| Multiple Mechanisms of Ligand Interaction with the Human Organic Cation Transporter, OCT2. | |
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MedLine Citation:
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PMID: 23034939 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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OCT2 is the entry step for organic cation (OC) 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 recently described by Kido et al. (24), 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 (which contains known OCT2 substrates), 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 (i.e., decreasing J(max) and increasing K(t)). A Cluster III (neutral steroid) representative, adrenosterone, and a Cluster I (large, flexible cation) representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive Counterflow (CCF) was used to determine if the inhibitory ligands served as substrates of hOCT2. Carvedilol (Cluster I) and adrenosterone (Cluster III) did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. The Cluster II representatives MPP, metformin, cimetidine and TEA all supported CED, consistent with independent assessments of their OCT2-mediated transport. However, the other Cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. An independent assessment of diphenidol transport (using liquid chromatography with tandem mass spectroscopy) confirmed this observation. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters. |
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Authors:
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Jaclyn N Harper; Stephen H Wright |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-10-3 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: - ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2012 Oct |
Date Detail:
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Created Date: 2012-10-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1University of Arizona. |
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