Multiple Mechanisms of Ligand Interaction with the Human Organic Cation Transporter, OCT2

Persistent Link:
http://hdl.handle.net/10150/297644
Title:
Multiple Mechanisms of Ligand Interaction with the Human Organic Cation Transporter, OCT2
Author:
Harper, Jaclyn Nicole
Issue Date:
2013
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.
Abstract:
OCT2 is the entry step for organic cation secretion by renal proximal tubules. Although many drugs inhibit OCT2 activity, neither the mechanistic basis of their inhibition nor their transport status is generally known. Using representatives of several structural classes of OCT2 inhibitory ligands described by Kido et al, we determined the kinetic basis of their inhibition of 1-methyl-4- phenylpyridinium (MPP) transport into CHO cells that stably expressed hOCT2. The 'Cluster II' inhibitors, metformin and cimetidine, interacted competitively with MPP. However, other Cluster II compounds, including tetraethylammonium (TEA), diphenidol and phenyltoloxamine, were mixed-type inhibitors of MPP transport. Cluster III representative, adrenosterone, and Cluster I representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive Counterflow (CCF) was used to determine if the inhibitory ligands served as substrates of hOCT2. Carvedilol and adrenosterone did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. Cluster II representatives MPP, metformin, cimetidine and TEA all supported CCF, consistent with independent assessments of their OCT2-mediated transport. Other Cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters.
Type:
text; Electronic Thesis
Degree Name:
B.S.H.S.
Degree Level:
bachelors
Degree Program:
Honors College; Physiology
Degree Grantor:
University of Arizona
Advisor:
Wright, Stephen

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleMultiple Mechanisms of Ligand Interaction with the Human Organic Cation Transporter, OCT2en_US
dc.creatorHarper, Jaclyn Nicoleen_US
dc.contributor.authorHarper, Jaclyn Nicoleen_US
dc.date.issued2013-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © 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.en_US
dc.description.abstractOCT2 is the entry step for organic cation secretion by renal proximal tubules. Although many drugs inhibit OCT2 activity, neither the mechanistic basis of their inhibition nor their transport status is generally known. Using representatives of several structural classes of OCT2 inhibitory ligands described by Kido et al, we determined the kinetic basis of their inhibition of 1-methyl-4- phenylpyridinium (MPP) transport into CHO cells that stably expressed hOCT2. The 'Cluster II' inhibitors, metformin and cimetidine, interacted competitively with MPP. However, other Cluster II compounds, including tetraethylammonium (TEA), diphenidol and phenyltoloxamine, were mixed-type inhibitors of MPP transport. Cluster III representative, adrenosterone, and Cluster I representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive Counterflow (CCF) was used to determine if the inhibitory ligands served as substrates of hOCT2. Carvedilol and adrenosterone did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. Cluster II representatives MPP, metformin, cimetidine and TEA all supported CCF, consistent with independent assessments of their OCT2-mediated transport. Other Cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters.en_US
dc.typetexten_US
dc.typeElectronic Thesisen_US
thesis.degree.nameB.S.H.S.en_US
thesis.degree.levelbachelorsen_US
thesis.degree.disciplineHonors Collegeen_US
thesis.degree.disciplinePhysiologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorWright, Stephen-
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