Imelda (之樺) Jeunesse Global; 婕斯環球

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 kinase，ERK) [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（proteinkinase）D [10]、轉錄因子（transcription factors）NF-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 reductase）2 [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（cytochrome）P450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-sulfate、trans-resveratrol 4'-O-sulfate、trans -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 年4 月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-stilbene、3,4,4'-trihydroxy-trans-stilbene 與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 與Milbrandt 在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 kinase，AMPK），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 或50 mg/kg 白藜蘆醇 [類似缺血預處理 (ischemic preconditioning，IPC)]，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（hippocampus）CA1 區的作用 [30]。

在 2009 年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 coupled、cannabinoid 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。

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