Distribution of RESV and its metabolite peaks in mouse tissues after oral and skin administration

Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV. RESV (1 mg in 200 µl saline) was orally administered to hairless mice or 1 mg RESV dissolved in ethanol was applied on the dorsal skin of hairless mice. After 4 h mice were sacrificed, metabolites were extracted from the tissues and analyzed by the LC-MS. Peak areas of metabolites were normalized by the peak areas of spiked internal standards (10 nmol 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and piperazine-N,N’-bis(2-ethanesulfonic acid) (PIPES).白藜芦醇（Resveratrol, RESV）是一种植物多酚，被认为在实验动物及人类体内均具有有益的代谢调控效应。口服给药后，白藜芦醇会迅速被代谢分解，导致其生物利用度较低。本研究对比了口服摄取与皮肤吸收途径下，白藜芦醇的代谢物及其组织分布特征。对多种小鼠组织开展的代谢组学分析显示，白藜芦醇可通过皮肤途径被吸收并代谢。本研究检测到了硫酸化、葡萄糖醛酸化的白藜芦醇代谢物，以及二氢白藜芦醇。现有研究认为，这些代谢物的药理活性低于白藜芦醇本身。在给药4小时后，多数白藜芦醇代谢物的含量在口服组与皮肤给药组中无显著差异，但局部涂抹白藜芦醇后，皮肤组织内的葡萄糖醛酸化白藜芦醇代谢物含量显著高于口服给药组。该结果与我们在培养皮肤细胞中检测到葡萄糖醛酸化白藜芦醇代谢物的发现相一致。涂抹于小鼠耳部的白藜芦醇可显著抑制TPA炎症模型中的炎症反应。皮肤吸收途径或可作为一种补充且高效的白藜芦醇给药方式，以实现其治疗效应。 本实验向无毛小鼠分别开展两种给药方式：一是经口给予1 mg白藜芦醇（溶于200 μl生理盐水）；二是将1 mg溶于乙醇的白藜芦醇涂抹于无毛小鼠的背部皮肤。给药4小时后处死小鼠，从其组织中提取代谢物，并通过液相色谱-质谱联用法（LC-MS）开展分析。代谢物的峰面积通过添加的内标物（10 nmol的4-(2-羟乙基)-1-哌嗪乙磺酸（HEPES）与哌嗪-N,N'-二(2-乙磺酸)（PIPES））的峰面积进行归一化处理。