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 dist inguish multidrug-resistant tumors expressing the multidrug resistance -associated protein (MRP) from those expressing P-glycoprotein (Pgp). Genistein would block drug transport by MRP without affecting Pgp-medi ated drug transport. However, we found that exposure to 200 mu M genis tein elicited an elevation in intracellular accumulation of rhodamine 123 (R123) and daunorubicin (DNR) in Pgp-expressing cell lines. Genist ein inhibited R123 efflux in a rapidly reversible manner (ca. 2 min). The flavonoid also decreased photoaffinity labeling of Pgp by [H-3]azi dopine, a Pgp substrate. The present results show that genistein inter acts with Pgp and inhibits Pgp-mediated drug transport. Hence, geniste in cannot be used in simple assays to distinguish MRP- and Pgp-express ing cells. Copyright (C) 1996 Elsevier Science Inc.