Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein mediated drug transport may lead to a multidrug resistance phenotype often associated with a poor response to the successful treatment of a variety of human disorders. Several agents have been found to modulate P-glycoprotein drug resistance, most probably by blocking its transport function. The aim of this study was to examine the effects of some benzodiazepines (bromazepam, chlordiazepoxide, diazepam and flurazepam) able to bind to P-glycoprotein in proteoliposomes on its transport function and ATPase activity in the human cancer cell line, KB-V1. The toxicity of the benzodiazepines drugs towards KB-V1 cells was first evaluated and the non toxic drugs concentrations were used to assess the drug efflux and the ATPase activity. Using the flow cytometry approach, the accumulation and efflux of daunorubicin were followed by measuring the daunorubicin associated geometric mean fluorescence intensity. Vanadate was employed as a comparative inhibitory compound. Flurazepam was able to inhibit the daunorubicin efflux in 80%. ATPase activity determined by a colorimetric assay revealed that flurazepam inhibits the P-glycoprotein enzymatic activity, indicating coupling between drug transport and ATP hydrolysis. Bromazepam, chlordiazepoxide and diazepam behaved as activators of the P-glycoprotein ATPase activity, suggesting a role as transported substrates and did not interfere in the daunorubicin transport.
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PMID:Flurazepam inhibits the P-glycoprotein transport function: an insight to revert multidrug-resistance phenotype. 1819 Sep 7

P-glycoprotein expressed in Pichia pastoris was used to study the drug binding sites of different benzodiazepines. The effect of bromazepam, chlordiazepoxide, diazepam and flurazepam on P-glycoprotein structure was investigated by measuring the intrinsic fluorescence of the transporter tryptophan residues. Purified mouse mdr1a transporter in mixed micelles of 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonic acid and 1,2-dimiristoyl-sn-glycerol-3-phosphocholine emitted fluorescence at 340 nm indicative of the fluorophores in a relatively apolar environment. Acrylamide and iodide ion were used as collisional quenchers toward distinct regions of the transporter, the protein and the interface protein-surface, respectively. Binding of ATP induced conformational changes at the protein surface level in accordance with the location of the nucleotide binding sites. Bromazepam interaction with the transporter was located at the protein-surface interface, diazepam at the membrane region and chlordiazepoxide at the protein surface. Only the flurazepam interaction site was not detected by the quenchers used. All benzodiazepines were able to elicit reorientation of the protein fluorophores on the P-glycoprotein-ATP complex.
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PMID:Benzodiazepine-mediated structural changes in the multidrug transporter P-glycoprotein: an intrinsic fluorescence quenching analysis. 1879 34