Received for publication June 6, 2005.
Revised July 28, 2005.
Accepted for publication August 4, 2005.

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 (BCRP)) 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 while genistein did and rutin stimulated uptake while 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.

Key words: drug interactions, drug transport, hepatobiliary transport, transporters

This article has been cited by other articles:

				Q. Wang and M. E. Morris Flavonoids Modulate Monocarboxylate Transporter-1-Mediated Transport of {gamma}-Hydroxybutyrate in Vitro and in Vivo Drug Metab. Dispos., February 1, 2007; 35(2): 201 - 208. [Abstract] [Full Text] [PDF]

				J. J. Blakeslee, A. Bandyopadhyay, O. R. Lee, J. Mravec, B. Titapiwatanakun, M. Sauer, S. N. Makam, Y. Cheng, R. Bouchard, J. Adamec, et al. Interactions among PIN-FORMED and P-Glycoprotein Auxin Transporters in Arabidopsis PLANT CELL, January 1, 2007; 19(1): 131 - 147. [Abstract] [Full Text] [PDF]

				H. Fuchikami, H. Satoh, M. Tsujimoto, S. Ohdo, H. Ohtani, and Y. Sawada EFFECTS OF HERBAL EXTRACTS ON THE FUNCTION OF HUMAN ORGANIC ANION-TRANSPORTING POLYPEPTIDE OATP-B Drug Metab. Dispos., April 1, 2006; 34(4): 577 - 582. [Abstract] [Full Text] [PDF]