Intrahepatic cholestasis is a serious symptom of liver disorders with limited
therapies. In this study, we investigated the efficacy of
Huangqi decoction (HQD), a two-herb classic
traditional Chinese medicine (TCM), in the treatment of
alpha-naphthylisothiocyanate (ANIT)-induced
intrahepatic cholestasis in mice. HQD treatment ameliorated impaired hepatic function and tissue damage. A metabolomics study revealed that the endogenous metabolites significantly affected by HQD were related to
bile acid (BA) biosynthesis and
glutathione metabolism pathways. HQD treatment decreased the intrahepatic accumulation of cytotoxic BAs, normalized serum BA levels, and increased biliary and urinary BA excretion. Additionally, HQD restored the hepatic
glutathione content and suppressed
reactive oxygen species (ROS) in cholestatic mice.
Protein and gene analysis revealed that HQD increased the expression of the hepatic metabolizing
enzymes cytochrome P450 (CYP) 2B10 and
UDP glucuronosyltransferase family 1 member A1 (UGT1A1), as well as
multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4, which play crucial roles in BA homeostasis. Further, HQD increased the
protein expression of
glutamate-cysteine ligase, which is involved in the synthesis of
glutathione. Importantly, HQD increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). In conclusion, HQD protects against
intrahepatic cholestasis by reversing the disordered homeostasis of BAs and
glutathione.