Interactions of the major effective components in Shengmai formula with breast cancer resistance protein at the cellular and vesicular levels
Interactions of the major effective components in Shengmai formula with breast cancer resistance protein at the cellular and vesicular levels
复制标题
生脉方主要有效成分与乳腺癌抗性蛋白在细胞和囊泡水平上的相互作用
DOI：
10.1016/j.biopha.2020.110939
复制
发表时间：
2021-01-01
影响因子：
7.5
通讯作者：
Xia, Chunhua
中科院分区：
文献类型：
--
作者：
Wu, Lingna;Liu, Jianming;Xia, Chunhua
生脉方是中药代表性方剂之一，广泛用于治疗心脑血管疾病。以往的研究表明，SMF中的主要有效成分可以通过一些摄取转运体相互作用。然而，外排转运体乳腺癌耐药蛋白（BCRP）在这些涉及SMF的相互作用中的作用尚不清楚。本研究旨在探讨SMF中主要活性成分与BCRP的相互作用，以及这些复合物在SMF中以BCRP为基础的配型机制。选取人参总皂苷（GTS）、麦冬总皂苷（OTS）、麦冬总黄酮（OTF）、五味子总木脂素（STL）等4个主要部位和人参皂苷Re、Rd、Rb1、Rg1、麦冬皂苷D、D、甲基麦冬皂酮A、B、五味子甲素A、B、五味子甲素A、B等12种生物活性成分，探讨SMF与BCRP在LLC-PK1、LLC-PK1/BCRP细胞及BCRP膜泡中的相互作用。结果表明，人参皂苷Re和Rg1、甲基皂苷B和五味子甲素A可以通过BCRP转运到lc - pk1 /BCRP细胞中。五味子酚B对BCRP的转运功能有明显的抑制作用，可以显著抑制甲基参皂酮B和五味子甲素a进入lc - pk1 /BCRP细胞的摄取。在“由内到外”的BCRP膜泡中，BCRP介导人参皂苷Re和Rg1、甲基参皂酮B和五味子甲素A的转运，其K-m值分别为111.9 +/- 31.26 μ M、82.01 +/- 16.72 μ M、57.06 +/- 8.789 μ M和37.19 +/- 6.512 μ M。GTS、STL、人参皂苷Rd、Rb1、五味子酚B是BCRP的有效抑制剂，对人参皂苷Re、Rg1、甲基参皂酮B、五味子甲素A经BCRP转运均有不同程度的抑制作用。综上所述，GTS、STL、人参皂苷Rd和Rb1、五味子醇B是BCRP的潜在抑制剂。人参皂苷Re和Rg1、甲基皂苷B和五味子甲素A是BCRP的潜在底物，它们在SMF中由BCRP介导的运输可能被潜在的抑制剂抑制。这些SMF的主要有效成分在细胞和水泡水平上有潜在的相互作用，这些作用是由BCRP介导的。基于BCRP的这些生物活性成分的相互作用可能是SMF的重要相容性机制。
Shengmai Formula (SMF) is one of the traditional Chinese medicine representative formulas and is widely used for the treatment of cardio- and cerebrovascular disease. Previous studies demonstrated that the major effective ingredients in SMF can interact with each other based on some uptake transporters. However, the role of the efflux transporter breast cancer resistance protein (BCRP) in these interactions involving SMF remains unclear. The purpose of this study was to investigate the interactions of the major active components of SMF with BCRP and the compatibility mechanism of these complex components in SMF based on BCRP. We selected 4 main fractions, including ginseng total saponins (GTS), ophiopogon total saponins (OTS), ophiopogon total flavonoids (OTF), and fructus schisandrae total lignans (STL), and 12 bioactive components, including ginsenosides Re, Rd, Rb1, and Rg1, ophiopogonins D and D, methylophiopogonanones A and B, schizandrins A and B, and schizandrols A and B to explore the interactions of SMF with BCRP in LLC-PK1 and LLC-PK1/BCRP cells and BCRP membrane vesicles. The results showed that ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A can be transported by BCRP into LLC-PK1/BCRP cells. Schisandrol B exhibited a markedly inhibitory effect on the transport function of BCRP and can significantly inhibit the uptake of methylophiopogonanone B and schizandrin A into LLC-PK1/BCRP cells. In "Inside-Out" BCRP membrane vesicles, BCRP mediated the transport of ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A, with K-m values of 111.9 +/- 31.26 mu M, 82.01 +/- 16.72 mu M, 57.06 +/- 8.789 mu M, and 37.19 +/- 6.512 mu M, respectively. GTS, STL, ginsenosides Rd and Rb1, and schisandrol B were potent inhibitors of BCRP and showed different degrees of inhibition on the transport of ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A via BCRP. In conclusion, GTS, STL, ginsenosides Rd and Rb1, and schizandrol B are potential inhibitors of BCRP. Ginsenosides Re and Rg1, methylophiopogonanone B, and schizandrin A are potential substrates of BCRP, and their transport, which is mediated by BCRP, may be inhibited by potential inhibitors in SMF. There are potential interactions of these main effective components of SMF at the cellular and vesicular levels that are mediated by BCRP. The interplay of these bioactive components based on BCRP may be an important compatibility mechanism in SMF.