Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China; Pharmacy Department, Long Hua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
Phytomedicine. 2019 Feb;53:154-162. doi: 10.1016/j.phymed.2018.09.028. Epub 2018 Sep 4.
Isorhamnetin (IS) is a flavonoid component with many biological activities such as antioxidant, anti-inflammatory, and anticancer, which is also the main active component in total flavones of Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) (TFH); however, the interaction between IS and other components in TFH is unclear.
The aim of the present study was to investigate the enhancement of quercetin (QU) or kaempferol (KA) on the intestinal absorption of IS coexisting in TFH, and then preliminarily illuminate the related mechanisms.
Firstly, the intestinal absorption of IS in the presence or absence of QU or KA was conducted by in vivo pharmacokinetics model, in situ single-pass intestinal perfusion model (SPIP), and MDCK II-MRP2 monolayer cell model to confirm the enhancement of QU or KA on IS absorption. Secondly, the effects of multidrug resistance-associated protein 2 (MRP2) inhibitors on the IS intestinal absorption were investigated to ascertain the mediation of MRP2 on IS absorption. Finally, the effects of QU or KA on MRP2 activity, protein expression, and mRNA level were performed by SPIP, everted-gut sacs, western blotting, and real-time polymerase chain reaction experiments to elucidate the related mechanisms.
QU or KA increased IS intestinal absorption according to the increased AUC, C, and P of IS after co-administrated with QU or KA to rats; the oral absorption of IS was mediated by MRP2 based on the facts that the average plasma concentration, AUC, and P of IS were increased when co-administrated with PR or MK571 (MRP2 inhibitors) as well as the P(BL/AP) of IS was decreased by MK571 in MDCK II-MRP2 cell monolayer; the activity, protein expression, and mRNA level of MRP2 were inhibited or down-regulated by QU or KA because of the increased P of MRP2 substrate calcein (CA) and the down-regulated relative protein and mRNA intensity after co-treated with QU or KA.
QU and KA increased the intestinal absorption of IS in TFH by regulating the activity and expression of MRP2, which provides useful information for the investigation of the transporter-mediated interaction of flavonoid components in herbal extracts.
山奈酚（IS）是一种具有多种生物活性的类黄酮成分，如抗氧化、抗炎和抗癌作用，也是柳属植物（Elaeagnaceae）总黄酮（TFH）中主要的活性成分；然而，IS 与 TFH 中其他成分之间的相互作用尚不清楚。
本研究旨在探讨槲皮素（QU）或山柰酚（KA）对 TFH 中山奈酚共存时肠吸收的增强作用，并初步阐明相关机制。
首先，通过体内药代动力学模型、原位肠灌流模型（SPIP）和 MDCK II-MRP2 单层细胞模型，观察 IS 在存在或不存在 QU 或 KA 时的肠吸收情况，以证实 QU 或 KA 对 IS 吸收的增强作用。其次，通过 SPIP、外翻肠囊和 Western blot 及实时聚合酶链反应实验，研究多药耐药相关蛋白 2（MRP2）抑制剂对 IS 肠吸收的影响，以确定 MRP2 对 IS 吸收的介导作用。最后，研究 QU 或 KA 对 MRP2 活性、蛋白表达和 mRNA 水平的影响，以阐明相关机制。
根据 QU 或 KA 与 IS 共给药后 IS 的 AUC、C 和 P 增加，QU 或 KA 增加 IS 肠吸收；IS 的口服吸收由 MRP2 介导，因为当与 PR 或 MK571（MRP2 抑制剂）共给药时，IS 的平均血浆浓度、AUC 和 P 增加，并且 MK571 降低了 IS 在 MDCK II-MRP2 细胞单层中的 P（BL/AP）；QU 或 KA 抑制或下调了 MRP2 的活性、蛋白表达和 mRNA 水平，因为 MRP2 底物钙黄绿素（CA）的 P 增加，并且与 QU 或 KA 共处理后相对蛋白和 mRNA 强度降低。
QU 和 KA 通过调节 MRP2 的活性和表达增加了 TFH 中山奈酚的肠吸收，这为研究草药提取物中类黄酮成分的转运体介导相互作用提供了有用信息。
