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DOI: 10.1055/s-0029-1185685
© Georg Thieme Verlag KG Stuttgart · New York
Induction of the Phase II Detoxification Enzyme NQO1 in Hepatocarcinoma Cells by Lignans from the Fruit of Schisandra chinensis through Nuclear Accumulation of Nrf2
Publication History
received Dec. 7, 2008
revised February 17, 2009
accepted March 21, 2009
Publication Date:
18 May 2009 (online)
Abstract
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.
Key words
Schisandra chinensis Baillon - Magnoliaceae - Nrf2 - quinone reductase - tigloylgomisin H
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References
- 1 Lojková L, Jiří S, Mikešová M, Táborská E, Vejrosta J. Supercritical fluid extraction of lignan from seeds and leaves of Schizandra chinensis. Phytochem Anal. 1997; 8 261-265
- 2 Hikino H, Kiso Y, Taguchi H, Ikeya Y. Anti-hepatotoxic actions of lignoids from Schisandra chinensis fruits. Planta Med. 1984; 50 213-218
- 3 Ohtaki Y, Nomura M, Hida T, Miyamoto K, Kanitani M, Aizawa T, Aburada M. Inhibition by gomisin A, a lignan compound, of hepatocarcinogenesis by 3′-methyl-4-dimethylaminoazobenzene in rats. Biol Pharm Bull. 1994; 17 808-814
- 4 Kiso Y, Tokhin M, Hikino H, Ikeya Y, Taguchi H. Mechanism of antihepato-toxic activity of wuweizisu C and gomisin A. Planta Med. 1985; 52 331-334
- 5 Chiu P Y, Mak D H, Poon M K, Ko K M. In vivo antioxidant action of a lignan-enriched extract of Schisandra fruit and an anthraquinone-containing extract of Polygonum root in comparison with schisandrin B and emodin. Planta Med. 2002; 68 951-956
- 6 Prestera T, Holtzclaw W D, Zhang Y S, Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA. 1993; 90 2965-2969
- 7 Prochaska H J, Talalay P. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res. 1988; 48 4776-4782
- 8 Rushmore T H, Pickett C B. Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem. 1990; 265 14648-14653
- 9 Favreau L V, Pickett C B. Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J Biol Chem. 1991; 266 4556-4561
- 10 Okey A B, Riddick D S, Harper P A. The Ah receptor: mediator of the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Toxicol Lett. 1994; 70 1-22
- 11 Nguyen T, Sherratt P J, Pickett C B. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003; 43 233-260
- 12 Dinkova-Kostova A T, Holtzclaw W D, Cole R N, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002; 99 11908-11913
- 13 Fahey J W, Dinkova-Kostova A T, Stephenson K K, Talalay P. The “Prochaska” microtiter plate bioassay for inducers of NQO1. Methods Enzymol. 2004; 382 243-258
- 14 Zhang Y S, Talalay P, Cho C G, Posner G H. A major inducer of anticarcinogenic protective enzymes from broccoli – isolation and elucidation of structure. Proc Natl Acad Sci USA. 1992; 89 2399-2403
- 15 Ip S P, Yiu H Y, Ko K M. Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity. Mol Cell Biochem. 2000; 208 151-155
- 16 Kang K, Lee H J, Kim C Y, Lee S B, Tunsag J, Batsuren D, Nho C W. The chemopreventive effects of Saussurea salicifolia through induction of apoptosis and phase II detoxification enzyme. Biol Pharm Bull. 2007; 30 2352-2359
- 17 Whitlock J P, Okino S T, Dong L Q, Ko H P, Clarke-Katzenberg R, Ma Q, Li H. Cytochromes P450. 5. Induction of cytochrome P4501A1: a model for analyzing mammalian gene transcription. Faseb J. 1996; 10 809-818
- 18 Israel D I, James P, Whitlock J. Regulation of cytochrome P1–450 gene transcription by 2,3,7,8-tetrachlorodibenzo-p-dioxin in wild type and variant mouse hepatoma cells. J Biol Chem. 1984; 259 5400-5402
- 19 Numazawa S, Yoshida T. Nrf2-dependent gene expressions: a molecular toxicological aspect. J Toxicol Sci. 2004; 29 81-89
- 20 Shibata T, Ohta T, Tong K I, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA. 2008; 105 13568-13573
- 21 Dinkova-Kostova A T, Holtzclaw W D, Cole R N, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002; 99 11908-11913
- 22 Balogun E, Hoque M, Gong P F, Killeen E, Green C J, Foresti R, Alam J, Motterlini R. Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 2003; 371 887-895
- 23 Dickinson D A, Iles K E, Zhang H Q, Blank V, Forman H J. Curcumin alters EpRE and AP‐1 binding complexes and elevates glutamate-cysteine ligase gene expression. Faseb J. 2003; 17 473-475
Dr. Chu Won Nho
Korea Institute of Science and Technology
Natural Products Research Center
290 Daejeon-dong
Gangneung
Gangwon-do 210–340
Korea
Phone: + 82 3 36 50 71 02
Fax: + 82 3 36 50 74 99
Email: cwnho@kist.re.kr
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