Schisandrol B protects against acetaminophen- induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway

• Published in: Acta pharmacologica Sinica Vol. 37; no. 3; pp. 382 - 389
• Main Authors: Jiang, Yi-ming, Wang, Ying, Tan, Hua-sen, Yu, Tao, Fan, Xiao-mei, Chen, Pan, Zeng, Hang, Huang, Min, Bi, Hui-chang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2016; Nature Publishing Group
• Subjects: Acetaminophen - toxicity; Analgesics, Non-Narcotic - toxicity; Animals; Antioxidant Response Elements - drug effects; Biomedical and Life Sciences; Biomedicine; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Cyclooctanes - isolation & purification; Cyclooctanes - therapeutic use; Dioxoles - isolation & purification; Dioxoles - therapeutic use; Gene Expression Regulation - drug effects; Hep G2 Cells; HepG2细胞; Humans; Immunology; Internal Medicine; Lignans - isolation & purification; Lignans - therapeutic use; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Original; original-article; Pharmacology/Toxicology; Protective Agents - isolation & purification; Protective Agents - therapeutic use; RNA, Messenger - genetics; Schisandra; Schisandra - chemistry; Signal Transduction - drug effects; Vaccine; 五味子; 信号转导通路; 对乙酰氨基酚; 小鼠; 急性肝损伤; 激活; 诱导; acetaminophen; liver injury; NRF2; antioxidant resporse element; hepatotoxicity; glutathione; schisandrol B
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2015.120

Aim： The nuclear factor erythroid 2-related factor 2 （NRF2） acts through the antioxidant response element （ARE） to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that schisandrol B （SolB） isolated from Schisandra sphenanthera produced a protective effect against acetaminophen （APAP）-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. Methods： Male C57BL/6 mice were treated with SolB （200 mg.kg-l.d-1, ig） for 3 d before injection of APAP （400 mg/kg, ip）. Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. Results： SolB pretreatment significantly alleviated the hepatic injury （large patchy necrosis and hyperemia of the hepatic sinus）, the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP- treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQ01, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB （2.5-20 pmol/L） dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. Conclusion： SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.