The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids.
The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids.
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DOI：
10.1016/j.ijpharm.2013.05.053
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发表时间：
2013-09
影响因子：
5.8
通讯作者：
Ye Tian;Sainan Qian;Yan Jiang;Qian Shen;Jiang Zheng;Hui Zhou;S. Zeng
中科院分区：
文献类型：
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作者：
Ye Tian;Sainan Qian;Yan Jiang;Qian Shen;Jiang Zheng;Hui Zhou;S. Zeng
BCRP是影响药物吸收、分布和消除的关键因素之一。双苄基异喹啉生物碱是一类具有巨大临床应用潜力的天然植物化学物质。本研究采用LLC-PK 1/BCRP细胞模型评价了BCRP与5种双苄基异喹啉生物碱（甲基莲心碱、异莲心碱、莲心碱、蝙蝠葛碱和粉防己碱）的相互作用。进行了细胞内蓄积和双向转运研究，然后采用BCRP的同源模型进行分子对接分析。我们的研究表明，这五种生物碱的渗透性都不高，Papp值均小于6.5 × 10 - 6cm/s。莲心碱和蝙蝠葛碱是BCRP的底物：在较低浓度（10 μM）下，净外排率分别为2.87和1.64。LLC-PK 1/BCRP细胞中的细胞蓄积量低于LLC-PK 1细胞。另一方面，粉防己碱、异莲心碱和甲基莲心碱不是BCRP的底物。基于对接研究，莲心碱与精氨酸482之间形成直接氢键，精氨酸482是BCRP的底物特异性热点;蝙蝠葛碱与BCRP具有疏水相互作用。结论：BCRP可介导莲心碱和蝙蝠葛碱的排泄，从而影响其药理活性和体内分布。
BCRP is one of the key factors to drug absorption, distribution and elimination. Bisbenzylisoquinoline alkaloids are a large family of natural phytochemicals with great potential for clinical use. In this study, the interaction between BCRP and five bisbenzylisoquinoline alkaloids (neferine, isoliensinine, liensinine, dauricine and tetrandrine) were evaluated using LLC-PK1/BCRP cell model. The intracellular accumulation and bi-directional transport studies were conducted, and then molecular docking analysis was carried out employing a homology model of BCRP. Our study revealed that the permeability of these five alkaloids was not high, thePappvalues were all less than 6.5 × 10−6cm/s. Liensinine and dauricine were substrates of BCRP: at lower concentration (10 μM), the net efflux ratios were 2.87 and 1.64 respectively. And their cellular accumulation was lower in LLC-PK1/BCRP cells than in LLC-PK1 cells. On the other hand, tetrandrine, isoliensinine and neferine were not substrates of BCRP. On the basis of docking studies, a direct hydrogen bond was formed between liensinine and arginine 482 which is a hot spot of BCRP for substrate specificity; and dauricine had hydrophobic interaction with BCRP. In conclusion, our study indicated that BCRP could mediate the excretion of liensinine and dauricine, thus influence their pharmacological activity and disposition.