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Volume 272, Number 10, Issue of March 7, 1997 pp. 6647-6652
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Molecular Interactions of Cyclosporin A with P-glycoprotein
PHOTOLABELING WITH CYCLOSPORIN DERIVATIVES

(Received for publication, September 4, 1996, and in revised form, November 19, 1996)

Michel Demeule , Roland M. Wenger ^§ and Richard Béliveau

From the  Laboratoire d'Oncologie Moléculaire, Département de Chimie-biochimie, Université du Québec-Hopital Ste-Justine, Montréal, Québec H3C 3P8, Canada and ^§ Sandoz Pharma Ltd., CH-4002 Basel, Switzerland

The interaction between P-glycoprotein (140-180 kDa) from the multidrug-resistant Chinese hamster ovary cell line CH^RC5 and cyclosporin A was characterized using three different photoactivable cyclosporin A analogs. Two monoclonal antibodies, which are able to discriminate between two major domains of cyclosporin A (the cyclophilin and calcineurin binding domains), were used to detect the photolabeled proteins. A protein of 155 kDa corresponding to P-glycoprotein was much more strongly photolabeled in membranes of CH^RC5 cells than in membranes of their drug-sensitive parent cell line AuxB1. The antitumor drug vinblastine and the reversal agents verapamil and cyclosporin A inhibited the photolabeling, and the nonimmunosuppressive derivative PSC-833 caused a stronger inhibition than cyclosporin A. P-glycoprotein photolabeled with cyclosporin A analogs was only detected with the monoclonal antibody that recognizes cyclosporin A and its metabolites, indicating that the calcineurin binding domain recognized specifically by the other antibody is not exposed. These results suggest that the portion of cyclosporin A that binds to calcineurin plays a role in the interaction of cyclosporin A with P-glycoprotein.

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