title: Tanshinone IIA protects against acetaminophen-induced hepatotoxicity via activating the Nrf2 pathway.
abstract: BACKGROUND
  Tanshinone IIA (Tan), the main active component of Salvia miltiorrhiza, has been demonstrated to have antioxidant activity. Acetaminophen (APAP), a widely used antipyretic and analgesic, can cause severe hepatotoxicity and liver failure when taken overdose. Oxidative stress has been reported to be involved in APAP-induced liver failure.
  
  
  OBJECTIVE
  This study aimed to investigate the effect of Tan on APAP-induced hepatotoxicity and the underlying mechanisms involved.
  
  
  METHODS
  C57BL/6J mice were divided into six groups: (1) control, (2) APAP group, (3) APAP+Tan (30mg/kg) group, (4) Tan (30mg/kg) group, (5) APAP+Tan (10mg/kg) group, (6) Tan (10mg/kg) group. Mice in group 3 and 5 were pre-treated with specified dose of Tan by gavage and subsequently injected with an overdose of APAP intraperitoneally (i.p., 300mg/kg). The effect of Tan on Nrf2 pathway was investigated in HepG2 cells and mice.
  
  
  METHODS
  Plasma aspartate transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), liver glutathione (GSH), glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) levels were determined after mice were sacrificed. Lipid peroxidation and histological examination were performed. The effect of Tan on the Nrf2 pathway was detected by western blotting and qRT-PCR.
  
  
  RESULTS
  Tan pretreatment reduced APAP-induced liver injury. Tan was able to activate Nrf2 and increase the expression levels of Nrf2 target genes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1 (HO-1), in a dose-dependent manner in HepG2 cells. Consistent with our observations in HepG2 cells, Tan increased nuclear Nrf2 accumulation and upregulated mRNA and protein levels of the Nrf2 target genes GCLC, NQO1 and HO-1 in C57BL/6J mice compared with mice treated with APAP alone.
  
  
  CONCLUSIONS
  Our results demonstrate that Tan pretreatment could protect the liver from APAP-induced hepatic injury by activating the Nrf2 pathway. Tan may provide a new strategy for the protection against APAP-induced liver injury.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; The Third People's Hospital, Nanhai District, Foshan 528244, PR China.
authors.forename: Cuiwen
authors.initials: C
authors.lastname: Guan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Sun
authors.affiliation: School of Chinese MateriaMedica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Xinlu
authors.initials: X
authors.lastname: Fu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: jinjing@mail.sysu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: hzhiying@mail.sysu.edu.cn.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010936:Plant Extracts / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D027561:Salvia miltiorrhiza / Q000737:chemistry
chemical_list: D045784:Abietanes; D010936:Plant Extracts; D020011:Protective Agents; C021751:tanshinone; D000082:Acetaminophen
keywords: Acetaminophen; Hepatoprotection; Nrf2; Oxidative stress; Tanshinone IIA