Ginsenoside Rg1 protects against acetaminophen-induced liver injury via activating Nrf2 signaling pathway in vivo and in vitro

Acetaminophen (APAP) is a worldwide used drug for treating fever and pain. However, APAP overdose is the leading cause of drug-induced liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of ginsenoside Rgl (Rgl), the main pharmacologically active compounds of Panax ginseng, against APAP-induced acute liver injury, and further to elucidate the involvement of Nrf2 signaling pathway by in vivo and in vitro experiments. Male C57BL/6 mice were treated with Rgl for 3 days before injection of APAP. Serum and liver tissue samples were collected 6 h later. The results indicated that Rgl significantly attenuated APAP-induced hepatotoxicity and oxidative stress in a dose-dependent manner. Rgl effectively enhanced antioxidant and detoxification capacity, which is largely dependent on up-regulating Nrf2 nuclear translocation, reducing Keapi protein expression and up-regulating Nrf2 target genes including GCLC, GCLM, HO-1, NQO1, Ugtlal, Ugt1a6, Ugt2b1, Sult2a1, Mrp2, Mrp3 and Mrp4. Furthermore, Rgl repressed the activities of Cyp2e1, Cyp3a1 1, Cypla2, which are important enzymes in the formation of APAP toxic metabolite N-acetyl-p-benzoquinone imine. However, the changes in transporters and enzymes, as well as ameliorative liver histology induced by Rgl were abrogated by Nrf2 antagonist all-transretinoic acid in vivo and Nrf2 siRNA in vitro. In conclusion, Rgl produced hepatoprotective effects against APAP-induced acute liver injury via Nrf2 signaling pathway. Rgl might be an effective approach for the prevention against acute liver injury.