MODULATION OF ADRIAMYCIN(R) ACCUMULATION AND EFFLUX BY FLAVONOIDS IN HCT-15 COLON CELLS - ACTIVATION OF P-GLYCOPROTEIN AS A PUTATIVE MECHANISM

Since P-glycoprotein (P-gp) in normal tissues may serve as a cellular defense mechanism against naturally occurring xenobiotics, we consider ed whether physiologically active components of commonly ingested plan t foods could influence P-gp function. To examine this possibility, a series of flavonoids commonly found in plant foods was tested for thei r ability to modulate [C-14]Adriamycin(R) ([C-14]ADR) accumulation and efflux in P-gp-expressing HCT-15 colon cells. Many flavonoids, in the micromolar range, inhibited the accumulation of [C-14]ADR. Detailed e xperiments utilizing flavonoids with the greatest activity in reducing [C-14]ADR accumulation, i.e. galangin, kaempferol, and quercetin, rev ealed that the efflux of [C-14]ADR is increased markedly in the presen ce of these compounds. Flavonoid-induced stimulation of efflux was rap id and was blocked by the multidrug-resistant (MDR) reversal agents ve rapamil, vinblastine, and quinidine. The magnitude of flavonoid-stimul ated efflux in sodium butyrate-treated cells with a 4-fold induction o f P-gp protein was similar to that in uninduced cells. [H-3]Azidopine photoaffinity labeling of P-gp in crude membrane preparations revealed mild to no competition for binding by flavonoids possessing either ac tivity or inactivity in reducing ADR accumulation. Although flavonoid hydrophobicity was found to be unrelated to flavonoid activity in alte ring [C-14]ADR accumulation, certain structural features were associat ed with enhancement or diminution of activity. Finally, the significan ce of flavonoid-related reduction of [C-14]ADR accumulation was unders cored in cell growth studies, showing partial protection by quercetin against ADR-induced growth inhibition. It is concluded that certain na turally occurring plant flavonoids may acutely upregulate the apparent activity of P-gp.