TY - JOUR T1 - FLAVONOIDS AS A NOVEL CLASS OF HUMAN ORGANIC ANION-TRANSPORTING POLYPEPTIDE OATP1B1 (OATP-C) MODULATORS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1666 LP - 1672 DO - 10.1124/dmd.105.005926 VL - 33 IS - 11 AU - Xiaodong Wang AU - Allan W. Wolkoff AU - Marilyn E. Morris Y1 - 2005/11/01 UR - http://dmd.aspetjournals.org/content/33/11/1666.abstract N2 - 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 μM. 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 μM. Taken together, these results indicate that flavonoids are a novel class of OATP1B1 modulators, suggesting the potential for diet-drug interactions. The American Society for Pharmacology and Experimental Therapeutics ER -