Gentiana Manshurica Kitagawa Prevents Acetaminophen-induced Acute Hepatic Injury In Mice Via Inhibiting Jnk/erk Mapk Pathway

Objective:To investigate the in vivo hepatoprotective effects and mechanisms of Gentiana manshurica Kitagawa (GM) in acetaminophen (APAP)-induced liver injury in mice and investigate gentiopicroside (GPS) is one of the effective contents of Gentiana manshurica Kitagawa. Methods:GM or N-acetyl-L-cysteine (NAC; 300 mg/kg body weight) was administrated orally with a single dose (200,100 or 50 mg/kg body weight) 2 h prior to APAP (300 mg/kg body weight) injection in mice. GPS or N-acetyl-L-cysteine (NAC; 300 mg/kg body weight) was administrated orally with a single dose (100,50 or 25 mg/kg body weight) 2 h prior to APAP (300 mg/kg body weight) injection in mice. Results:APAP treatment significantly depleted hepatic GSH, increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malonyldialdehyde (MDA) and decreased hepatic activity of glutathione peroxidase (GSH-px) and superoxide dismutase (SOD). However, the pretreatment of GM or GPS significantly alleviated APAP-induced oxidative stress by increasing GSH content, decreasing serum ALT, AST and MDA, and retaining the activity of GSH-px and SOD in the liver. Furthermore, GM and GPS pretreatments can inhibit caspase-3 activation and phosphorylation of c-Jun-NH2-terminal protein kinase 2 (JNK1/2) and extracellular signal-regulated kinase (ERK). GPS pretreatment also inhibits the increasing of cytochrome P-450 (CYP2E1). GM remarkably attenuated hepatocyte apoptosis confirmed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and DNA fragmentation assay. Conclusion:Hepatoprotective effects of GM against APAP-induced acute toxicity are mediated either by preventing the decline of hepatic antioxidant status or its direct anti-apoptosis capacity. These results support that GM is a potent hepatoprotective agent and GPS is one of hepatoprotective content of GM.