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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Cellular Uptake and Efflux of the Tea Flavonoid (-)Epicatechin-3-gallate in the Human Intestinal Cell Line Caco-2

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina

(-)-Epicatechin gallate (ECG) is one of the flavonoids in green tea, which has been demonstrated to have cancer-preventive properties in many model systems. However, the extent and mechanisms of accumulation of these flavonoids in cells is unknown. The objectives of this study were to determine the accumulation of ECG by the intestinal epithelial cell Caco-2 and to characterize the transport mechanism involved. The cells were exposed to ECG ± various transport inhibitors and incubated at 37°C. Absorbed flavonoids were extracted and quantified by high-performance liquid chromatography. The uptake of ECG included a nonsaturable initial rapid process as well as a much slower saturable process. The saturable ECG uptake by the Caco-2 cells was sodium-independent but clearly dependent on a pH gradient. Phloretin and benzoic acid, inhibitors of the monocarboxylate transporter (MCT), significantly reduced ECG uptake. The uptake of ECG in the Caco-2 cells increased 2-fold in the presence of 50 µM 3-[{3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl}-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK-571), suggesting the involvement of multidrug-associated protein (MRP)2 in efflux of ECG. This was confirmed using Madin-Darby canine kidney cells transfected with MRP2. Also P-glycoprotein was responsible for some ECG efflux. MK-571 also caused a dramatic increase in ECG accumulation in Chinese hamster ovary cells, suggesting that ECG was also a substrate for MRP1. Together, these observations demonstrate important roles of membrane transporters, i.e., MCT, MRP2, P-glycoprotein, and MRP1, in the cellular accumulation and potential effects of ECG.

Address correspondence to: Dr. Thomas Walle, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Ave., P.O. Box 250505, Charleston, SC 29425. E-mail: wallet{at}musc.edu

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