Document Detail

Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2.
MedLine Citation:
PMID:  23034939     Owner:  NLM     Status:  MEDLINE    
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 described recently (Kido Y, Matsson P, Giacomini KM. J Med Chem 54: 4548-4558, 2011), we determined the kinetic basis of their inhibition of 1-methyl-4-phenylpyridinium (MPP) transport into Chinese hamster ovary cells that stably expressed hOCT2. The "cluster II" inhibitors (which contain 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 whether 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 CCF, 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.
Jaclyn N Harper; Stephen H Wright
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-03
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  304     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-04-03     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F56-67     Citation Subset:  IM    
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MeSH Terms
1-Methyl-4-phenylpyridinium / metabolism*
Androstenes / pharmacology
Benzhydryl Compounds / metabolism
CHO Cells
Carbazoles / pharmacology
Cimetidine / metabolism
Inhibitory Concentration 50
Metformin / metabolism
Organic Cation Transport Proteins / antagonists & inhibitors,  metabolism*
Piperidines / metabolism
Propanolamines / pharmacology
Tetraethylammonium / metabolism
Grant Support
Reg. No./Substance:
0/Androstenes; 0/Benzhydryl Compounds; 0/Carbazoles; 0/Ligands; 0/Organic Cation Transport Proteins; 0/Piperidines; 0/Propanolamines; 0/SLC22A2 protein, human; 0K47UL67F2/carvedilol; 66-40-0/Tetraethylammonium; 80061L1WGD/Cimetidine; 9100L32L2N/Metformin; AE4E9102GY/adrenosterone; K65LB6598J/phenyltoloxamine; NQO8R319LY/diphenidol; R865A5OY8J/1-Methyl-4-phenylpyridinium

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