Isoalantolactone from Inula helenium caused Nrf2-mediated induction of detoxifying enzymes.
Our previous study demonstrated that methanolic extract of Inula helenium (Elecampane) has the potential to induce detoxifying enzymes such as NAD(P)H:(quinone acceptor) oxidoreductase 1 (EC 1.6.99.2) (NQO1, QR) activity and glutathione S-transferase (GST) and found isoalantolactone and alantolactone as the active components. In this study we investigated the detoxifying enzyme-inducing potential of isoalantolactone, which is present in I. helenium and has a structure similar to that of alantolactone. The compound induced QR in a dose-dependent manner in both Hepa1c1c7 cells and its mutant BPRc1 cells lacking the arylhydrocarbon receptor translocator. Like with most phase 2 enzyme inducers, other phase 2 detoxifying enzymes, including GST, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, were also induced by isoalantolactone in a dose-dependent manner in the cultured cells. Furthermore, isoalantolactone caused a proportionate increase in luciferase activity depending upon concentration and exposure time in the reporter assay in which HepG2-C8 cells, transfectants carrying antioxidant response element-luciferase gene, were used. The nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) was stimulated by the compound and attenuated by phosphatidylinositol 3-kinase inhibitors such as LY294002 and wortmannin. In conclusion, isoalantolactone is a candidate for chemoprevention and acts as potent phase 2 enzyme inducer by stimulating the accumulation of Nrf2 in the nucleus.
Seo
Ji Yeon
JY
Department of Animal Science and Biotechnology and School of Applied Biosciences, Kyungpook National University, Daegu, Republic of Korea.
Park
Jia
J
Kim
Hyo Jung
HJ
Lee
In Ae
IA
Lim
Ji-Sun
JS
Lim
Soon Sung
SS
Choi
Se-Jin
SJ
Park
Jung Han Yoon
JH
Kang
Hui Jung
HJ
Kim
Jong-Sang
JS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000378:metabolism*; D005638:Fruit; D056945:Hep G2 Cells; D006801:Humans; D008658:Inactivation, Metabolic; D038143:Inula / Q000737:chemistry*; D008113:Liver Neoplasms / Q000517:prevention & control; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018517:Plant Roots; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D004798:Enzymes; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D012717:Sesquiterpenes; C032787:isoalantolactone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human