白藜蘆醇(Resveratrol)的研究回顧與新知

陳行慧 編譯 

白藜蘆醇(Resveratrol, trans-3,5,4'-trihydroxystilbene)為一種天然的植物抗毒素(phytoalexin),首先自毛葉藜蘆(Veratrum grandiflorum O. Loes,又稱白藜蘆)根中分離出來,在中藥虎杖(Polygonum cuspidatum)根中也有此成分。白藜蘆醇具有抗凝血 [1]、血管舒張、抗氧化、抗腫瘤、抗發炎等作用 [2, 3],能用於預防心血管疾病 [4],以葡萄(皮濃度最高)、藍莓、花生含量較多,亦少量存在於其他植物。法國人飲食習慣多為高脂肪,但是罹患心血管疾病的發生率卻未隨著其飲食狀況增加,因此被稱為法國矛盾(French Paradox),造成此種現象的主要因素可能與法國人飲用適量富含白藜蘆醇的紅酒有關 [5] 

白藜蘆醇為一多功能植化素,活化細胞外訊息調節激酶 (extracellular signal-regulated kinaseERK) [6],並能抑制酵素及其他調控蛋白,影響細胞訊息傳遞,例如:核糖核苷酸還原酶(ribonucleotide reductase[7]、一氧化氮合成酶(nitric oxide synthase[8]F0F1-ATPase/ATP synthase [9]、蛋白激酶(proteinkinaseD [10]、轉錄因子(transcription factorsNF-κB [11] 以及芳香烴受體(arylhydrocarbon receptor[12]。此外,白藜蘆醇能調控許多分子,例如:第二型磷脂醯肌醇4-激酶(type II phosphatidylinositol 4-kinase[13]sirtuin 1 [14]cytochrome P450 3A4 [15]、醌還原酶(quinone reductase2 [16]、氧化還原因子(redox factor)-1 [17]、黏連蛋白(Integrin)αVβ3 [18]、硫醯基尿素類受體(sulfonylurea receptor[19]、雌激素受體(estrogen receptor[20]以及F1-ATPase[21] 

白藜蘆醇有許多自然的類似物(analogs),例如甲氧基化(methoxylated)的pterostilbene,具有抗氧化性質並能防止致癌物所致癌前病變 [22]Piceatannol (trans-3, 4, 3', 5'-tetrahydroxystilbene) 具有抗白血病與抑制酪胺酸激酶(tyrosine kinase)的活性 [23],而在人類腫瘤中過度表現的細胞色素(cytochromeP450酵素CYP1B1 能將白藜蘆醇轉換成piceatannol [24]oxyresveratrol (2, 3', 4, 5'-tetrahydroxystilbene) 為桑白皮成分之一,有酪胺酶抑制劑之功能 [25]。關於白藜蘆醇衍生物,最近有一篇相當有趣的研究:白藜蘆醇酚基共軛硫酸形成3種硫化共軛物:trans-resveratrol 3-O-sulfatetrans-resveratrol 4'-O-sulfatetrans -resveratrol 3-O-4'-O-disulfate,在體外實驗,對3 種乳癌細胞株的細胞毒殺活性均較白藜蘆醇弱,但在體內實驗則無此影響,推測人體內硫酸酯酶 (sulfatases) 能將白藜蘆醇硫化代謝物轉換回白藜蘆醇,這項研究發表於2009 4 6 日的Planta Medica [26]

 

白藜蘆醇能防止細胞膜脂質過氧化與自由基所致DNA 損傷,為一優良的自由基清除劑 [27]。最近有一篇相關研究:帶有o-二羥基(dihydroxyl groups)之白藜蘆醇相關合成化合物:3,4-dihydroxy-trans-stilbene3,4,4'-trihydroxy-trans-stilbene 3,4,5-trihydroxy-transstilbene 在實驗中具有顯著抑制自由基所致與銅離子存在時加速的DNA 損傷,在人類白血病細胞株HL-60體外實驗觀察到白藜蘆醇及其相關合成化合物抗氧化活性、原氧化物(prooxidant)活性、細胞毒殺性與引起細胞凋亡活性,並從氧化產物分析出結構-活性關係,為設計抗氧化與化學保護的抗癌藥物提供了有用的資訊 [28]

 

有關白藜蘆醇的神經保護作用,Dasgupta Milbrandt 2007 年發表的論文證實在體內外實驗,白藜蘆醇能藉由腫瘤抑制因子LKB-1 活化神經元之AMP-活化激酶(AMP-activated kinaseAMPK),促進軸突生長(neurite outgrowth)與粒線體生物合成(mitochondrial biogenesis),推測白藜蘆醇具有神經保護效用[29]。最近有一項研究顯示:預先給予大鼠10 50 mg/kg 白藜蘆醇 [類似缺血預處理 (ischemic preconditioningIPC)],再造成大鼠全腦缺血模型,結果白藜蘆醇能藉由活化菸醯胺腺嘌呤雙核苷酸去乙醯基酶 [nicotinamide adenine dinucleotide (NAD+) deacetylase] sirtuin 1 (SIRT1),降低粒線體中mitochondrial uncoupling protein 2 (UCP2)水平,增加ATP 生成,而達到保護海馬迴(hippocampusCA1 區的作用 [30]

 

2009 3 月我們談論的薑黃素(curcumin)與白藜蘆醇兩者有許多相似性質:同屬於多酚類,均有抗發炎、抗氧化的作用,結構上有類似的motifs,對G-protein coupledcannabinoid 受體CB1 具有高度親和力,且在相似濃度下具有拮抗劑(antagonists/反向激活劑(inverse agonists)的作用,可能具有開發成為天然無毒、治療與CB1 有關疾病的藥物的潛力 [31],另一方面也使得薑黃素與白藜蘆醇此類植物多酚的藥物設計研發躍進了一大步。

 

參考文獻

1. Pace-Asciak, C.R., Hahn, S., Diamandis, E.P., Soleas, G., and Goldberg,

D.M. The red wine phenolics trans-resveratrol and quercetin block human platelet

aggregation and eicosanoid synthesis: Implications for protection against coronary

heart disease. Clin. Chim. Acta, 235:207–219, 1995.

2. Fitzpatrick, D.F., Hirschfield, S.L., and Coffey, R.G. Endothelium-dependent

vasorelaxing activity of wine and other grape products. Am. J. Physiol.,

265:H774–778, 1993.

3. Frankel, E.N., Waterhouse, A.L., and Kinsella, J.E. Inhibition of human LDL

oxidation by resveratrol. Lancet, 341:1103–1104, 1993.

4. Das, D.K., and Maulik, N. Resveratrol in cardioprotection: a therapeutic

promise of alternative medicine. Mol. Interv., 6:36–47, 2006.

5. Kopp, P. Resveratrol a phytoestrogen found in red wine a possible

explanation for the conundrum of the ’French paradox’. Eur. J. Endocrinol.,

138:619–620, 1998.

6. Miloso, M., Bertelli, A.A., Nicolini, G., and Tredici, G. Resveratrol-induced

activation of the mitogen-activated protein kinases ERK1 and ERK2 in human

neuroblastoma SH-SY5Y cells. Neurosci. Lett., 264:141–144, 1999.

7. Fontecave, M., Lepoivre, M., Elleingand, E., Gerez, C., and Guittet, O.

Resveratrol a remarkable inhibitor of ribonucleotide reductase. FEBS Lett.,

421:277–279, 1998.

8. Tsai, S.H., Lin-Shiau, S.Y., and Lin, J.K. Suppression of nitric oxide

synthase and the down-regulation of the activation of NFκB in macrophages by

resveratrol. Br. J. Pharmacol., 126:673–680, 1999.

9. Zheng, J., and Ramirez, V.D. Inhibition of mitochondrial proton

F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br. J.Pharmacol.,

130:1115–1123, 2000.

10. Stewart, J.R., Christman, K.L., and O'Brian, C.A. Effects of resveratrol on the

autophos-phorylation of phorbol ester-responsive protein kinases: inhibition of protein

kinase D but not protein kinase C isozyme autophosphorylation. Biochem. Pharmacol.,

60:1355–1359, 2000.

11. Manna, S.K., Mukhopadhyay, A., and Aggarwal, B.B. Resveratrol suppresses

TNF-induced activation of nuclear transcription factors NF-κB activator protein-1 and

apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J.

Immunol., 164:6509–6519, 2000.

12. Casper, R.F., Quesne, M., Rogers, I.M., Shirota, T., Jolivet, A., Milgrom, E., and

Savouret, J.F. Resveratrol has antagonist activity on the aryl hydrocarbon receptor:

implications for prevention of dioxin toxicity. Mol. Pharmacol., 56:784–790, 1999.

13. Srivastava, R., Ratheesh, A., Gude, R.K., Rao, K.V., Panda, D., and

Subrahmanyam, G. Resveratrol inhibits type II phosphatidylinositol 4-kinase: a key

component in pathways of phosphoinositide turn over. Biochem. Pharmacol.,

70:1048–1055, 2005.

14. Borra, M.T., Smith, B.C., and Denu, J.M. Mechanism of human SIRT1

activation by resveratrol. J. Biol. Chem., 280:17187–17195, 2005.

15. Regev-Shoshani, G., Shoseyov, O., and Kerem, Z. Influence of lipophilicity on

the interactions of hydroxy stilbenes with cytochrome P450 3A4. Biochem. Biophys.

Res. Commun., 323:668–673, 2004.

16. Vella, F., Ferry, G., Delagrange, P., and Boutin, J.A. NRH: quinone reductase 2:

an enzyme of surprises and mysteries. Biochem. Pharmacol., 71:1–12, 2005.

17. Yang, S., Irani, K., Heffron, S.E., Jurnak, F., and Meyskens, F.L. Jr. Alterations

in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1

(APE/Ref-1) in human melanoma and identification of the therapeutic potential of

resveratrol as an APE/Ref-1 inhibitor. Mol. Cancer Ther., 4:1923–1935, 2005.

18. Lin, H.Y., Lansing, L., Merillon, J.M., Davis, F.B., Tang, H.Y., Shih, A., Vitrac,

X., Krisa, S., Keating, T., Cao, H.J., Bergh, J., Quackenbush, S., and Davis, P.J.

Integrin αVβ3 contains a receptor site for resveratrol. FASEB J., 20:1742–1744, 2006.

19. Hambrock, A., de Oliveira Franz, C.B., Hiller, S., Grenz, A., Ackermann, S.,

Schulze, D.U., Drews, G., and Osswald, H. Resveratrol binds to the sulfonylurea

receptor (SUR) and induces apoptosis in a SUR subtype-specific manner. J. Biol.

Chem., 282:3347–3356, 2007.

20. Singh, N.P., Hegde, V.L., Hofseth, L.J., Nagarkatti, M., and Nagarkatti, P.

Resveratrol (trans-3, 5, 4'-trihydroxystilbene) ameliorates experimental allergic

encephalomyelitis primarily via induction of apoptosis in T cells involving activation

of aryl hydrocarbon receptor and estrogen receptor. Mol. Pharmacol., 72:1508–1521,

2007.

21. Gledhill, J.R., Montgomery, M.G., Leslie, A.G., and Walker, J.E. Mechanism of

inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl.

Acad. Sci. USA, 104:13632–13637, 2007.

22. Rimando, A.M., Cuendet, M., Desmarchelier, C., Mehta, R.G., Pezzuto, J.M.,

and Duke, S.O. Cancer chemopreventive and antioxidant activities of pterostilbene a

naturally occurring analogue of resveratrol. J. Agric. Food Chem., 50:3453–3457,

2002.

23. Wolter, F., Clausnitzer, A., Akoglu, B., and Stein, J. Piceatannol a natural analog

of resveratrol inhibits progression through the S phase of the cell cycle in colorectal

cancer cell lines. J. Nutr., 132:298–302, 2002.

24. Potter, G.A., Patterson, L.H., Wanogho, E., Perry, P.J., Butler, P.C., Ijaz, T.,

Ruparelia, K.C., Lamb, J.H., Farmer, P.B., Stanley, L.A., and Burke, M.D. The cancer

preventative agent resveratrol is converted to the anticancer agent piceatannol by the

cytochrome P450 enzyme CYP1B1. Br. J. Cancer, 86:774–778, 2002.

25. Shin, N.H., Ryu, S.Y., Choi, E.J., Kang, S.H., Chang, I.M., Min, K.R., and Kim,

Y. Oxyresveratrol as the potent inhibitor on dopa oxidase activity of mushroom

tyrosinase. Biochem. Biophys. Res. Commun., 243:801–803, 1998.

26. Miksits, M., Wlcek, K., Svoboda, M., Kunert, O., Haslinger, E., Thalhammer, T.,

Szekeres, T., and Jäger, W. Antitumor activity of resveratrol and its sulfated

metabolites against human breast cancer cells. Planta Med., Epub ahead of print, 2009

Apr 6.

27. Leonard, S.S., Xia, C., Jiang, B.H., Stinefelt, B., Klandorf, H., Harris, G.K., and

Shi, X. Resveratrol scavenges reactive oxygen species and effects radical-induced

cellular responses. Biochem. Biophys. Res. Commun., 309:1017–1026, 2003.

28. Qian, Y.P., Cai, Y.J., Fan, G.J., Wei, Q.Y., Yang, J., Zheng, L.F., Li, X.Z., Fang,

J.G., and Zhou, B. Antioxidant-based lead discovery for cancer chemoprevention: the

case of resveratrol. J. Med. Chem., 52:1963-1974, 2009.

29. Dasgupta, B., and Milbrandt, J. Resveratrol stimulates AMP kinase activity in

neurons. Proc. Natl. Acad. Sci. USA, 104:7217-7222, 2007.

30. Della-Morte, D., Dave, K.R., Defazio, R.A., Bao, Y.C., Raval, A.P., and

Perez-Pinzon, M.A. Resveratrol pretreatment protects rat brain from cerebral ischemic

damage via a sirtuin 1 -- uncoupling protein 2 pathway. Neuroscience, 159:993-1002,

2009.

31. Seely, K.A., Levi, M.S., and Prather, P.L. The dietary polyphenols

trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors

with nanomolar affinities and function as antagonists/inverse agonists. J. Pharmacol.

Exp. Ther., Epub ahead of print, 2009 Apr 9.

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