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Vol. 58, Issue 3, 624-632, September 2000
Department of Clinical Laboratory Sciences, John Radcliffe
Hospital, University of Oxford, United Kingdom (C.M., G.B., R.C.); MRC
Clinical Sciences Centre, Imperial College School of Medicine,
Hammersmith Hospital, London, United Kingdom (C.F.H.); and Xenova
Limited, Slough, United Kingdom (P.M., P.C.).
P-glycoprotein, a member of the ATP-binding cassette transporter
family, is able to confer resistance on tumors against a large number
of functionally and chemically distinct cytotoxic compounds. Several
recent investigations suggest that P-glycoprotein contains multiple
drug binding sites rather than a single site of broad substrate
specificity. In the present study, radioligand-binding techniques were
used to directly characterize drug interaction sites on P-glycoprotein
and how these multiple sites interact. The drugs used were classified
as either 1) substrates, which are known to be transported by
P-glycoprotein (e.g., vinblastine) or 2) modulators, which alter
P-glycoprotein function but are not themselves transported by the
protein (e.g., XR9576). Drug interactions with P-glycoprotein were
either competitive, at a common site, or noncompetitive, and therefore
at distinct sites. Based on these data, we can assign a minimum of four
drug binding sites on P-glycoprotein. These sites fall into two
categories: transport, at which translocation of drug across the
membrane can occur, and regulatory sites, which modify P-glycoprotein
function. Intriguingly, however, some modulators interact with
P-glycoprotein at a transport site rather than a regulatory site. The
pharmacological data also demonstrate that both transport and
regulatory sites are able to switch between high- and low-affinity
conformations. The multiple sites on P-glycoprotein display complex
allosteric interactions through which interaction of drug at one site
switches other sites between high- or low-affinity conformations. The
data are discussed in terms of a model for the mechanism of transport by P-glycoprotein.
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