1. Inhibition of P-glycoprotein by cyclosporin A analogues and metabolites
- Author
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Edith Beaulieu, Roland Wenger, Arash Sepehr-Araé, Diana A. Averill-Bates, Richard Béliveau, Alain Laplante, and Michel Demeule
- Subjects
Time Factors ,Cyclosporins ,CHO Cells ,Endosomes ,Photoaffinity Labels ,Vinblastine ,Biochemistry ,Adenosine Triphosphate ,Cricetinae ,Cyclosporin a ,Animals ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Molecular Biology ,Cells, Cultured ,P-glycoprotein ,Dose-Response Relationship, Drug ,biology ,Chemistry ,Chinese hamster ovary cell ,Cell Membrane ,Cell Biology ,Membrane ,Models, Chemical ,Verapamil ,Cyclosporine ,biology.protein - Abstract
The interaction between P-glycoprotein (P-gp) from membranes isolated from multidrug-resistant Chinese hamster ovary cells and cyclosporin A (CsA) analogues and its metabolites was characterized. Screening of these latter as chemosensitizers was performed using three different assays: (i) vinblastine uptake, (ii) photoaffinity labeling by [125I]iodoaryl azidoprazosin, and (iii) P-gp ATPase activity. Oxidation of the hydroxyl group at position 1 of CsA (200-096), CsG (215-834), or CsD (PSC-833) increased their inhibition of P-gp. CsA analogues (208-032, 208-183) modified at position 11 retained their ability to inhibit P-gp while analogues modified at position 2 (CsC and CsD) lost their efficiency. The inhibitions induced by metabolites of CsA were also compared to those obtained with CsG metabolites. From all the molecules tested, PSC-833 and 280-446 peptolide were the strongest inhibitors. Our results indicate that modifications of CsA analogues at position 1 and 2 are critical for their interaction with P-gp and that CsA metabolites retain a portion of the inhibitory activity of the parent drug.Key words: P-glycoprotein, cyclosporin A, vinblastine uptake, photolabeling, ATPase activity.
- Published
- 1999
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