Induction of the phase II detoxification enzyme NQO1 in hepatocarcinoma cells by lignans from the fruit of Schisandra chinensis through nuclear accumulation of Nrf2.
The upregulation of phase II detoxification genes is believed to play an important role in cancer prevention. The molecular mechanism underlying the changes in gene expression that accompany cancer prevention involves activation of the transcription factor, NF-E2-related factor 2 (Nrf2). In traditional medicine, the fruit of Schisandra chinensis Baill is used as a tonic, an anti-tussive and an anti-aging drug. In the current study, nine lignans were isolated from S. chinensis and tested for their ability to induce quinone reductase (QR) activity in Hepa1c1c7 mouse hepatocarcinoma cells. Tigloylgomisin H (TGH) and angeloylgomisin H (AGH) significantly induced QR activity and exhibited a relatively high chemoprevention index (CI) (10.80 and 4.59, respectively) as compared to control. TGH also induced QR activity in BPrc1 mouse hepatocarcinoma cells as well, which are defective in aryl hydrocarbon nuclear translocator (Arnt). In HepG2 human hepatocarcinoma cells, TGH significantly activated gene expression mediated by the antioxidant response element (ARE), a key regulatory region in the promoters of detoxification enzymes, through the nuclear accumulation of Nrf2. The results of the current study suggest that TGH functions as a novel monofunctional inducer that specifically upregulates phase II enzymes through the Nrf2-ARE pathway. TGH thus represents a potential liver cancer prevention agent.
Lee
Saet Byoul
SB
Natural Products Research Center, KIST Gangneung Institute, Gangneung, Gangwon-do, Korea.
Kim
Chul Young
CY
Lee
Hee Ju
HJ
Yun
Ji Ho
JH
Nho
Chu Won
CW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009252:NADPH Dehydrogenase / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D032141:Schisandra / Q000737:chemistry*
D016588:Anticarcinogenic Agents; D017705:Lignans; D051267:NF-E2-Related Factor 2; C547031:tigloylgomisin H; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase