AIMS Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.

中文翻译：

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Saikosaponin b2通过抑制与多药耐药相关的药物转运蛋白，增强了抗癌药物的肝靶向作用。

AIMS醋制柴胡（VBRB）通过增加肝脏中的肝分布来增强肝脏中抗癌药物的活性。但是，这种现象可能与药物转运蛋白有关。我们研究了皂苷b2（SSb2； VBRB的主要成分）对正常细胞和过表达转运蛋白的药物转运蛋白活性和表达的影响。主要方法通过转运蛋白的细胞底物浓度分析转运蛋白的活性。通过高效液相色谱（HPLC）测定秋水仙碱（Pgp和MRP1的底物）和顺铂（OCT2和MRP2的底物）的浓度。罗丹明B的浓度通过流式细胞仪测定。通过qRT-PCR和蛋白质印迹分析确定转运蛋白基因和蛋白的表达。主要发现SSb2通过主要增加Mrp1活性（独立于基因和蛋白质表达）来增加HEK293细胞中的秋水仙碱外流。SSb2通过上调Mrp2基因表达来增强BRL3A细胞中的Mrp2功能并增加顺铂流出，而对正常细胞中的Pgp却没有什么影响。SSb2通过增加OCT2蛋白和mRNA的表达来增加OCT2-HEK293细胞中OCT2的活性。但是，SSb2通过降低MRP2蛋白表达来抑制MRP2-HEK293细胞中的MRP2活性，并降低Pgp-和MRP1-HEK293细胞中的Pgp和MRP1活性。重要性SSb2可能是VBRB的关键活性成分，通过以环境依赖性方式抑制多药耐药相关药物转运蛋白（Pgp，MRP1和MRP2），可增强抗癌药物的肝靶向性。