Interaction of tamoxifen with the multidrug resistance P-glycoprotein.
Tamoxifen is an anti-oestrogen which is currently being assessed as a prophylactic for women at high risk of breast cancer. Taxoxifen has also been shown to reverse multidrug resistance in P-glycoprotein (P-gp)-expressing cells, although the mechanism of action is unknown. In this study we demonstrate that tamoxifen interacts directly with P-gp. Plasma membranes from P-gp-expressing cells bound [3H]tamoxifen in a specific and saturable fashion. A 180 kDa membrane protein in these membranes, labelled by the affinity analogue tamoxifen aziridine and azidopine, was shown to be P-gp. Tamoxifen reduced the binding of vinblastine and azidopine to P-gp, and tamoxifen increased [3H]vinblastine accumulation in P-gp-expressing cells to levels approaching those in non-P-gp-expressing cells. However, the cellular accumulation of [3H]tamoxifen itself was not influenced by the presence of P-gp. Thus, tamoxifen appears to reverse multidrug resistance by binding to P-gp and inhibiting the transport of cytotoxic drugs, but does not itself appear to be transported by the protein.
Callaghan
R
R
Imperial Cancer Research Fund Laboratories, Institute for Molecular Medicine, Oxford, UK.
Higgins
C F
CF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D018432:Drug Resistance, Multiple; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D013629:Tamoxifen; D014747:Vinblastine; C031859:tamoxifen aziridine