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0026-895X/97/061024-10$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 51:1024-1033 (1997).

P-Glycoprotein Substrates and Antagonists Cluster into Two Distinct Groups

Stefania Scala, Nadia Akhmed, U. S. Rao, Ken Paull, Lu-Bin Lan, Bruce Dickstein, Jong-Seok Lee, Galal H. Elgemeie, Wilfred D. Stein, and Susan E. Bates

Medicine Branch, Division of Clinical Sciences (S.S., N.A., B.D., S.E.B.), and Information Technology Branch, Division of Basic Sciences (K.P.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina (U.S.R.), Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel (L.-B.L., W.D.S.), Department of Internal Medicine, Gyeongsang National University, Kyungnam, South Korea (J.-S.L.) and Helwan University, Cairo, Egypt (G.H.E.)

To gather further insight into the interaction between P-glycoprotein (Pgp) and its substrates, 167 compounds were analyzed in multidrug resistant human colon carcinoma cells. These compounds were selected from the National Cancer Institute Drug Screen repository using computer-generated correlations with known Pgp substrates and antagonists. The compounds were prospectively defined as Pgp substrates if cytotoxicity was increased >= 4-fold by the addition of cyclosporin A (CsA) and as Pgp antagonists if inhibition of efflux increased rhodamine accumulation by 4-fold. Among the 84 agents that met either criterion, 35 met only the criterion for substrates, 42 met only the criterion for antagonists, and only seven met both criteria. Thus, compounds interacting with Pgp form two distinct groups: one comprising cytotoxic compounds that are transported and have poor or no antagonistic activity and a second comprising compounds with antagonistic activity and no evidence of significant transport. Vinblastine accumulation and kinetic studies performed on a subset of 18 compounds similarly differentiated substrates and antagonists, but inhibition of 3H-azidopine labeling and induction of ATPase activity did not. These data support an emerging concept of Pgp in which multiple regions instead of specific sites are involved in drug transport.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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