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    Multidrug And Toxin Extrusion's (MATE) Role in Renal Organic Cation Secretion

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    Author
    Astorga, Bethzaida
    Issue Date
    2011
    Keywords
    Pharmacophore
    Renal Organic Cation Secretion
    Physiological Sciences
    Cellular Membrane Transport
    Organic Cation
    Advisor
    Wright, Stephen H.
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Embargo: Release after 06/02/2012
    Abstract
    Organic cations (OCs) make up ~40% of all prescribed drugs and renal secretion plays a major role in clearing these (and other OCs), from the plasma. The active and rate-limiting step of renal OC secretion is mediated by luminal OC/H+ exchange, the molecular basis of which is suspected to involve two homologous transport proteins, Multidrug And Toxin Extruders 1&2-K (MATE1 and MATE2-K). This study has two aims to resolve outstanding issues dealing with the mechanism of MATE-mediated OC transport: (Aim 1) develop predictive models of ligand interaction with hMATE1; (Aim 2) establish the kinetic mechanism(s) of ligand interaction with MATE transporters and the extent to which inhibitory ligands serve as transported substrates of MATE transporters. Transport was measured using human MATE1 and MATE2-K stably expressed in Chinese Hamster Ovary cells. Both MATEs had similar affinities for the prototypic OC substrate, 1-methyl-4-phenylpyridinium (MPP), and had overlapping selectivity for most of the test inhibitors. The IC50 values for 59 structurally diverse inhibitory ligands were used to generate a common features (HIPHOP) pharmacophore and three quantitative pharmacophores for hMATE1 (each displaying a significant correlation between predicted and measured IC50 values). The models identified (i) structural features that influence ligand interaction with hMATE1, including hydrophobic regions, H-bond donor and acceptor sites and an ionizable feature; and (ii) novel high affinity inhibitors of MATE-mediated transport from 13 new drug classes. Whereas metformin and creatinine were shown to be competitive inhibitors of MPP, the inhibition of MATE1-mediated MPP transport produced by pyrimethamine (PYR) and related analogs was not competitive but, instead, had a "linear, mixed-type" inhibitory profile suggestive of a MATE binding surface rather than a singular binding site. "Competitive exchange diffusion" showed that selected inhibitory ligands (including quinidine, caffeine, and the organic anion, PAH) also serve as transported substrates for MATE1. In conclusion, these data are consistent with the presence of a MATE binding surface with multiple, non-overlapping binding sites that can display different kinetic interactions with structurally distinct substrates. The creation of hMATE1 pharmacophores offers insight into development and interpretation of predictive models of drug-drug interaction in the kidney.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Physiological Sciences
    Degree Grantor
    University of Arizona
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    Dissertations

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