Protective effect of rutaecarpine against t-BHP-induced hepatotoxicity by upregulating antioxidant enzymes via the CaMKII-Akt and Nrf2/ARE pathways

• Published in: Food and chemical toxicology 2017-02, Vol.100, p.138-148
• Main Authors: Jin, Sun Woo, Hwang, Yong Pil, Choi, Chul Yung, Kim, Hyung Gyun, Kim, Se Jong, Kim, Yongan, Chung, Young Chul, Lee, Kyung Jin, Jeong, Tae Cheon, Jeong, Hye Gwang
• Format: Article
• Language: English
• Subjects: Akt; Animals; Antioxidants - metabolism; Apoptosis - drug effects; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CaMKII; Cell Survival - drug effects; Chromatin Immunoprecipitation; Hep G2 Cells; HO-1; Humans; Indole Alkaloids - pharmacology; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative stress; Protective Agents - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - pharmacology; Reactive Oxygen Species - metabolism; Rutaecarpine; Signal Transduction - drug effects; tert-Butylhydroperoxide - toxicity; Up-Regulation; Vasodilator Agents - pharmacology; Vesicular Transport Proteins - metabolism
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2016.12.031

Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, has been shown to have cytoprotective potential, but the molecular mechanism underlying this activity remains unclear. Our study was designed to investigate the cytoprotective effect of rutaecarpine against tert-butyl hydroperoxide (t-BHP) and to elucidate its action mechanism of action of rutaecarpine in a cultured HepG2 cell line and in mouse liver. Rutaecarpine decreased t-BHP–induced reactive oxygen species (ROS) production, cytotoxicity, and apoptosis in HepG2 cells. Pretreatment with rutaecarpine prior to the injection of t-BHP significantly prevented the increase in serum levels of AST, ALT, and lipid peroxidation in mice liver. It increased the transcriptional activity of NF-E2–related factor 2 (Nrf2) as well as the products of the Nrf2 target genes hemeoxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate cysteine ligase (GCL). Moreover, rutaecarpine also enhanced the phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase-II (CaMKII). The pharmaceutical inhibitors, such as KN-93 (CaMKII inhibitor) and LY294002 (Akt inhibitor) suppressed rutaecarpine-induced HO-1 expression and cytoprotection. Our findings identify the CaMKII-PI3K/Akt-Nrf2 cascade as an antioxidant pathway mediating rutaecarpine signaling and leading to HO-1 expression in hepatocytes. [Display omitted] •Rutaecarpine protects human hepatocytes against t-BHP-induced cell death.•Rutaecarpine enhanced HO-1, NQO-1, and GCL expression.•Antioxidative enzyme expression was upregulated by activation of Nrf2 and CaMKII/Akt.