TAMOXIFEN AZIRIDINE, A NOVEL AFFINITY PROBE FOR P-GLYCOPROTEIN IN MULTIDRUG-RESISTANT CELLS

In this study for the first time we used an electrophilic analog of tamoxifen, [H-3]tamoxifen aziridine. and demonstrated that it covalently and specifically binds to P-glycoprotein in multidrug resistant cells. Tamoxifen and its metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, were potent inhibitors of [H-3]tamoxifen aziridine binding to P-glycoprotein with 4-hydroxytamoxifen > tamoxifen > N-desmethyltamoxifen. The multidrug resistance-related drugs inhibited [H-3]tamoxifen aziridine binding with vinblastine > vincristine > doxorubicin > actinomycin D, while colchicine enhanced the binding. Moreover, the multidrug resistance modulators verapamil, nicardipine, diltiazem, prenylamine, cyclosporin A, FK506, dibucaine, reserpine, monensin and progesterone were all potent inhibitors of [H-3]tamoxifen aziridine binding to P-glycoprotein. Our data provide the first evidence that [H-3]tamoxifen aziridine directly binds to P-glycoprotein and interacts with the binding sites for multidrug resistance-related drugs and modulators. (C) 1994 Academic Press, Inc.