Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors.
Article Details
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Wang EJ, Casciano CN, Clement RP, Johnson WW
Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors.
Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5.
- PubMed ID
- 11716514 [ View in PubMed]
- Abstract
With P-glycoprotein (P-gp) continuing to have prominence among the ABC transporters for its ability to remove various xenobiotics from many cell types, accurate and robust methods for estimating the exposure of drug, carcinogen, toxicant, pesticide, and even some endobiotics to tissues and cells affected by P-gp are valuable. The inhibition of P-gp active transport of molecules, therefore, has often been quantified by concentration dependence of inhibitor effect on fluorescent substrate marker efflux mediated by this enzyme, with much evidence indicating two asymmetric yet interdependent substrate binding sites on P-gp. A uniqueness in the pair of binding sites could result in distinct effects of an inhibitor on the transport of certain substrates, thus leading to differences in fluorescent substrate responsiveness or sensitivity. Seven different fluorescent substrates of P-gp were quantitatively tested for their responsiveness to inhibition by a wide range of P-gp substrates/inhibitors. Interesting differences were observed in the IC(50) values caused by each of the inhibitors employed, in part exemplified by DNR and LDS being generally more sensitive to inhibition effects than any other fluorescent marker. However, no clear trend emerged to designate any fluorochrome marker as the most or least responsive to inhibition. Furthermore, LDS is more sensitive to some P-gp inhibitors than the substrate marker DNR, generally the most responsive. These results support the assertion of two unequal substrate binding sites that are allosterically dependent on each other. Therefore, an inhibitor that favors binding to the site opposite from that favored by a particular marker may have significant transduced effects through the protein between the two binding sites. Nevertheless, although either DNR or LDS is generally the fluorescent substrate most responsive to inhibition, there may be other substrates yet even more sensitive.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Carvedilol P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Clarithromycin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Colforsin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Dipyridamole P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Felodipine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Fluphenazine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Indomethacin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Itraconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Ketoconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Lovastatin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Nicardipine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Paclitaxel P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Progesterone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Quinidine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Quinine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Reserpine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Simvastatin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Terfenadine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Trifluoperazine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Troleandomycin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Vinblastine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails - Binding Properties