Tamoxifen Aziridine, a Novel Affinity Probe for P-Glycoprotein in Multidrug-Resistant Cells

Ahmad Safa, S. Roberts, M. Agresti, R. L. Fine

Research output: Contribution to journalArticle

29 Citations (Scopus)

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

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P-Glycoprotein
Multiple Drug Resistance
Tamoxifen
Modulators
Prenylamine
Dibucaine
Nicardipine
Monensin
Vinblastine
Diltiazem
Reserpine
Colchicine
Dactinomycin
Tacrolimus
Vincristine
Metabolites
Verapamil
Pharmaceutical Preparations
Doxorubicin
Cyclosporine

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

Cite this

Tamoxifen Aziridine, a Novel Affinity Probe for P-Glycoprotein in Multidrug-Resistant Cells. / Safa, Ahmad; Roberts, S.; Agresti, M.; Fine, R. L.

In: Biochemical and Biophysical Research Communications, Vol. 202, No. 1, 15.07.1994, p. 606-612.

Research output: Contribution to journalArticle

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