药学学报, 2015, 50(7): 848-853
引用本文:
石美智, 刘煜, 卞佳琳, 金梦, 贵春山. 天然产物与有机阴离子转运多肽1B1相互作用的研究[J]. 药学学报, 2015, 50(7): 848-853.
SHI Mei-zhi, LIU Yu, BIAN Jia-lin, JIN Meng, GUI Chun-shan. The interactions between natural products and OATP1B1[J]. Acta Pharmaceutica Sinica, 2015, 50(7): 848-853.

天然产物与有机阴离子转运多肽1B1相互作用的研究
石美智, 刘煜, 卞佳琳, 金梦, 贵春山
苏州大学药学院, 江苏 苏州 215123
摘要:
有机阴离子转运多肽1B1 (OATP1B1) 是一种重要的肝摄取转运蛋白, 介导许多内源性物质和药物转运进入肝细胞。为了鉴别和研究天然产物中潜在的OATP1B1调节剂, 本实验采用稳定表达OATP1B1的中国仓鼠卵巢细胞 (CHO-OATP1B1), 在96孔板中测定了21种常见天然化合物和提取物对OATP1B1介导荧光素甲氨蝶呤转运的影响。该方法可进一步运用于对化合物库的高通量筛选。本研究表明, 一些黄酮类化合物 (如槲皮素、槲皮苷、芦丁、菊花梗叶总黄酮和桑皮黄素等) 和三萜类化合物 (如甘草次酸和甘草酸等) 在体外对OATP1B1的功能有显著抑制作用, 其IC50值均小于16 μmol·L-1。甘草次酸的IC50值与其临床血药浓度相当, 预示其有可能引起OATP1B1介导的药物-药物相互作用。构效关系分析表明, 黄酮苷元比其相应的糖苷对OATP1B1的抑制作用更强, 而且糖的类型和糖链长度对其活性均有影响。此外, 以OATP1B1的底物氟伐他汀和罗伐他汀为探针药物, 体外研究了几种天然化合物对OATP1B1功能影响的底物依赖性。结果表明, 天然产物对OATP1B1转运功能的影响具有底物依赖性, 有助于预测和避免潜在的OATP1B1介导的不良药物-药物和药物-食物相互作用, 为临床合理用药提供实验依据和指导。
关键词:    有机阴离子转运多肽      天然产物      药物-药物相互作用      液相色谱-质谱     
The interactions between natural products and OATP1B1
SHI Mei-zhi, LIU Yu, BIAN Jia-lin, JIN Meng, GUI Chun-shan
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Abstract:
Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 μmol·L-1. The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATP1B1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATP1B1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use.
Key words:    OATP    natural product    drug-drug interaction    LC-MS/MS   
收稿日期: 2014-12-29
基金项目: 国家自然科学基金资助项目 (31200623).
通讯作者: 贵春山
Email: guichunshan@suda.edu.cn
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参考文献:
[1] Hagenbuch B, Gui C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family [J]. Xenobiotica, 2008, 38: 778-801.
[2] Zhang S, Yang X, Morris ME. Flavonoids are inhibitors of breast cancer resistance protein (ABCG2)-mediated transport [J]. Mol Pharmacol, 2004, 65: 1208-1216.
[3] Wang X, Wolkoff AW, Morris ME. Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators [J]. Drug Metab Dispos, 2005, 33: 1666-1672.
[4] Fan L, Zhang W, Guo D, et al. The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1 [J]. Clin Pharmacol Ther, 2008, 83: 471-476.
[5] Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides [J]. Drug Metab Dispos, 2011, 39: 920-926.
[6] Roth M, Araya JJ, Timmermann BN, et al. Isolation of modulators of the liver-specific organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae) [J]. J Pharmacol Exp Ther, 2011, 339: 624-632.
[7] Wu LX, Guo CX, Qu Q, et al. Effects of natural products on the function of human organic anion transporting polypeptide 1B1 [J]. Xenobiotica, 2012, 42: 339-348.
[8] Gui C, Obaidat A, Chaguturu R, et al. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3 [J]. Curr Chem Genomics, 2010, 4: 1-8.
[9] Gui C, Hagenbuch B. Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport [J]. Biochemistry, 2008, 47: 9090-9097.
[10] Cao J, Zhang Y, Chen W, et al. The relationship between fasting plasma concentrations of selected flavonoids and their ordinary dietary intake [J]. Br J Nutr, 2010, 103: 249-255.
[11] Zhang Y, Hays A, Noblett A, et al. Transport by OATP1B1 and OATP1B3 enhances the cytotoxicity of epigallocatechin 3-O-gallate and several quercetin derivatives [J]. J Nat Prod, 2013, 76: 368-373.
[12] Nafisi S, Manouchehri F, Bonsaii M. Study on the interaction of glycyrrhizin and glycyrrhetinic acid with RNA [J]. J Photochem Photobiol B, 2012, 111: 27-34.
[13] Zhang M, Shen Y. Advances in studies on Glycyrrhizae Radix et Rhizoma and its active components in anti-inflammation and mechanism [J]. Drugs Clin (现代药物与临床), 2011, 26: 261-268.
[14] Krahenbuhl S, Hasler F, Frey BM, et al. Kinetics and dynamics of orally administered 18β-glycyrrhetinic acid in humans [J]. J Clin Endocrinol Metab, 1994, 78: 581-585.
[15] MacKenzie MA, Hoefnagels WH, Jansen RW, et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers [J]. J Clin Endocrinol Metab, 1990, 70: 1637-1643.
[16] Al-Dujaili EA, Kenyon CJ, Nicol MR, et al. Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity [J]. Mol Cell Endocrinol, 2011, 336: 102-109.
[17] Farese RV Jr, Biglieri EG, Shackleton CH, et al. Licorice-induced hypermineralocorticoidism [J]. N Engl J Med, 1991, 325: 1223-1227.
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