Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug-resistant cells

Ahmad R. Safa, Scott Roberts, Michael Agresti, Robert L. Fine

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)606-612
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume202
Issue number1
DOIs
StatePublished - Jul 15 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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