Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators

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 K_i 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.