title: Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug resistant cells.
abstract: In this study for the first time we used an electrophilic analog of tamoxifen, [3H]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 [3H]tamoxifen aziridine binding to P-glycoprotein with 4-hydroxytamoxifen > tamoxifen > N-desmethyltamoxifen. The multidrug resistance-related drugs inhibited [3H]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 [3H]tamoxifen aziridine binding to P-glycoprotein. Our data provide the first evidence that [3H]tamoxifen aziridine directly binds to P-glycoprotein and interacts with the binding sites for multidrug resistance-related drugs and modulators.
authors.affiliation: Department of Medicine, University of Chicago, IL 60637.
authors.forename: A R
authors.initials: AR
authors.lastname: Safa
authors.forename: S
authors.initials: S
authors.lastname: Roberts
authors.forename: M
authors.initials: M
authors.lastname: Agresti
authors.forename: R L
authors.initials: RL
authors.lastname: Fine
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000302:isolation & purification / Q000378:metabolism*; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D007700:Kinetics; D008168:Lung; D008562:Membrane Glycoproteins / Q000302:isolation & purification / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D013629:Tamoxifen; D014316:Tritium; D003609:Dactinomycin; D014750:Vincristine; D014747:Vinblastine; C031859:tamoxifen aziridine; D004317:Doxorubicin; D003078:Colchicine