Induction of antioxidant and phase 2 drug-metabolizing enzymes by falcarindiol isolated from Notopterygium incisum extract, which activates the Nrf2/ARE pathway, leads to cytoprotection against oxidative and electrophilic stress.
In the present study, we isolated falcarindiol from Notopterygium incisum and investigated the effect of falcarindiol on the expression of antioxidant enzymes (AOEs), such as catalase, and phase 2 drug-metabolizing enzymes (DMEs), such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1, in a cultured cell line from normal rat liver, Clone 9 cells. Exposure of Clone 9 cells to falcarindiol resulted in the significant induction of AOEs and phase 2 DMEs. Western blot analysis and transfection studies using a luciferase reporter construct demonstrated that the induction of AOEs and phase 2 DMEs by falcarindiol was caused through the Nrf2/ARE (nuclear factor-E2-related factor 2/antioxidant response element) pathway. Pretreatment of cells with falcarindiol accelerated the detoxification of a potentially toxic quinone (menadione) and mitigated menadione-induced cytotoxicity. We found that falcarindiol was a novel inducer of AOEs and phase 2 DMEs and falcarindiol might exhibit chemopreventive activity.
Ohnuma
Tomokazu
T
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
Komatsu
Takao
T
Nakayama
Shinji
S
Nishiyama
Takahito
T
Ogura
Kenichiro
K
Hiratsuka
Akira
A
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019661:Apiaceae / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D003603:Cytotoxins / Q000378:metabolism / Q000633:toxicity; D053280:Diynes / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology*; D004583:Electrons; D004790:Enzyme Induction / Q000187:drug effects; D004798:Enzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005233:Fatty Alcohols / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D050217:Metabolic Detoxication, Phase II; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D024483:Vitamin K 3 / Q000378:metabolism / Q000633:toxicity
D000975:Antioxidants; D003603:Cytotoxins; D053280:Diynes; D004798:Enzymes; D005233:Fatty Alcohols; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D012333:RNA, Messenger; C034379:falcarindiol; D024483:Vitamin K 3; D051547:Heme Oxygenase-1