Nrf2-mediated induction of detoxifying enzymes by alantolactone present in Inula helenium.
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, gamma-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.
Seo
Ji Yeon
JY
Department of Animal Science and Biotechnology, Kyungpook National University, Deagu 702-701, Republic of Korea.
Lim
Soon Sung
SS
Kim
Ju Ryoung
JR
Lim
Ji-Sun
JS
Ha
Young Ran
YR
Lee
In Ae
IA
Kim
Eun Ji
EJ
Park
Jung Han Yoon
JH
Kim
Jong-Sang
JS
D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D038143:Inula / Q000737:chemistry*; D007783:Lactones / Q000494:pharmacology*; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D020218:Response Elements; D045787:Sesquiterpenes, Eudesmane / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D007783:Lactones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D045787:Sesquiterpenes, Eudesmane; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; C004363:alantolactone