The emergence of multidrug resistance is a serious medical problem that has significantly affected the treatment of tumor cells and infectious diseases. This multidrug resistance phenotype is mediated by the action of a large family of membrane proteins that act as active transporters or energy driven efflux pumps in both of prokaryotic and eukaryotic cells. Most eukaryotic multidrug efflux pumps belong to the ATP binding cassette (ABC) family of transport proteins that include P-glycoprotein (P-gp1), Multidrug Resistance Associated Protein (MRP1), and Breast Cancer Resistance Protein (BCRP). In prokaryotic cells, Lactococcus lactis LmrA, a homolog of P-gp1, mediates drug resistance to antibiotics and cytotoxic drugs. The transport function of these proteins is facilitated by the hydrolysis of ATP. However, the mechanism by which these proteins bind to, and are able to transport structurally dissimilar drugs across the cell membrane remains poorly understood. In this thesis we have attempted to characterize the interactions of various ABC transporters (MRP1, BCRP, and LmrA) with structurally diverse drugs, using a well characterized photoreactive drug analogue of Rhodamine 123, [125I] iodoaryl azido-rhodamine 123 (IAARh123). In the case of MRP1 interaction with Rhodamine 123, it was of interest to determine the nature of MRP1 drug interactions. In that study, our results show that CHAPS (1-[(3-cholamidopropyl) dimethylamino]-1-propansulfate) and Brij35 inhibited the photolabeling of MRP1 with IAARh123, and this interaction occurred outside the lipid bilayer. These results were unexpected in light of previous results with another ABC transporter which also binds to Rhodamine 123. Consequently, we show that non-toxic concentrations of CHAPS and Brij35 potentiate the toxicity of two MRP1 substrates, vincristine and etoposide (VP16). In the second chapter, we have used IAARh123 to demonstrate for the first time that the BCRP mediates drug resi
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84460 |
| Date | January 2003 |
| Creators | Alqawi, Omar |
| Contributors | Georges, Elias (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Institute of Parasitology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002084296, proquestno: AAINQ98193, Theses scanned by UMI/ProQuest. |
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