Human, rat, and mouse metabolism of resveratrol
Human, rat, and mouse metabolism of resveratrol
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DOI：
10.1023/a:1021414129280
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发表时间：
2002-12-01
影响因子：
3.7
通讯作者：
van Breemen, RB
中科院分区：
文献类型：
--
作者：
Yu, CW;Shin, YG;van Breemen, RB
目的。白藜芦醇是一种存在于葡萄、葡萄酒、花生和蔓越莓中的酚类植物抗毒素，据报道具有抗癌、抗氧化、植物雌激素和心脏保护活性。由于对这种潜在重要化合物的代谢知之甚少，因此对反式白藜芦醇的体外和体内代谢进行了研究。方法。体外实验包括与人肝微粒体、人肝细胞和大鼠肝细胞一起孵育，体内研究包括对大鼠和小鼠口服或腹膜内施用白藜芦醇。使用反相高效液相色谱、在线紫外光电二极管阵列检测和质谱检测（LC-DAD-MS 和 LC-UV-MS-MS）分析大鼠尿液、小鼠血清、人肝细胞、大鼠肝细胞和人肝微粒体的甲醇提取物中的白藜芦醇代谢物。紫外光电二极管阵列分析有助于鉴定白藜芦醇及其代谢物的顺式和反式异构体。负离子电喷雾质谱分析提供了白藜芦醇代谢物的分子量确认，串联质谱分析获得了结构信息。结果。在微粒体孵育中没有检测到白藜芦醇代谢物，并且在任何样品中都没有观察到I相代谢物，例如氧化、还原或水解。然而，在大鼠尿液、小鼠血清以及大鼠和人肝细胞的培养物中发现了丰富的反式白藜芦醇-3-O-葡萄糖苷酸和反式白藜芦醇-3-硫酸盐。用β-葡萄糖醛酸酶和硫酸酯酶孵育以释放游离白藜芦醇来确认这些缀合物的结构。仅检测到微量的顺式白藜芦醇，表明异构化并不是白藜芦醇代谢和消除的重要因素。结论。我们的结果表明，反式白藜芦醇-3-O-葡萄糖苷酸和反式白藜芦醇-3-硫酸盐是白藜芦醇最丰富的代谢物。事实上，在尿液或血清样本中没有检测到未结合的白藜芦醇，这可能对仅使用未结合的白藜芦醇的体外研究的意义产生影响。
Purpose. Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of transresveratrol were investigated.Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed- phase highperformance liquid chromatography with on- line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD- MS and LC- UV- MS- MS). UV- photodiode array analysis facilitated the identification of cis- and trans- isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained.Results. No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans- resveratrol- 3- O- glucuronide and trans- resveratrol- 3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with beta- glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis- resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol.Conclusion. Our results indicate that trans- resveratrol- 3- O-glucuronide and trans- resveratrol- 3- sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol.