Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein.
It has been claimed that the flavonoid genistein could be used to distinguish multidrug-resistant tumors expressing the multidrug resistance-associated protein (MRP) from those expressing P-glycoprotein (Pgp). Genistein would be block drug transport by MRP without affecting Pgp-mediated drug transport. However, we found that exposure to 200 microM genistein elicited an elevation in intracellular accumulation of rhodamine 123 (R123) and daunorubicin (DNR) in Pgp-expressing cell lines. Genistein inhibited R123 efflux in a rapidly reversible manner (ca. 2 min). The flavonoid also decreased photoaffinity labeling of Pgp by [3H]azidopine, a Pgp substrate. The present results show that genistein interacts with Pgp and inhibits Pgp-mediated drug transport. Hence, genistein cannot be used in simple assays to distinguish MRP- and Pgp-expressing cells.
Castro
A F
AF
Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston 77555-0641, USA.
Altenberg
G A
GA
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003630:Daunorubicin; D004791:Enzyme Inhibitors; D019833:Genistein; D007529:Isoflavones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011505:Protein-Tyrosine Kinases; D020112:Rhodamine 123; D012235:Rhodamines