rdf:type |
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lifeskim:mentions |
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pubmed:dateCreated |
1996-9-12
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pubmed:abstractText |
P-glycoprotein (P-gp) is a membranous ATPase responsible for the multidrug resistance (MDR) phenotype. Using membrane vesicles prepared from the highly resistant cell line DC-3F/ADX we studied the influence of P-gp ATPase activity of four progesterone derivatives which specifically bind to P-gp and reverse MDR. Progesterone and desoxycorticosterone stimulate P-gp ATPase activity with, respectively, apparent concentrations giving half-maximal activation of 20-25 microM and 40-50 microM, and activation factors of 2.3 (at 100 microM progesterone) and 1.8 (at 170 microM desoxycorticosterone). Hydrocortisone above 100 microM stimulates P-gp ATPase activity while corticosterone has no apparent stimulating effect. Our data are consistent with the location of the binding sites for the progesterone derivatives on the P-gp membranous domain. The effects of these steroids on verapamil-stimulated P-gp ATPase activity support a non-competitive mechanism, i.e. the binding sites for verapamil and steroids are mutually non-exclusive for P-gp ATPase modulation. A similar non-competitive inhibition of progesterone-stimulated P-gp ATPase activity by desoxycorticosterone or by corticosterone leads to the conclusion that these steroids, although sharing related structures, have distinct modulating sites on P-gp. As expected from their mutually non-exclusive interactions on P-gp, progesterone and verapamil when mixed induce a synergistic modulation of P-gp ATPase activity. Since drug transport by P-gp is believed to be coupled to its ATPase activity, a corresponding synergistic effect of these two modulators for the inhibition of P-gp-mediated drug resistance can be expected.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
|
pubmed:citationSubset |
IM
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pubmed:chemical |
|
pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0264-6021
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pubmed:author |
|
pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
317 ( Pt 2)
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
515-22
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:8713080-Adenosine Triphosphatases,
pubmed-meshheading:8713080-Adenosine Triphosphate,
pubmed-meshheading:8713080-Animals,
pubmed-meshheading:8713080-Cell Line,
pubmed-meshheading:8713080-Corticosterone,
pubmed-meshheading:8713080-Cricetinae,
pubmed-meshheading:8713080-Cricetulus,
pubmed-meshheading:8713080-Desoxycorticosterone,
pubmed-meshheading:8713080-Dose-Response Relationship, Drug,
pubmed-meshheading:8713080-Drug Resistance, Multiple,
pubmed-meshheading:8713080-Drug Synergism,
pubmed-meshheading:8713080-Hydrolysis,
pubmed-meshheading:8713080-P-Glycoprotein,
pubmed-meshheading:8713080-Progesterone,
pubmed-meshheading:8713080-Steroids,
pubmed-meshheading:8713080-Verapamil
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pubmed:year |
1996
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pubmed:articleTitle |
Effects of steroids and verapamil on P-glycoprotein ATPase activity: progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators.
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pubmed:affiliation |
Section de Biophysique des Protéines et des Membranes, DBCM, CEA, Gif/Yvette, France.
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pubmed:publicationType |
Journal Article,
Comparative Study
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