脑屏障机制的一个理想体外模型, 本文用稳定转染的方法建立了MDCK-MDR1细胞系并研究了几种重要的芳香药物对BBB透过性的作用。研究结果表明: 我们发现芳香开窍化合物可以在MDCK-MDR1模型上增加FD4的透过性并减少Rho123的外排, 说明这些化合物一方面可以打开细胞间的紧密联接, 另一方面可以抑制P-gp的作用, 从而影响药物吸收。此研究为阐明芳香化合物的作用机制提供了新的见解。

关键词: 芳香开窍药物, MDCK-MDR1, 紧密连接, P-gp

Abstract:

Inducing resuscitation with herbal aromatics is important to modulate the brain intake of drugs in traditional Chinese medicine, but limited information has been available on the mechanism of action. The MDCK-MDR1 monolayer is an excellent in vitro cell model to use as a tool to study blood brain barrier (BBB) screening. In this study, we established MDCK-MDR1 cell line by stable transfection and investigated the effects of several important herbal aromatics on BBB permeability. The characterization experiment demonstrated the MDCK-MDR1 used in this study was valid. In a transport study, we found several herbal aromatics increased the permeability of fluorescein isothiocyanate-labeled dextran 4kDa (FD4) and inhibited efflux of Rhodamine123 (Rho123). These results demonstrated that herbal aromatics enhanced the BBB permeation of drugs by both inhibition of P-gp and opening of the BBB tight junction, thus providing new insights for understanding the mechanisms of aromatic compounds’ BBB permeability.

Key words: Herbal aromatics, MDCK-MDR1, Tight junction, P-gp

中图分类号:

R962

Supporting:

Foundation items: Major New Medicine Project in Mega-projects of Science Research of China (Grant No.2009ZX09502-006) and National Natural Science Foundation of China (Grant No. 20971008).
^*Corresponding author. Tel.: 86-10-82801539; Fax: 86-10-66015584

张承悦, 赵攀, 施喆, 杨晓达^*. 芳香开窍化合物对MDCK-MDR1单层细胞透过性的影响[J]. , DOI: 10.5246/jcps.2011.06.075.

Cheng-Yue Zhang, Pan Zhao, Zhe Shi, Xiao-Da Yang^*. Effects of herbal aromatics on the permeability of MDCK-MDR1 monolayers [J]. , DOI: 10.5246/jcps.2011.06.075.

参考文献

[1] Lefauconnier, J.M.; Hauw, J.J. Rev. Neurol (Paris). 1984, 140, 89-109.
[2] Eckerand, G.F.; Noe, C.R. Curr. Med. Chem. 2004, 11, 1617-1628.
[3] Feng, B.; Mills, J.B.; Davidson, R.E.; Mireles, R.J.; Janiszewski, J.S.; Troutman, M.D.; de Morais, S.M. Drug Metab. Dispos. 2008, 36, 268-275.
[4] Hansch, C.; Bjorkroth, J.P.; Leo, A. J. Pharm. Sci. 1987, 76, 663-687.
[5] Dai, H.; Marbach, P.; Lemaire, M.; Hayes, M.; Elmquist, W.F. J. Pharmacol. Exp. Ther .2003, 304, 1085-1092.
[6] Wielinga, P.R.; de Waal, E.; Westerhoff, H.V.; Lankelma, J. J. Pharm. Sci. USA. 1999, 88, 1340-1347.
[7] Hombach, J.; Bernkop-Schnurch, A. Int. J. Pharm. 2009, 376, 104-109.
[8] Wu, S.; Cheng, G.; Feng, Y. Chin. Tradit. Herb. Drugs. 2001, 32, 1143-1145.
[9] Wang, X.R.; Wu, Y.K.; Miao, H. Chin. J. Integr. Med. 1994, 14, 349-351.
[10] Wang, J.H.; Ye, Z.G. Chin. J. Chin. Mater. Med. 2004, 29, 119-122.
[11] Li, D.C.; Zhong, X.K.; Zeng, Z.P.; Jiang, J.G.; Li, L.; Zhao, M.M.; Yang, X.Q.; Chen, J.; Zhang, B.S.; Zhao, Q.Z.; Xie, M.Y.; Xiong, H.; Deng, Z.Y.; Zhang, X.M.; Xu, S.Y.; Gao, Y.X. J. Control. Release. 2009, 138, 103-112.
[12] Jin, D.; Wang, F.; Qu, L.; Li, Z.; Jin, L.; Liu, P.; Xu, X.; Cui, H. Mol. Biol. Rep. 2011, 38, 913-920.
[13] Cecchelli, R.; Berezowski, V.; Lundquist, S.; Culot, M.; Renftel, M.; Dehouck, M.P.; Fenart, L. Nat. Rev. Drug Discov. 2007, 6, 650-661.
[14] Gumbletonand, M.; Audus, K.L. J. Pharm. Sci. 2001, 90, 1681-1698.
[15] Veronesi, B. Neurotoxicology. 1996, 17, 433-443.
[16] Garberg, P.; Ball, M.; Borg, N.; Cecchelli, R.; Fenart, L.; Hurst, R.D.; Lindmark, T.; Mabondzo, A.; Nilsson, J.E.; Raub, T.J.; Stanimirovic, D.; Terasaki, T.; Oberg, J.O.; Osterberg, T. Toxicol. In Vitro. 2005, 19, 299-334.
[17] Wang, Q.; Rager, J.D.; Weinstein, K.; Kardos, P.S.; Dobson, G.L.; Li, J.B.; Hidalgo, I.J. Int. J. Pharm. 2005, 288, 349-359.
[18] Madgula, V.L.; Avula, B.; Yu, Y.B.; Wang, Y.H.; Tchantchou, F.; Fisher, S.; Luo, Y.; Khan, I.A.; Khan, S.I. Planta Med. 2010, 76, 599-606.
[19] Navarro, C.; Gonzalez-Alvarez, I.; Gonzalez-Alvarez, M.; Manku, M.; Merino, V.; Casabo, V.G.; Bermejo, M. Eur. J. Pharm. Sci. 2011, 42, 290-299.
[20] Braun, A.; Hammerle, S.; Suda, K.; Rothen-Rutishauser, B.M.; Gunthert, B.; Kramer, S.D.; Wunderli-Allenspach, H. Eur. J. Pharm. Sci. 2000, 11, S51-60.