5,7,3′,4′-flavan-on-ol (taxifolin) protects against acetaminophen-induced liver injury by regulating the glutathione pathway

Taxifolin (TAX) reportedly exerts protective and therapeutic effects in liver. Herein, the effects of TAX against acetaminophen (APAP)-induced hepatotoxicity were investigated. Pharmacodynamics, pharmacology and metabolomics analyses of TAX were assessed on C57 mice and L-02 cells. TAX was administered for 7 days, and APAP was given on the last day to establish an acute liver injury model. ALT and AST levels were determined, and liver ROS, MDA, GST, GSH and GPX1 were analysed. The expression and protein abundance of GPX1, GPS-Pi, GCLC and GCLM were assessed by PCR and western blotting, and metabolic changes in cells and serum were investigated by UPLC-Q-Orbitrap-MS. Serum ALT and AST, and liver ROS, MDA, GST, GSH and GPX1 levels confirmed the protective effects of TAX. Besides, we found Only treating with TAX decreased the expression of CYP2E1 in mice liver tissue. TAX reversed the APAP-induced decrease in cell viability in L-02 cells, and reduced cellular ROS levels. Furthermore, TAX reversed the APAP-induced decrease in antioxidant enzymes at both mRNA and protein levels. Metabolomics analysis identified metabolites mainly related to glutathione metabolism (36 in vivo and 23 in vitro). The concentration of glutathione, oxidized glutathione, carnitine, succinic acid, pyroglutamic acid, citrulline, taurine, palmitoleic acid, phytoshingosine-1-P and sphingosine-1-P were close to normal levels after treating with TAX. These results indicate that TAX prevents APAP-induced liver injury by inhibiting APAP metabolic activation mediated by CYP450 enzymes, modulating glutathione metabolism, and expression of related antioxidative signals. These properties could be harnessed to prevent or treat hepatotoxicity.