Wang Xiaodong, Wolkoff Allan W, Morris Marilyn E
Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.
Drug Metab Dispos. 2005 Nov;33(11):1666-72. doi: 10.1124/dmd.105.005926. Epub 2005 Aug 4.
Flavonoids are a class of polyphenolic compounds widely present in the diet and herbal products. The interactions of flavonoids with some major efflux transporters [e.g., P-glycoprotein, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein] have been reported; however, their interactions with uptake transporters are largely unknown. Organic anion-transporting polypeptide OATP1B1 is a liver-specific uptake transporter important in hepatic drug disposition. Our objective was to evaluate the effects of 20 naturally occurring flavonoids, and some of their corresponding glycosides, on the uptake of [3H]dehydroepiandrosterone sulfate (DHEAS) in OATP1B1-expressing and OATP1B1-negative HeLa cells. Many of the tested flavonoids (including biochanin A, genistein, and epigallocatechin-3-gallate) significantly inhibited [3H]DHEAS uptake in a concentration-dependent manner in OATP1B1-expressing cells, with biochanin A being one of the most potent inhibitors with an IC50 of 11.3 +/- 3.22 microM. The flavonoids had negligible or small effects in OATP1B1-negative cells. Four of the eight pairs of tested flavonoids and their glycosides, namely, genistein/genistin, diosmetin/diosmin, epigallocatechin/epigallocatechin-3-gallate, and quercetin/rutin, exhibited distinct effects on [3H]DHEAS uptake. For example, genistin did not inhibit DHEAS uptake, whereas genistein did, and rutin stimulated uptake, whereas quercetin had no effect. [3H]Biochanin A uptake was similar in OATP1B1-expressing and OATP1B1-negative cells, suggesting that it is not a substrate for OATP1B1. A kinetic study revealed that biochanin A inhibited [3H]DHEAS uptake in a noncompetitive manner, with a Ki of 10.2 +/- 1.89 microM. Taken together, these results indicate that flavonoids are a novel class of OATP1B1 modulators, suggesting the potential for diet-drug interactions.
类黄酮是一类广泛存在于饮食和草药产品中的多酚化合物。已有报道类黄酮与一些主要的外排转运体（如P-糖蛋白、多药耐药相关蛋白1（MRP1）和乳腺癌耐药蛋白）之间的相互作用；然而，它们与摄取转运体之间的相互作用在很大程度上尚不清楚。有机阴离子转运多肽OATP1B1是一种肝脏特异性摄取转运体，在肝脏药物处置中起重要作用。我们的目的是评估20种天然存在的类黄酮及其一些相应糖苷对表达OATP1B1和不表达OATP1B1的HeLa细胞摄取[3H]硫酸脱氢表雄酮（DHEAS）的影响。许多受试类黄酮（包括鹰嘴豆芽素A、染料木黄酮和表没食子儿茶素-3-没食子酸酯）在表达OATP1B1的细胞中以浓度依赖性方式显著抑制[3H]DHEAS摄取，鹰嘴豆芽素A是最有效的抑制剂之一，IC50为11.3±3.22微摩尔。这些类黄酮在不表达OATP1B1的细胞中作用可忽略不计或作用较小。受试的八对类黄酮及其糖苷中的四对，即染料木黄酮/染料木苷、香叶木素/香叶木苷、表没食子儿茶素/表没食子儿茶素-3-没食子酸酯和槲皮素/芦丁，对[3H]DHEAS摄取表现出不同的影响。例如，染料木苷不抑制DHEAS摄取，而染料木黄酮可抑制，芦丁刺激摄取，而槲皮素无作用。[3H]鹰嘴豆芽素A在表达OATP1B1和不表达OATP1B1的细胞中的摄取相似，表明它不是OATP1B1的底物。动力学研究表明，鹰嘴豆芽素A以非竞争性方式抑制[3H]DHEAS摄取，Ki为10.2±1.89微摩尔。综上所述，这些结果表明类黄酮是一类新型的OATP1B1调节剂，提示存在饮食与药物相互作用的可能性。
