伊利諾斯大學: 從啤酒花中隔離的黃腐酚可通過醒還原酶反應抑制甲萘醌誘導DNA的損傷

Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase.

      从啤酒花中隔离的黄腐酚可通过醌还原酶反应抑制甲萘醌诱导DNA的损伤

作者：Dietz BM, Kang YH, Liu G, Eggler AL, Yao P, Chadwick LR, Pauli GF, Farnsworth NR, Mesecar AD, van Breemen RB, Bolton JL.

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231, USA.

作者單位：美國芝加哥伊利諾斯州M/C 781南木街833號，伊利諾斯大學藥劑系藥化學科和生藥學科，郵編：60612-7231

The female parts of hops (Humulus lupulus L.) show estrogenic effects as well as cancer chemopreventive potential. We analyzed the chemopreventive mechanism of hops by studying its antioxidative activities and its effect on the detoxification of a potentially toxic quinone (menadione). The detoxification enzyme quinone reductase [(NAD(P)H:quinone oxidoreductase, QR] protects against quinone-induced toxicity and has been used as a marker in cancer chemoprevention studies. Although the hop extract was only a weak quencher of free radicals formed from 1,1-diphenyl-2-picrylhydrazyl, it demonstrated strong QR induction in Hepa 1c1c7 cells. In addition, compounds isolated from hops including xanthohumol (XH) and 8-prenylnaringenin were tested for QR induction. Among these, XH was the most effective at inducing QR with a concentration required to double the specific activity of QR (CD value) of 1.7 +/- 0.7 microM. In addition, pretreatment of Hepa1c1c7 cells with XH significantly inhibited menadione-induced DNA single-strand breaks. The QR inhibitor dicumarol reversed the protective effect of XH against menadione-induced DNA damage. Because the expression of QR and other detoxifying enzymes is known to be upregulated by binding of the transcription factor Nrf2 to the antioxidant response element (ARE), the reporter activity mediated by ARE in HepG2-ARE-C8 cells was investigated after incubation with XH for 24 h. Under these conditions, XH increased ARE reporter activity in a dose-dependent manner. One mechanism by which XH might induce QR could be through interaction with Keap1, which sequesters Nrf2 in the cytoplasm, so that it cannot activate the ARE. Using LC-MS-MS, we demonstrated that XH alkylates human Keap1 protein, most likely on a subset of the 27 cysteines of Keap1. This suggests that XH induces QR by covalently modifying the Keap1 protein. Therefore, XH and hops dietary supplements might function as chemopreventive agents, through induction of detoxification enzymes such as QR.

啤酒花的雌性株體表現出雌激素作用，並有潛在的防癌作用。我們通過研究啤酒花的抗氧化活性及其對醌（甲萘醌）潛在毒性的解毒效果，分析了啤酒花的化學防癌機制。解毒酶醌還原酶[(NAD(P)H：醌氧化還原酶，QR]可防止醌誘導毒性，並已用作癌化學預防的研究。雖然蛇麻抽取物只是一種由1,1-二苯基-2-苦基肼組成的游離基弱淬火物，但它在Hepa 1c1c7細胞中表現出很強的QR反應。另外，從蛇麻中隔離出的混合物，包括黃腐酚（XH）和8-異戊二烯基三羥黃烷酮被測驗出有QR反應。其中，黃腐酚在所需的QR（CD值）為1.7 +/- 0.7 microM雙倍特殊活性濃度中可最有效地誘導QR。另外，帶有黃腐酚的Hepa1c1c7預處理細胞可很好地抑制甲萘醌誘導DNA單鏈斷裂。QR抑制劑雙香豆素可打亂黃腐酚抑制甲萘醌誘導DNA損傷的保護作用。因為瞭解到通過將轉錄因數Nrf2粘合到抗氧化感應元件（ARE）上可控制QR和其他解毒酶的表達，在黃腐酚孵化24小時後，可觀察到在HepG2-ARE-C8細胞中ARE可調節載體活性。在此種條件下，黃腐酚可在一定劑量上增強ARE的載體活性。黃腐酚誘導QR反應的機制可通過Keap1的相互作用，隔離細胞漿中的Nrf2，因此，它不能啟動ARE。利用液相色譜質譜聯用儀，我們論證了黃腐酚烷基化人類Keap1蛋白最可能存在於Keap1的27半胱氨酸的子集中。這表明黃腐酚通過Keap1蛋白的共價修飾可誘導QR反應。因此，黃腐酚及啤酒花膳食補充品可充當化學抗癌劑，儘管將誘導解毒酶的QR反應。

PMID: 16097803 [PubMed - indexed for MEDLINE]

PMID: 16097803 [PubMed – MEDLINE索引]

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