Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter

Abstract Radix Bupleuri exerts effective hepatoprotective and cholagogic effects through its Saikosaponins (SSs) component. Therefore, we attempted to determine the mechanism of saikosaponins used to promote bile excretion by studying their effects on intrahepatic bile flow, focusing on the synthesis, transport, excretion, and metabolism of bile acids. C57BL/6N mice were continuously gavaged with saikosaponin a (SSa), saikosaponin b 2 (SSb 2 ), or saikosaponin D (SSd) (200 mg/kg) for 14 days. Liver and serum biochemical indices were determined using Enzyme‐linked immunosorbent assay (ELISA) kits. In addition, an ultra‐performance liquid chromatography‐mass spectrometer (UPLC–MS) was used to measure the levels of the 16 bile acids in the liver, gallbladder, and cecal contents. Furthermore, SSs pharmacokinetics and docking between SSs and farnesoid X receptor (FXR)‐related proteins were analyzed to investigate the underlying molecular mechanisms. Administration of SSs and Radix Bupleuri alcohol extract (ESS) did not cause significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels. Saikosaponin‐regulated changes in bile acid (BA) levels in the liver, gallbladder, and cecum were closely related to genes involved in BA synthesis, transport, and excretion in the liver. Pharmacokinetic studies indicated that SSs were characterized by rapid elimination (t 1/2 as 0.68–2.47 h), absorption ( T max as 0.47–0.78 h), and double peaks in the drug–time curves of SSa and SSb 2 . A molecular docking study revealed that SSa, SSb 2 , and SSd docked well with the 16 protein FXR molecules and target genes (<−5.2 kcal/mol). Collectively, saikosaponins may maintain BA homeostasis in mice by regulating FXR‐related genes and transporters in the liver and intestine.