title: Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst, NY 14260-1200, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Allan W
authors.initials: AW
authors.lastname: Wolkoff
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D004347:Drug Interactions; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D019833:Genistein / Q000378:metabolism / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012293:Rifampin; D014162:Transfection; D014316:Tritium
chemical_list: D005419:Flavonoids; D006027:Glycosides; D027381:Liver-Specific Organic Anion Transporter 1; D014316:Tritium; D019314:Dehydroepiandrosterone Sulfate; D019833:Genistein; C004541:biochanin A; D012293:Rifampin