Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium

• Published in: Phytotherapy research Vol. 22; no. 11; pp. 1500 - 1505
• Main Authors: Seo, Ji Yeon, Lim, Soon Sung, Kim, Ju Ryoung, Lim, Ji-Sun, Ha, Young Ran, Lee, In Ae, Kim, Eun Ji, Park, Jung Han Yoon, Kim, Jong-Sang
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2008; Wiley
• Subjects: Active Transport, Cell Nucleus; alantolactone; Animals; Biological and medical sciences; Cell Line, Tumor; detoxifying enzymes; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; General pharmacology; Genes, Reporter; Glutathione Transferase - metabolism; Inula - chemistry; Inula helenium; Lactones - pharmacology; Medical sciences; Metabolic Detoxication, Phase II; Mice; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Plant Extracts - pharmacology; Plant Roots - chemistry; Response Elements; Sesquiterpenes, Eudesmane - pharmacology; Transcription, Genetic - drug effects; Transcriptional Activation; detoxifying enzymes; Enzyme; Induction; Pharmacognosy; Compositae; Medicinal plant; alantolactone; Inula helenium; PI3K; Nrf2; Dicotyledones; Angiospermae; Plant origin; Spermatophyta
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.2521

Our previous study showed that a methanol extract of Inula helenium had the potential to induce detoxifying enzymes such as quinone reductase (QR) and glutathione S-transferase (GST) activity. In this study the methanol extract was further fractionated using silica gel chromatography and vacuum liquid chromatography, to yield pure compounds alantolactone and isoalantolactone as QR inducers. Alantolactone caused a dose-dependent induction of antioxidant enzymes including QR, GST, γ-glutamylcysteine synthase, glutathione reductase, and heme oxygenase 1 in hepa1c1c7 mouse hepatoma cells. The compound increased the luciferase activity of HepG2-C8 cells, transfectants carrying antioxidant response element (ARE)-luciferase gene, in a dose-dependent manner, suggesting ARE-mediated transcriptional activation of antioxidant enzymes. Alantolactone also stimulated the nuclear accumulation of Nrf2 that was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitors. In conclusion, alantolactone appears to induce detoxifying enzymes via activation of PI3K and JNK signaling pathways, leading to translocation of Nrf2, and subsequent interaction between Nrf2 and ARE in the encoding genes. Copyright © 2008 John Wiley & Sons, Ltd.