Wang Yun, Lee Kai Woo, Chan Franky L, Chen Shiuan, Leung Lai K
Department of Biochemistry and Department of Anatomy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Toxicol Sci. 2006 Jul;92(1):71-7. doi: 10.1093/toxsci/kfj190. Epub 2006 Apr 11.
Estrogen plays a crucial role in the development of breast cancer, and the inhibition of estrogen synthesis has been an important target for the prevention and treatment of this disease. The rate-limiting reaction of the hormone biosynthesis is catalyzed by cytochrome P450 (CYP) 19 enzyme or aromatase. It has been of genuine interest to uncover an aromatase-inhibitory compound from a dietary source. Resveratrol is a polyphenolic compound that can be isolated from grape peel. Because of its structural resemblance to estrogen, resveratrol's agonistic and antagonistic properties on estrogen receptor have been examined and demonstrated. In the present study, the effect of resveratrol on the expression and enzyme activity of aromatase was investigated. By assaying on MCF-7 cells stably transfected with CYP19 (MCF-7aro cells), resveratrol inhibited the aromatase activity with an IC(50) value of 25 microM. Kinetic analysis indicated that both competitive and noncompetitive inhibition might be involved. The administration of 10 nmol/l testosterone-a substrate of aromatase-produced a 50% increase in the MCF-7aro cell number. This cell proliferation specifically induced by testosterone was significantly reduced by 10 microM resveratrol. In addition, 50 microM resveratrol significantly reduced the CYP19-encoding mRNA abundance in SK-BR-3 cells. The transcriptional control of CYP19 gene is tissue specific, and promoter regions I.3 and II have previously been shown to be responsible for CYP19 expression in breast cancer cells. Luciferase reporter gene assays revealed that resveratrol could repress the transcriptional control dictated by the promoter regulation. The present study illustrated that pharmacological dosage of resveratrol inhibited aromatase at both the enzyme and mRNA levels.
雌激素在乳腺癌的发展中起着关键作用，抑制雌激素合成一直是预防和治疗该疾病的重要靶点。激素生物合成的限速反应由细胞色素P450（CYP）19酶或芳香化酶催化。从饮食来源中发现一种芳香化酶抑制化合物一直是人们真正感兴趣的事情。白藜芦醇是一种可以从葡萄皮中分离出来的多酚化合物。由于其结构与雌激素相似，白藜芦醇对雌激素受体的激动和拮抗特性已得到研究和证实。在本研究中，研究了白藜芦醇对芳香化酶表达和酶活性的影响。通过对稳定转染CYP19的MCF-7细胞（MCF-7aro细胞）进行检测，白藜芦醇抑制芳香化酶活性，IC（50）值为25微摩尔。动力学分析表明可能涉及竞争性和非竞争性抑制。给予10纳摩尔/升睾酮（芳香化酶的一种底物）可使MCF-7aro细胞数量增加50%。这种由睾酮特异性诱导的细胞增殖被10微摩尔白藜芦醇显著降低。此外，50微摩尔白藜芦醇显著降低了SK-BR-3细胞中编码CYP19的mRNA丰度。CYP19基因的转录调控具有组织特异性，先前已表明启动子区域I.3和II负责乳腺癌细胞中CYP19的表达。荧光素酶报告基因检测显示白藜芦醇可抑制由启动子调控决定的转录控制。本研究表明，药理学剂量的白藜芦醇在酶和mRNA水平上均抑制芳香化酶。
