20(S)-原人参三醇和20(R)-原人参三醇差向异构体及达玛-20(22)E,24-二烯-3β,6α,12β-三醇在MDCK-pHaMDR细胞单层模型中的跨血脑屏障研究

doi:10.5246/jcps.2017.08.063

中国药学(英文版) ›› 2017, Vol. 26 ›› Issue (8): 566-573.DOI: 10.5246/jcps.2017.08.063

20(S)-原人参三醇和20(R)-原人参三醇差向异构体及达玛-20(22)E,24-二烯-3β,6α,12β-三醇在MDCK-pHaMDR细胞单层模型中的跨血脑屏障研究

郑怡然, 吴秀稳, 杨秀伟^*

北京大学医学部药学院天然药物学系; 天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2017-06-20 修回日期:2017-07-10 出版日期:2017-08-31 发布日期:2017-07-18
通讯作者: Tel.: +86-010-82801569, E-mail: xwyang@bjmu.edu.cn
基金资助:
The National New Drug R & D Program (Grant No. 2011BAI07B08; 2009ZX09301-010) of China.

The blood-brain barrier permeability of 20(S) and 20(R)-protopanaxatriol epimers and dammar-20(22)E,24-diene-3β,6α,12β-triol in MDCK-pHaMDR cell monolayer model

Yiran Zheng, Xiuwen Wu, Xiuwei Yang^*

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

Received:2017-06-20 Revised:2017-07-10 Online:2017-08-31 Published:2017-07-18
Contact: Tel.: +86-010-82801569, E-mail: xwyang@bjmu.edu.cn
Supported by:
The National New Drug R & D Program (Grant No. 2011BAI07B08; 2009ZX09301-010) of China.

摘要/Abstract

摘要：

本文应用MDCK-pHaMDR细胞单层模型, 评价20(S)-原人参三醇(1)和20(R)-原人参三醇(2) 差向异构体及达玛-20(22)E,24-二烯-3β,6α,12β-三醇(3) 在血脑屏障的吸收性。为了评价三个化合物的吸收性和预测其吸收机制, 对它们的双向透过性进行了研究, 并计算了相应的表观渗透系数(P_app)。在三个受试化合物中, 原人参三醇差向异构体化合物1和2显示了良好的吸收性, P_app值在1×10^–5 cm/s数量级; 而化合物3判断为吸收不良的化合物, 其P_app值小于1×10^–7 cm/s。三个化合物由于结构上的差异, 在细胞内产生了不同程度的蓄积。维拉帕米抑制P糖蛋白的转运实验结果表明, 化合物1和2在MDCK-pHaMDR细胞单层模型中的转运机制不仅仅是单纯的被动扩散。本文的研究结果为化合物1和2作用于脑的研究提供了实验依据。

关键词: 20(S)-原人参三醇, 20(R)-原人参三醇, 达玛-20(22)E,24-二烯-3β,6α,12β-三醇, MDCK-pHaMDR细胞单层模型, 表观渗透系数, 血脑屏障

Abstract:

The blood-brain barrier permeability of 20(S) and 20(R)-protopanaxatriol epimers and dammar-20(22)E,24-diene-3β,6α,12β-triol were investigated using the MDCK-pHaMDR cell monolayer model. The bidirectional permeability tests were carried out, and the apparent permeability coefficients (P_app) were calculated. The two protopanaxatriol epimers showed good permeability with P_app values of ~10^–5 cm/s, whereas dammar-20(22)E,24-diene-3β,6α,12β-triol showed poor permeability with P_app of <1×10^–7 cm/s. The three compounds showed differences in intracellular accumulations due to their different structures. Inhibition of P-gp with verapamil showed that the transport mechanisms in MDCK-pHaMDR cell monolayer for compounds 1and 2 epimers were not only simple passive diffusion but also involving an efflux way mediated by P-gp. These findings provided new basis for the further study of compounds 1 and 2 acting on the brain.

Key words: 20(S)-Protopanaxatriol, 20(R)-Protopanaxatriol, Dammar-20(22)E,24-diene-3β,6α,12β-triol, MDCK-pHaMDR, Permeability, Blood-brain barrier

中图分类号:

R284

Supporting:

郑怡然, 吴秀稳, 杨秀伟. 20(S)-原人参三醇和20(R)-原人参三醇差向异构体及达玛-20(22)E,24-二烯-3β,6α,12β-三醇在MDCK-pHaMDR细胞单层模型中的跨血脑屏障研究[J]. 中国药学(英文版), 2017, 26(8): 566-573.

Yiran Zheng, Xiuwen Wu, Xiuwei Yang. The blood-brain barrier permeability of 20(S) and 20(R)-protopanaxatriol epimers and dammar-20(22)E,24-diene-3β,6α,12β-triol in MDCK-pHaMDR cell monolayer model[J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(8): 566-573.

参考文献

[1] Yang, X.W. Mod. Chin. Med. 2016, 18, 7-15, 55.

[2] Yang, X.W. Mod. Chin. Med. 2016, 18, 16-35.

[3] Yang, X.W.; Fu, L. Mod. Chin. Med. 2016, 18, 36-55.

[4] Chinese Pharmacopeia Commission. Pharmacopeia of People's Republic of China, Beijing: China Medical Science and Technology Press: Beijing, China, 2015; Volume I, pp. 389-391.

[5] Li, K.K.; Yang, X.W. Mod. Chin. Med. 2012, 14, 47-50.

[6] Li, K.K.; Yao, C.M.; Yang, X.W. Planta Med. 2012, 78, 189-192.

[7] Li, K.K.; Yang, X.B.; Yang, X.W.; Liu, J.X.; Gong, X.J. Fitoterapia. 2012, 83, 1030-1035.

[8] Yang, X.W.; Li, K.K.; Zhou, Q.L. Chin. Tradit. Herb. Drugs. 2015, 46, 3137-3145.

[9] Li, K.K.; Yang, X.W. Chin. Tradit. Herb. Drugs. 2015, 46, 169-173.

[10] Qiu, S.; Yang, W.Z.; Shi, X.J.; Yao, C.L.; Yang, M.; Liu, X.; Jiang, B.H.; Wu, W.Y.; Guo, D.A. Anal. Chim. Acta. 2015, 893, 65-76.

[11] Ma, L.Y.; Zhou, Q.L.; Yang, X.W. Bioorg. Med. Chem. Lett. 2015, 25, 5321-5325.

[12] Ma, L.Y.; Yang, X.W. Phytochem. Lett. 2015, 13, 406-412.

[13] Ma, L.Y.; Yang, X.W. Chin. Tradit. Herb. Drugs. 2015, 46, 2522-2533.

[14] Ma, L.Y.; Yang, X.W. Chin. Tradit. Herb. Drugs. 2016, 47, 6-14.

[15] Choi, S.Y.; Cho, C.W.; Lee, Y.M.; Kim, S.S.; Lee, S.H.; Kim, K.T. J. Ginseng Res. 2012, 36, 425-429.

[16] Wang, Y.Z.; Chen, J.; Chu, S.F.; Wang, Y.S.; Wang, X.Y.; Chen, N.H.; Zhang, J.T. J. Pharmacol. Sci. 2009, 109, 504-510.

[17] Xiang, Q.L.; Cheng, J.W.; Ma, R.Q.; Li, J.; Li, C.; Zhu, J.M.; Cao, W.W. J. Suu Yat-Sen Univ. (Med. Sci.) 2008, 29, 705-709.

[18] Lee, B.H.; Hwang, S.H.; Choi, S.H.; Kim, H.J.; Lee, J.H.; Lee, S.M.; Ahn, Y.G.; Nah, S.Y. Korean J. Physiol. Pharmacol. 2013, 17, 127-132.

[19] Gao, Y.; Chu, S.F.; Li, J.P.; Zhang, Z.; Yan, J.Q.; Wen, Z.L.; Xia, C.Y.; Mou, Z.; Wang, Z.Z.; He, W.B.; Guo, X.F.; Wei, G.N.; Chen, N.H. Acta Pharmacol. Sin. 2015, 36, 311-322.

[20] Zhou, Q.L.; Zhu, D.N.; Yang, Y.F.; Xu, W.; Yang, X.W. J. Pharm. Biomed. Anal. 2017, 137, 1-12.

[21] Wang, Q.; Joseph, D.R.; Kathyrn, W.; Paula, S.K.; Glenn, L.D.; Li, J.B.; Ismael, J.H. Int. J. Pharm. 2005, 288, 349-359.

[22] Hellinger, E.; Vezelka, S.; Toth, A.E.; Walter, F.; Kittel, A.; Bakk, M.L.; Tihanyi, K.; Hada, V.; Nakagawa, S.; Duy, T.D.H.; Niwa, M.; Deli, M.A.; Vastag, M. Eur. J. Pharm. Biopharm. 2012, 82, 340-351.

[23] Madgula, V.L.; Avula, B.; Reddy, V.L.N.; Khan, I.A.; Khan, S.I. Planta Med. 2007, 73, 330-335.

[24] Pastan, I.; Gottesman, M.M.; Ueda, K.; Lovelace, E.; Rutherford, A.V.; Willingham, M.C. Proc. Natl. Acad. Sci. USA. 1988, 85, 4486-4490.

[25] Yang, Y.F.; Wu, N.; Yang, X.W. China J. Chin. Mater. Med. 2016, 41, 2706-2711.

[26] Sylvester, P.W. Optimization of the tetrazolium dye (MTT) colorimetric assay for cellular growth and viability. Drug Design and Discovery: Methods and Protocols (Satyanarayanajois, S. D.), 716. Totowa, NJ: Humana Press. 2011, 157-168.

[27] Yang, Z.; Wang, J.R.; Niu, T.; Gao, S.; Yin, T.J.; You, M.; Jiang, Z.H.; Hu, M. Drug Metab. Dispos. 2012, 40, 1538-1544.
[28] Meng, Z.; Zhang, H.; Zhao, Y.; Lan, J.Q.; Du, L.J. Biomed. Chromatogr. 2007, 21, 635-641.

20(S)-原人参三醇和20(R)-原人参三醇差向异构体及达玛-20(22)E,24-二烯-3β,6α,12β-三醇在MDCK-pHaMDR细胞单层模型中的跨血脑屏障研究

The blood-brain barrier permeability of 20(S) and 20(R)-protopanaxatriol epimers and dammar-20(22)E,24-diene-3β,6α,12β-triol in MDCK-pHaMDR cell monolayer model

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 6

编辑推荐

Metrics

本文评价

[1]	拓文静, 华若辰, 李星玥, 宋继红, 卢闻. 基于不同种属细胞体外血脑屏障模型的药物渗透性比较[J]. 中国药学(英文版), 2023, 32(4): 237-249.
[2]	杨滢霖, 张姗姗, 刘漫, 王月华, 杜冠华. 小续命汤提取物改善血栓性局灶性脑缺血大鼠脑损伤及利用蛋白质组学探讨其可能治疗靶点[J]. 中国药学(英文版), 2021, 30(6): 468-483.
[3]	吴柏林, 郝亚萌, 陈颖, 刘乾, 田超, 张志丽, 刘俊义, 王孝伟. 咖啡酸酯类衍生物作为神经保护剂的构效关系研究[J]. 中国药学(英文版), 2019, 28(9): 615-626.
[4]	朱仁宗, 宁显玲, 张志丽, 王孝伟, 田超, 刘俊义^*. 咖啡酸苯乙酯酰化衍生物的设计、合成及其作为抗氧化应激损伤的中枢神经保护剂的活性评估[J]. 中国药学(英文版), 2013, 22(6): 475-482.
[5]	刘春云, 丰玲, 尉杰忠, 郭敏芳, 孙永胜, 纪宁, 孟健, 梁丽云, 马存根^*. 氨基葡萄糖对EAE大鼠BBB和MMP-9的作用[J]. , 2011, 20(2): 188-194.
[6]	赵康峰, 王琪, 蒲小平^*, 杨秀伟, 朱玉真. 一种新型微孔底膜插入式培养皿的制作方法[J]. , 2004, 13(4): 276-281.