Pleiotropic mechanisms facilitated by resveratrol and its metabolites.
Pleiotropic mechanisms facilitated by resveratrol and its metabolites.
复制标题
DOI：
10.1042/bj20091857
复制
发表时间：
2010-07-15
期刊：
影响因子：
--
通讯作者：
Mesecar AD
中科院分区：
文献类型：
--
作者：
Calamini B;Ratia K;Malkowski MG;Cuendet M;Pezzuto JM;Santarsiero BD;Mesecar AD
白藜芦醇已在动物模型中显示出癌症化学预防活性，一些临床试验正在进行中。此外，白藜芦醇被证明可以促进细胞存活，延长寿命和模拟热量限制，从而改善高热量饮食小鼠的健康和生存。所有这些作用都可能通过白藜芦醇与不同酶靶点的多效性相互作用来介导，所述酶靶点包括考克斯-1（环氧合酶-1）和考克斯-2、NAD+依赖性组蛋白脱乙酰酶SIRT 1（去乙酰化酶1）和QR 2（醌还原酶2）。尽管如此，白藜芦醇作为与分子靶点相互作用的直接结果而引起的健康益处受到质疑，因为它被快速和广泛地代谢为硫酸盐和葡糖苷酸缀合物，导致血浆浓度低。为了帮助解决这些问题，我们测试了白藜芦醇及其代谢产物在体外调节一些已知靶标功能的能力。在本研究中，我们已经表明，考克斯-1，考克斯-2和QR 2是有效的抑制白藜芦醇，考克斯-1和考克斯-2也抑制白藜芦醇4′-O-硫酸代谢产物。我们确定了与考克斯-1结合的白藜芦醇的X-射线结构，并证明它占据了与其他NSAID（非甾体抗炎药）相似的考克斯活性位点。最后，我们观察到白藜芦醇3-和4′-O-硫酸酯代谢物激活SIRT 1的能力与白藜芦醇相当，但这种激活可能是一种底物依赖性现象，与体内相关性很小。总的来说，这项研究的结果表明，在体内白藜芦醇及其代谢产物与不同分子靶点之间的相互作用可能是以前只归因于白藜芦醇本身的整体有益健康效果的原因。
Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4′-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4′-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.