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Vol. 304, Issue 3, 1258-1267, March 2003
Department of Pharmaceutical Sciences, School of Pharmacy and
Pharmaceutical Sciences, University at Buffalo, State University of New
York, Amherst, New York
Flavonoids are constituents of fruits, vegetables, and plant-derived
beverages, as well as components in herbal-containing dietary
supplements. The objective of this investigation was to characterize
the effect of flavonoids on P-glycoprotein (P-gp)-mediated cellular
efflux and to determine the molecular mechanism(s) of the
flavonoid-drug interaction. Studies were conducted in the sensitive and
multidrug resistant human breast cancer cell lines MCF-7 and
MDA435/LCC6 and examined the effects of the flavonoids biochanin A,
morin, phloretin, and silymarin on daunomycin (DNM) accumulation and
doxorubicin cytotoxicity. The potential mechanism(s) involved in the
interaction was evaluated by determining flavonoid effects on 1) P-gp
ATPase activity, 2) [3H]azidopine photoaffinity labeling
of P-gp, and 3) cellular P-gp levels. The flavonoids increased
[3H]DNM accumulation in P-gp positive cells, but not P-gp
negative cells, and these effects were both flavonoid concentration-
and P-gp expression level-dependent. Biochanin A and silymarin
potentiated doxorubicin cytotoxicity in P-gp positive cells. Biochanin
A and phloretin stimulated, whereas morin and silymarin inhibited P-gp ATPase activity, confirming that these flavonoids interact with P-gp.
Morin and silymarin significantly inhibited [3H]azidopine
photoaffinity labeling of P-gp, suggesting a direct interaction with
P-gp substrate binding. A 24-h preincubation with all flavonoids,
followed by flavonoid removal, did not alter cellular P-gp level in
P-gp positive cells. In conclusion, biochanin A, morin, phloretin, and
silymarin all inhibited P-gp-mediated cellular efflux and the mechanism
of the interaction involved, at least in part, a direct interaction.
The findings of this study indicate a potential for significant
flavonoid-drug interactions with P-gp substrates.
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