Plant polyphenols and multidrug resistance: Effects of dietary flavonoids on drug transporters in Caco-2 and MDCKII-MDR1 cell transport models

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.