Abstract
Vinegar-baked Radix Bupleuri (VBRB) is clinically used to enhance the pharmacological activity of drugs used to treat liver diseases. Our previous study demonstrated that this effect is dependent on increased drug accumulation in the liver; however, the underlying mechanism remains unclear. We hypothesize that VBRB mediated its effects by altering drug transporters. Thus, the present study was designed to determine the effects of VBRB's main components, saikosaponin A, C, and D, on drug transporters. Transporter activity was determined by measuring the intracellular concentration of transporter substrates. Protein and mRNA levels were measured by Western blot and qPCR, respectively. Colchicine was used as the substrate for P-glycoprotein (Pgp) and multidrug resistance protein (MRP) 1, cisplatin was used as the substrate for Mrp2 and organic cation transporters 2 (Oct2), and verapamil and MK571 were used as inhibitors of Pgp and MRP1, respectively. Saikosaponin A, C, and D differentially affected transporter activity. All of the saikosaponins inhibited Pgp activity in Pgp over-expressing HEK293 cells and increased substrate uptake of OCT2 in OCT2 over-expressing HEK293. Saikosaponin C and D inhibited MRP2 activity in HEK293 cells and BRL 3A cell with high MRP2 expression; saikosaponin A increased colchicine accumulation in GSH-stimulated HEK293 cells, but decreased colchicine uptake in HEK293 cells. Saikosaponin D inhibited MRP1 activity in GSH-stimulated HEK293 cells, but marginally affected the uptake of colchicine in HEK293 cells. In conclusion, saikosaponins play a role in VBRB's induced liver targeting effect through affecting drug transporters with a transporter expression amount depending manner.
Highlights
Liver cancer is one of the leading causes of death in China and other countries
Colchicine was used as the substrate for P-glycoprotein (Pgp) and multidrug resistance protein (MRP) 1, cisplatin was used as the substrate for Mrp2 and organic cation transporters 2 (Oct2), and verapamil and MK571 were used as inhibitors of Pgp and MRP1, respectively
Previous studies have shown that Vinegar-baked Radix Bupleuri (VBRB) inhibits cytochrome p450 enzymes (CYP) 3A3 and CYP2D6 [25], partly explaining its liver-targeting effects
Summary
Surgery is the first choice for treating liver cancer, but chemotherapy still remains a necessary modality of treatment. Targeted drug delivery to the liver is needed to improve the effects of chemotherapeutic agents to treat liver cancer. In traditional Chinese medicine, several herbal medicines have been shown to have organ targeting effects; these are named “medicinal guide herbs”. VBRB has been demonstrated to be beneficial in the treatment of unresectable hepatocellular carcinoma, improving the therapeutic effects of transarterial chemoembolization [2]. Our previous studies have shown that VBRB increases liver accumulation of resveratrol, oxymatrine, and rhein, while simultaneously decreasing accumulation of these drugs in other organs/tissues [3,4,5], indicating that VBRB enhances the liver targeting effect by changing the tissue distribution patterns of other drugs
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