Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II)
Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II)
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DOI：
10.1016/j.bmc.2005.09.070
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Okuda, H
中科院分区：
文献类型：
--
作者：
Fukuhara, K;Nagakawa, M;Okuda, H
白藜芦醇（1,3,5,4 '-三羟基-反式二苯乙烯）是葡萄和其他食品中发现的一种多酚，被认为是一种抗氧化剂和癌症化学预防剂。然而，1在体外通过高频率的微核和姐妹染色单体交换以及Cu（II）存在下的dna切割活性诱导遗传毒性。本研究旨在探讨1在DNA链断裂中的构效关系，并表征其对Cu（II）和DNA结合的底物特异性。当pBR322DNA与I或其在Cu（II）存在下羟基数目和位置不同的类似物孵育时，4-羟基苯乙烯类似物诱导DNA链断裂的能力比3-羟基类似物强得多。4-羟基苯乙烯类似物与Cu（II）和DNA均具有较高的结合亲和力。Cu（II）的还原是激活分子氧所必需的，通过在Cu(II)-DNA络合物的溶液中加入1来进行，而在添加异白藜芦醇时没有观察到这种还原，其中1的4羟基变为3位。结果表明，1的4-羟基苯乙烯结构是导致DNA链断裂的活性氧产生的主要决定因素。(c) 2005 Elsevier Ltd版权所有。
Resveratrol (1, 3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes and other food products, is known as an antioxidant and cancer chemopreventive agent. However, 1 was shown to induce genotoxicity through a high frequency of micronucleus and sister chromatid exchange in vitro and DNA-cleaving activity in the presence of Cu(II). The present study was designed to explore the structure-activity relationship of 1 in DNA strand scission and to characterize the substrate specificity for Cu(II) and DNA binding. When pBR322DNA was incubated with I or its analogues differing in the number and positions of hydroxyl groups in the presence of Cu(II), the ability of 4-hydroxystilbene analogues to induce DNA strand scission is much stronger than that of 3-hydroxy analogues. The high binding affinity with both Cu(II) and DNA was also observed by 4-hydroxystilbene analogues. The reduction of Cu(II) which is essential for activation of molecular oxygen proceeded by addition of 1 to the solution of the Cu(II)-DNA complex, while such reduction was not observed with the addition of isoresveratrol, in which the 4-hydroxy group of 1 is changed to the 3-position. The results show that the 4-hydroxystilbene structure of 1 is a major determinant of generation of reactive oxygen species that was responsible for DNA strand scission. (c) 2005 Elsevier Ltd. All rights reserved.