(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1

Thomas Perrotton, Doriane Trompier, Xiu-Bao D Chang, Attilio Di Pietro, Hélène Baubichon-Cortay

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Abstract

The multidrug-resistant protein MRP1 (involved in the cancer cell multidrug resistance phenotype) has been found to be modulated by racemic verapamil (through stimulation of glutathione transport), inducing apoptosis of human MRP1 cDNA-transfected baby hamster kidney 21 (BHK-21) cells and not of control BHK-21 cells. In this study, we show that the two enantiomers of verapamil have different effects on MRP1 activity. Only the S-isomer (not the R-isomer) potently induced the death of MRP1-transfected BHK-21 cells. The decrease in cellular glutathione content induced by the S-isomer, which was not observed with the R-isomer, was stronger than that induced by the racemic mixture, indicating that the R-isomer antagonized the S-isomer effect. Both enantiomers altered leukotriene C4 and calcein transport by MRP1. Thus, the R-isomer behaved as an inhibitor, which was confirmed by its ability to revert the multidrug resistance phenotype toward vincristine. Molecular studies on purified MRP1 using fluorescence spectroscopy showed that both enantiomers bound to MRP1 with high affinity, with the binding being prevented by glutathione. Furthermore, conformational changes induced by the two enantiomers (monitored by sodium iodide accessibility of MRP1 tryptophan residues) were quite different, correlating with their distinct effects. (S)-Verapamil induces the death of potentially resistant tumor cells, whereas (R)-verapamil sensitizes MRP1-overexpressing cells to chemotherapeutics. These results might be of great potential interest in the design of new compounds able to modulate MRP1 in chemotherapy.

Original languageEnglish (US)
Pages (from-to)31542-31548
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number43
DOIs
StatePublished - Oct 26 2007

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Verapamil
Isomers
Enantiomers
Cricetinae
Glutathione
Proteins
Multiple Drug Resistance
Kidney
Sodium Iodide
Phenotype
Leukotriene C4
Cells
Fluorescence Spectrometry
Vincristine
Chemotherapy
Tryptophan
Fluorescence spectroscopy
Neoplasms
Complementary DNA
Tumors

ASJC Scopus subject areas

  • Biochemistry

Cite this

Perrotton, T., Trompier, D., Chang, X-B. D., Di Pietro, A., & Baubichon-Cortay, H. (2007). (R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1. Journal of Biological Chemistry, 282(43), 31542-31548. https://doi.org/10.1074/jbc.M703964200

(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1. / Perrotton, Thomas; Trompier, Doriane; Chang, Xiu-Bao D; Di Pietro, Attilio; Baubichon-Cortay, Hélène.

In: Journal of Biological Chemistry, Vol. 282, No. 43, 26.10.2007, p. 31542-31548.

Research output: Contribution to journalArticle

Perrotton, T, Trompier, D, Chang, X-BD, Di Pietro, A & Baubichon-Cortay, H 2007, '(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1', Journal of Biological Chemistry, vol. 282, no. 43, pp. 31542-31548. https://doi.org/10.1074/jbc.M703964200
Perrotton T, Trompier D, Chang X-BD, Di Pietro A, Baubichon-Cortay H. (R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1. Journal of Biological Chemistry. 2007 Oct 26;282(43):31542-31548. https://doi.org/10.1074/jbc.M703964200
Perrotton, Thomas ; Trompier, Doriane ; Chang, Xiu-Bao D ; Di Pietro, Attilio ; Baubichon-Cortay, Hélène. / (R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 43. pp. 31542-31548.
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