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Abstract
The hypothesis tested was that specific flavonoids such as epicatechin gallate, epigallocatechin gallate, genistein, genistin, naringenin, naringin, quercetin and xanthohumol will modulate cellular uptake and permeability (Pe) of multidrug-resistant substrates, cyclosporin A (CSA) and digoxin, across Caco-2 and MDCKII-MDR1 cell transport models. 3H-CSA/3H-digoxin transport and uptake experiments were performed with and without co-exposure of the flavonoids. Aglycone flavonoids reduced the Pe of CSA to a greater extent than glycosylated flavonoids with 30 µM xanthohumol producing the greatest effect (7.2 × 10–6 to 6.6 × 10–7 and 17.9 × 10–6 to 4.02 × 10–6 cm s–1 in Caco-2 and MDCKII-MDR1 cells, respectively); while no measurable effects were seen with digoxin. Xanthohumol significantly demonstrated (1) saturable efflux, (2) increased uptake of 3H-digoxin and (3) decreased uptake of 3H-CSA in the Caco-2 cells. The transport data suggests that xanthohumol effects transport of CSA in a manner that is distinct from the digoxin efflux pathway and suggests that intestinal transport of these MDR1 substrates is more complex than previously reported.
Acknowledgements
Thanks to Dr Jiin-Long Chen, Ms Kelly Hall and Ms Tomoko Tanaka for technical assistance on the project. The authors also thank Dr Richard Hemingway, Plant Polyphenols, LLC, for the novel compound catechin-(4α-8)-epigallocatechin-3-gallate, and Dr Piet Borst, The Netherlands Cancer Research Institute, for the MDCKII-MDR1 and MDCKII wild-type cells. The paper was made possible by NIH Grants AT00853, CA090890 and ES00210. AT00853 was from the National Center for Complementary and Alternative Medicine (NCCAM) and the contents are solely the responsibility of the authors and do not necessarily represent the official view of NCCAM, or the National Institutes of Health. In addition, this work was supported by a grant from the Hop Research Council. Part of this paper was presented at the Society of Toxicology's 43rd Annual Meeting, Baltimore, MD, USA, 2004, abst no. #1514: Mata et al. (Citation2004).