三七-红花有效组分复方对人肝微粒体中UGT1A1、1A4和2B7活性抑制作用的研究

doi:10.5246/jcps.2019.04.023

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (4): 229-237.DOI: 10.5246/jcps.2019.04.023

三七-红花有效组分复方对人肝微粒体中UGT1A1、1A4和2B7活性抑制作用的研究

李岩, 孟雨晴, 逯颖媛, 常坤, 高鹏, 姜勇, 屠鹏飞, 郭晓宇^*

北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2018-09-04 修回日期:2018-11-13 出版日期:2019-04-30 发布日期:2018-12-15
通讯作者: Tel.: +86-010-82805641, E-mail: guoxiaoyu@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81573684), National Key Technology R & D Program “New Drug Innovation” of China (Grant No. 2018ZX09711001-008-003) and Beijing Municipal Science and Technology Project (Grant No. Z181100002218028).

Inhibitory effect of the combination of notoginseng total saponins and safflower total flavonoids on UDP-glucuronosyltransferases 1A1, 1A4, and 2B7 in human liver microsomes

Yan Li, Yuqing Meng, Yingyuan Lu, Kun Chang, Peng Gao, Yong Jiang, Pengfei Tu, Xiaoyu Guo^*

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

Received:2018-09-04 Revised:2018-11-13 Online:2019-04-30 Published:2018-12-15
Contact: Tel.: +86-010-82805641, E-mail: guoxiaoyu@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81573684), National Key Technology R & D Program “New Drug Innovation” of China (Grant No. 2018ZX09711001-008-003) and Beijing Municipal Science and Technology Project (Grant No. Z181100002218028).

摘要/Abstract

摘要：

为探讨三七-红花有效组分复方(CNS)的配伍作用机制, 本研究考察了CNS、三七总皂苷(NS)和红花总黄酮(SF)对人肝微粒体中三种主要尿苷二磷酸葡萄糖醛酸转移酶(UGT)亚型活性的影响。采用人肝微粒体作为体外孵育模型, 分别以依托泊苷、三氟拉嗪和叠氮胸苷作为UGT1A1、1A4及2B7的特异性探针底物, 利用LC-MS/MS检测技术测定底物代谢产物的含量。研究结果表明, CNS、NS和SF对UGT1A1、1A4和2B7具有显著的抑制作用(P<0.05), 其IC₅₀值均小于30 mg/mL。与NS和SF相比较, CNS对UGT1A1、1A4和2B7具有更强的抑制作用(P<0.05)。综上, 在人肝微粒体中CNS配伍给药可显著提高对UGT1A1、1A4和2B7的抑制能力, 可能有利于减少CNS中主要活性成分在体内的II相代谢。基于UGT酶的CNS潜在草药-药物相互作用研究将为CNS的合理开发和利用提供有力的实验依据。

关键词: 尿苷二磷酸葡萄糖醛酸转移酶, 人肝微粒体, 草药-药物相互作用, 三七, 红花

Abstract:

In the present study, the potential inhibition behaviors of notoginseng total saponins (NS), safflower total flavonoids (SF), and their combination (CNS) towards three major isoforms of UDP-glucuronosyltransferases (UGTs) in human liver microsomes (HLMs) were investigated to study the mechanism of the synergistic effect of CNS. Etoposide, trifluoperazine and azidothymidine were selected as the probe drugs to elucidate the activities of UGT1A1, 1A4 and 2B7 by UPLC-MS/MS method, respectively. The results showed that CNS, NS and SF significantly inhibited the activities of UGT1A1, 1A4 and 2B7 (P<0.05)with the IC₅₀values less than 30 mg/mL. Furthermore, the inhibitory effects of CNS towards UGT1A1, 1A4 and 2B7 were stronger than those of NS and SF (P<0.05). In conclusion, the combination of NS and SF could increase their inhibitory effects on UGT1A1, 1A4 and 2B7 activities in HLMs and might be conducive to reduce the phase II metabolism of the effective constituents in CNS. The potential herb-drug interactions of CNS based on UGT enzymes provided a useful experimental basis for its further research and development.

Key words: UDP-glucuronosyltransferases, Human liver microsomes, Herb-drug interaction, Notoginseng Radix et Rhizoma, Carthami Flos

中图分类号:

R284

Supporting:

李岩, 孟雨晴, 逯颖媛, 常坤, 高鹏, 姜勇, 屠鹏飞, 郭晓宇. 三七-红花有效组分复方对人肝微粒体中UGT1A1、1A4和2B7活性抑制作用的研究[J]. 中国药学(英文版), 2019, 28(4): 229-237.

Yan Li, Yuqing Meng, Yingyuan Lu, Kun Chang, Peng Gao, Yong Jiang, Pengfei Tu, Xiaoyu Guo. Inhibitory effect of the combination of notoginseng total saponins and safflower total flavonoids on UDP-glucuronosyltransferases 1A1, 1A4, and 2B7 in human liver microsomes[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(4): 229-237.

参考文献

[1] Zhang, Sh.Y.; Song, N.N.; Fan, H.R.; Liu, C.X. Effects of components in Biqi Capsulae prescription compatibility on activities of cytochrome P450 in vivo. Chin. Tradit. Herbal. Drugs. 2011, 42, 1571-1575.

[2] Yang, N.; Sun, R.B.; Liao, X.Y.; Aa, J.Y.; Wang, G.J. UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine. Pharmacol. Res. 2017, 121, 169-183.

[3] Burchell, B.; Soars, M.; Monaghan, G.; Cassidy, A.; Smith, D.; Ethell, B. Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol. Lett. 2000, 112-113, 333-340.

[4] Liu, C.; Cao, Y.F.; Fang, Z.Z.; Zhang, Y.Y.; Hu, C.M.; Sun, X.Y.; Huang, T.; Zeng, J.; Fan, X.R.; Mo, H. Strong inhibition of deoxyschizandrin and schisantherin A toward UDP-glucuronosyltransferase (UGT) 1A3 indicating UGT inhibition-based herb-drug interaction. Fitoterapia. 2012, 83, 1415-1419.

[5] Wang, L.C.; Zhang, W.S.; Liu, Q.; Li, J.; Alolga, R.N.; Liu, K.; Liu, B.L.; Li, P.; Qi, L.W. A standardized notoginseng extract exerts cardioprotection by attenuating apoptosis under endoplasmic reticulum stress conditions. J. Funct. Foods. 2015, 16, 20-27.

[6] Chen, J.F.; Song, Y.L.; Guo, X.Y.; Tu, P.F.; Jiang, Y. Characterization of the herb-derived components in rats following oral administration of Carthamus tinctorius extract by extracting diagnostic fragment ions (DFIs) in the MS(n) chromatograms. Analyst. 2014, 139, 6474-6485.

[7] Chen, J.F.; Guo, X.Y.; Song, Y.L.; Zhao, M.B.; Tu, P.F.; Jiang, Y. MRM-based strategy for the homolog-focused detection of minor ginsenosides from notoginseng total saponins by ultra-performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry. RSC Adv. 2016, 6, 96376-96388.

[8] Han, S.Y.; Li, H.X.; Bai, C.C.; Wang, L.; Tu, P.F. Component analysis and free radical-scavenging potential of Panax notoginseng and Carthamus tinctorius extracts. Chem. Biodivers. 2010, 7, 383-391.

[9] Han, S.Y.; Li, H.X.; Tu, P.F. Ameliorative effects of Panax notoginseng saponins combined with Carthamus tinctorius flavonoids on hemorheology in rats with acute blood stasis. Chin. J. Pharmacol. Toxicol. 2011, 25, 62-67.

[10] Watanabe, Y.; Nakajima, M.; Ohashi, N.; Kume, T.; Yokoi, T. Glucuronidation of etoposide in human liver microsomes is specifically catalyzed by UDP-glucuronosyltransferase 1A1. Drug Metab. Dispos. 2003, 31, 589-595.

[11] Uchaipichat, V.; Mackenzie, P.I.; Elliot, D.J.; Miners, J.O. Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) “probes” for human UDP-glucuronosyltransferases. Drug Metab. Dispos. 2006, 34, 449-456.

[12] Radominska-Pandya, A.; Little, J.M.; Czernik, P.J. Human UDP-glucuronosyltransferase 2B7. Curr. Drug Metab. 2001, 2, 283-298.

[13] Knights, K.M.; Rowland, A.; Miners, J.O. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br. J. Clin. Pharmacol. 2013, 4, 587-602.

[14] Oliveira, E.J.; Watson, D.G. In vitro glucuronidation of kaempferol and quercetin by human UGT-1A9 microsomes. FEBS Lett. 2000, 471, 1-6.

[1]	魏东升, 刘孝生, 李路珍, 齐佳杰, 王雨轩, 张哲. 基于综合生物信息学和单细胞测序方法揭示红花-丹参治疗冠心病的生物学和免疫学机制[J]. 中国药学(英文版), 2023, 32(10): 796-812.
[2]	陈绪龙, 廖正根, 李成, 黄国勇, 宋云燕, 董伟, Abid Naeem, 梁新丽. 白术内酯II在人肝微粒体中与CYP450酶之间的相互作用研究[J]. 中国药学(英文版), 2021, 30(8): 645-656.
[3]	李双, 郭春燕, 李双双, 尤斯涵, 余秀娟. 羟基红花黄色素A对帕金森细胞模型的保护作用及其网络药理学分析[J]. 中国药学(英文版), 2020, 29(12): 880-895.
[4]	程士轩, 马迎聪, 刘瑜洁, 庞宁, 李骥, 沙勐, 任汝通, Nuramatjan Ablat, 曹静, 孙懿, 蒲小平, 叶敏, 齐宪荣. 红花抗帕金森病有效成分滴丸的制备和表征[J]. 中国药学(英文版), 2019, 28(1): 27-39.
[5]	孟雨晴, 王丽超, 李岩, 宋金洋, 杜智勇, 李春, 姜勇, 屠鹏飞, 郭晓宇. 三七-红花有效组分复方对心肌梗死大鼠的保护作用[J]. 中国药学(英文版), 2018, 27(2): 116-122.
[6]	赵一懿, 郭洪祝, 陈有根, 傅欣彤. 基于UPLC-QTOF-MSE 的代谢组学方法研究三七皂苷提取物及注射液的化学组分[J]. 中国药学(英文版), 2017, 26(5): 335-345.
[7]	牛凯, 李晨光, 袁松, 张雷, 施杞, 王拥军, 郑为超. 桃仁-红花药对抑制IL-1β诱导椎间盘软骨终板细胞发生退变的体外实验研究[J]. 中国药学(英文版), 2016, 25(8): 590-597.
[8]	戎怿, 黄碧云, 黄珺珺, 朱柳, 刘夏雯. 一种快速简单的超高效液相色谱串联四极杆质谱方法检测激素的葡糖醛酸化代谢产物[J]. 中国药学(英文版), 2016, 25(4): 291-301.
[9]	林珠灿, 张龙, 张睿卓, 黄安玉, 郭素华. 基于炎症细胞模型的景天三七醋酸乙酯部位抗炎活性及其HPLC指纹图谱的研究[J]. 中国药学(英文版), 2015, 24(10): 647-653.
[10]	刘毅, 王伟, 赵玉英, 陈虎彪, 梁鸿, 张庆英. 红花岩黄芪药材的化学指纹分析[J]. 中国药学(英文版), 2015, 24(10): 654-659.
[11]	陈金凤, 屠鹏飞, 姜勇. 加压制备色谱技术结合HPLC指纹图谱导向快速分离制备红花提取物中的主要黄酮类成分[J]. 中国药学(英文版), 2014, 23(7): 490-495.
[12]	丁仁博, 鲍娇琳, 曹怡纬, 何承伟, 王一涛, 万建波. 三七总皂苷对慢性酒精性脂肪肝的保护作用研究[J]. 中国药学(英文版), 2014, 23(6): 361-368.
[13]	贾凌晗, 刘一^*, 李玉珍 . 超声波辅助溶剂萃取西藏和河南藏红花中挥发油的GC-MS分析[J]. , 2011, 20(4): 404-409.
[14]	贾凌晗, 刘一^*, 李玉珍. ICP-AES/ICP-MS测定西藏和河南产藏红花中主要金属元素及重金属含量[J]. , 2011, 20(3): 297-301.
[15]	范莉, 濮润, 赵海誉, 刘璇, 马超, 王宝荣, 果德安^*. HPLC-DAD-ESI-MSn法研究红花注射液中羟基红花黄色素A和脱水红花黄色素B的稳定性及降解过程[J]. , 2011, 20(1): 47-56.

三七-红花有效组分复方对人肝微粒体中UGT1A1、1A4和2B7活性抑制作用的研究

Inhibitory effect of the combination of notoginseng total saponins and safflower total flavonoids on UDP-glucuronosyltransferases 1A1, 1A4, and 2B7 in human liver microsomes

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 15

编辑推荐

Metrics

本文评价