Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
|
| pubmed:dateCreated |
1990-4-9
|
| pubmed:abstractText |
P-glycoprotein is a 130-180-kDa integral membrane protein that is overproduced in multidrug-resistant cells. The protein appears to act as an energy-dependent drug efflux pump that has broad specificity for structurally diverse hydrophobic antitumor drugs. Many agents, such as the calcium channel blocker verapamil, reverse multidrug resistance and also interact with P-glycoprotein. The goal of this work was to determine if a common binding site participates in the transport of antitumor drugs and/or the reversal of drug resistance. This was done by comparing the peptide maps of P-glycoprotein (encoded by mdr1b) after it was labeled with a photoactive calcium channel blocker, [3H]azidopine, and a newly identified photoaffinity analog for P-glycoprotein 2-[4-(4-azido-3-[125I]iodobenzoyl) piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline [( 125I]iodoaryl azidoprazosin). [125I] Iodoaryl azidoprazosin, which classically has been used to identify the alpha 1-adrenergic receptor, bound to P-glycoprotein and was preferentially competed by vinblastine greater than actinomycin D greater than doxorubicin greater than colchicine. Peptide maps derived from P-glycoprotein labeled with [3H]azidopine or [125I]iodoaryl azidoprazosin were identical. After maximal digestion under conditions for Cleveland mapping, a single major 6-kDa fragment was obtained after digestion with V8 protease, whereas two major fragments, 6.5 and 5.5 kDa, were detected after digestion with chymotrypsin. The 6.0-kDa V8 fragment and the 6.5-kDa chymotrypsin fragment were both found when P-glycoprotein encoded by mdr1a and mdr1b was compared. Despite its specific interaction with P-glycoprotein, neither iodoaryl azidoprazosin nor prazosin markedly reversed resistance compared with verapamil or azidopine. Further, multidrug-resistant cells were 900-fold resistant to vinblastine but only 5-fold resistant to prazosin. These data demonstrate that structurally diverse reversal and/or antitumor agents are likely to have differential affinity for a small common domain of P-glycoprotein.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Affinity Labels,
http://linkedlifedata.com/resource/pubmed/chemical/Azides,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Chymotrypsin,
http://linkedlifedata.com/resource/pubmed/chemical/Dihydropyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/P-Glycoprotein,
http://linkedlifedata.com/resource/pubmed/chemical/Prazosin,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, alpha,
http://linkedlifedata.com/resource/pubmed/chemical/Verapamil,
http://linkedlifedata.com/resource/pubmed/chemical/azidopine,
http://linkedlifedata.com/resource/pubmed/chemical/azidoprazosin
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Mar
|
| pubmed:issn |
0021-9258
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
15
|
| pubmed:volume |
265
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4394-401
|
| pubmed:dateRevised |
2007-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:1968459-Affinity Labels,
pubmed-meshheading:1968459-Animals,
pubmed-meshheading:1968459-Azides,
pubmed-meshheading:1968459-Binding, Competitive,
pubmed-meshheading:1968459-Binding Sites,
pubmed-meshheading:1968459-Calcium Channels,
pubmed-meshheading:1968459-Cell Line,
pubmed-meshheading:1968459-Cell Membrane,
pubmed-meshheading:1968459-Chymotrypsin,
pubmed-meshheading:1968459-Dihydropyridines,
pubmed-meshheading:1968459-Drug Resistance,
pubmed-meshheading:1968459-Macrophages,
pubmed-meshheading:1968459-Membrane Glycoproteins,
pubmed-meshheading:1968459-Mice,
pubmed-meshheading:1968459-P-Glycoprotein,
pubmed-meshheading:1968459-Peptide Mapping,
pubmed-meshheading:1968459-Prazosin,
pubmed-meshheading:1968459-Receptors, Adrenergic, alpha,
pubmed-meshheading:1968459-Sequence Homology, Nucleic Acid,
pubmed-meshheading:1968459-Verapamil
|
| pubmed:year |
1990
|
| pubmed:articleTitle |
Photoaffinity probes for the alpha 1-adrenergic receptor and the calcium channel bind to a common domain in P-glycoprotein.
|
| pubmed:affiliation |
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461-1602.
|
| pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|