PMID: 9432000Feb 7, 1998Paper

Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities

European Journal of Biochemistry
A B Shapiro, V Ling

Abstract

In this paper, we show that P-glycoprotein contains two distinct sites for drug binding and transport, and that, unexpectedly, these sites interact in a positively cooperative manner. The kinetics of transport of rhodamine 123 and Hoechst 33342 in isolated P-glycoprotein-rich plasma membrane vesicles from Chinese hamster ovary CH(R)B30 cells were followed by continuous fluorescence monitoring. Each substrate stimulated P-glycoprotein-mediated transport of the other. Colchicine and quercetin stimulated rhodamine 123 transport and inhibited Hoechst 33342 transport. In contrast, anthracyclines such as daunorubicin and doxorubicin stimulated Hoechst 33342 transport and inhibited rhodamine 123 transport. Vinblastine, actinomycin D, and etoposide inhibited transport of both dyes. The results are consistent with a functional model of P-glycoprotein containing at least two positively cooperative sites (H site and R site) for drug binding and transport. This model is consistent with earlier observations of competitive and non-competitive effects of P-glycoprotein substrates and chemosensitizers. Such a two-site model may be fundamental to multidrug transport by P-glycoprotein, and it may be a feature common to other ATP-dependent transp...Continue Reading

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Citations

Jul 25, 2006·Pflügers Archiv : European journal of physiology·Jonathan A Sheps, Victor Ling
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May 13, 2006·Journal of Bioenergetics and Biomembranes·Frances J SharomPaul D W Eckford
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