Department of Pharmaceutical Sciences, College of Pharmacy, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdullah International Medical Research Center (KAIMRC) and King Abdulaziz Medical City, National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia.
Crit Rev Toxicol. 2020 May;50(5):439-462. doi: 10.1080/10408444.2020.1762538.
-Resveratrol, a polyphenolic stilbene of plant origin is structurally similar to natural and synthetic estrogens and has been classified a phytoestrogen. Direct binding of resveratrol to the nuclear estrogen receptor (ER) and modulation of its genomic activity was among the first of its reported pharmacological actions. Additionally, resveratrol in some investigations interacted with membrane bound ER and modulated non-genomic estrogenic activities. The compound was also reported to interfere in steroidogenesis and estrogen biosynthesis at multiple steps along the pathway. Resveratrol also inhibited hepatic and intestinal metabolism of estrogens and increased circulating levels of sex hormone binding globulin (SHBG). Recent investigations report estrogenic activities for resveratrol metabolites, especially for the predominant sulfate conjugate. The majority of these estrogenic effects have been observed using micro-molar concentrations. However, the daily consumption of 0.5-1 of resveratrol supplements is sufficient to furnish plasma levels sufficient to initiate most of these actions. The diverse modes of estrogenic and hormonal activities of resveratrol can produce a progressive shift in the homeostatic balance of estrogens and other steroidal hormones to a new operational set point. While this could represent an opportunity for therapeutic benefit in a variety of endocrine related diseases, it may also pose risk of endocrine disruption following chronic exposure that warrants caution. Herein, a review of the current knowledge of resveratrol's estrogenic activity at the molecular, cellular and whole organism since it was reported two decades ago is provided followed by an assessment of endocrine disruption via an estrogenic mode of action.KEY MESSAGEResveratrol interacts with ER and modulates its genomic and non-genomic activities. It also inhibits several enzymes in steroidogenesis and competes in estrogen metabolism. Commercial supplements reach dosages of 1000 mg per serving and the consumption of 0.5-1 per day furnishes low micro-molar plasma levels sufficient to start these activities. The pleiotropic hormonal actions of resveratrol open an opportunity for clinical benefit, but also risk endocrine disruption if exposure is chronic or during critical windows of development.
白藜芦醇是一种植物来源的多酚二苯乙烯，其结构与天然和合成雌激素相似，被归类为植物雌激素。白藜芦醇与核雌激素受体 (ER) 的直接结合及其基因组活性的调节是其最早报道的药理学作用之一。此外，在一些研究中，白藜芦醇与膜结合的 ER 相互作用并调节非基因组雌激素活性。该化合物还被报道在甾体生成和雌激素生物合成的多个步骤中干扰。白藜芦醇还抑制雌激素的肝和肠代谢，并增加性激素结合球蛋白 (SHBG) 的循环水平。最近的研究报告称，白藜芦醇代谢物具有雌激素活性，特别是主要的硫酸盐结合物。这些雌激素作用中的大多数是在使用微摩尔浓度的情况下观察到的。然而，每天消耗 0.5-1 毫克的白藜芦醇补充剂足以提供足够的血浆水平来启动大多数这些作用。白藜芦醇的雌激素和激素活性的多种模式可以导致雌激素和其他甾体激素的内稳态平衡向新的操作点逐渐转移。虽然这可能代表在各种与内分泌相关的疾病中获得治疗益处的机会，但长期暴露后也可能存在内分泌干扰的风险，这需要谨慎。在此，提供了自二十年前报道以来，白藜芦醇的雌激素活性在分子、细胞和整体水平上的最新知识综述，随后通过雌激素作用模式评估了内分泌干扰。
白藜芦醇与 ER 相互作用并调节其基因组和非基因组活性。它还抑制类固醇生成中的几种酶，并参与雌激素代谢。商业补充剂的剂量达到 1000 毫克/份，每天消耗 0.5-1 毫克可提供足够的低微摩尔血浆水平来启动这些活性。白藜芦醇的多效激素作用为临床获益提供了机会，但如果暴露是慢性的或在发育的关键窗口期间，则存在内分泌干扰的风险。
