Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules

2000 ◽  
Vol 114 (3) ◽  
pp. 175-180 ◽  
Author(s):  
Minako Sugawara-Yokoo ◽  
Yumiko Urakami ◽  
Haruko Koyama ◽  
Keiko Fujikura ◽  
Satohiro Masuda ◽  
...  
Keyword(s):  
Organic Cation ◽  
Rat Kidney ◽  
Basolateral Membrane ◽  
Proximal Tubules ◽  
Organic Cation Transporters ◽  
Differential Localization ◽  
Cation Transporters ◽  
Kidney Proximal Tubules

Localization of organic cation transporters OCT1 and OCT2 in rat kidney

2000 ◽  
Vol 279 (4) ◽  
pp. F679-F687 ◽  
Author(s):  
Ulrich Karbach ◽  
Jörn Kricke ◽  
Friederike Meyer-Wentrup ◽  
Valentin Gorboulev ◽  
Christopher Volk ◽  
...  
Keyword(s):  
Organic Cation ◽  
Renal Excretion ◽  
Rat Kidney ◽  
Proximal Tubules ◽  
Organic Cation Transporters ◽  
Cation Uptake ◽  
Cation Transporters ◽  
Renal Expression ◽  
Lower Expression

Renal excretion and reabsorption of organic cations are mediated by electrogenic and electroneutral organic cation transporters, which belong to a recently discovered family of polyspecific transporters. These transporters are electrogenic and exhibit differences in substrate specificity. In rat, the renal expression of the polyspecific cation transporters rOCT1 and rOCT2 was investigated. By in situ hybridization, significant amounts of both rOCT1 and rOCT2 mRNA were detected in S1, S2, and S3 segments of proximal tubules. By immunohistochemistry, expression of the rOCT1 protein was mainly observed in S1 and S2 segments of proximal tubules, with lower expression levels in the S3 segments. At variance, rOCT2 protein was mainly expressed in the S2 and S3 segments. Both transporters were localized to the basolateral cell membrane. Neither rOCT1 nor rOCT2 was detected in the vasculature, the glomeruli, and nephron segments other than proximal tubules. The data suggest that rOCT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.

scholarly journals Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

2003 ◽  
Vol 23 (21) ◽  
pp. 7902-7908 ◽  
Author(s):  
Johan W. Jonker ◽  
Els Wagenaar ◽  
Sven van Eijl ◽  
Alfred H. Schinkel
Keyword(s):  
Organic Cation ◽  
Basolateral Membrane ◽  
Hepatic Uptake ◽  
The Body ◽  
Organic Cations ◽  
Organic Cation Transporters ◽  
Renal Secretion ◽  
Double Knockout ◽  
Intestinal Excretion ◽  
Cation Transporters

ABSTRACT The polyspecific organic cation transporters 1 and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1 −/− mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2 −/− and Oct1/2 −/− mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2 −/− mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2 −/− mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.

scholarly journals Human Organic Cation Transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as Disposition Pathways for Fluoroquinolone Antimicrobials

2013 ◽  
Vol 57 (6) ◽  
pp. 2705-2711 ◽  
Author(s):  
Aditi Mulgaonkar ◽  
Jürgen Venitz ◽  
Dirk Gründemann ◽  
Douglas H. Sweet
Keyword(s):  
Proximal Tubule ◽  
Antimicrobial Agents ◽  
Organic Cation ◽  
Biological Fluids ◽  
Basolateral Membrane ◽  
Organic Cation Transporters ◽  
Proximal Tubule Cells ◽  
Wide Range ◽  
Tubule Cells ◽  
Cation Transporters

ABSTRACTFluoroquinolones (FQs) are important antimicrobials that exhibit activity against a wide range of bacterial pathogens and excellent tissue permeation. They exist as charged molecules in biological fluids, and thus, their disposition depends heavily on active transport and facilitative diffusion. A recent review of the clinical literature indicated that tubular secretion and reabsorption are major determinants of their half-life in plasma, efficacy, and drug-drug interactions. In particular, reportedin vivointeractions between FQs and cationic drugs affecting renal clearance implicated organic cation transporters (OCTs). In this study, 13 FQs, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, and sparfloxacin, were screened for their ability to inhibit transport activity of human OCT1 (hOCT1) (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). All, with the exception of enoxacin, significantly inhibited hOCT1-mediated uptake under initial test conditions. None of the FQs inhibited hOCT2, and only moxifloxacin inhibited hOCT3 (∼30%), even at a 1,000-fold excess. Gatifloxacin, moxifloxacin, prulifloxacin, and sparfloxacin were determined to be competitive inhibitors of hOCT1. Inhibition constants (Ki) were estimated to be 250 ± 18 μM, 161 ± 19 μM, 136 ± 33 μM, and 94 ± 8 μM, respectively. Moxifloxacin competitively inhibited hOCT3-mediated uptake, with aKivalue of 1,598 ± 146 μM. Despite expression in enterocytes (luminal), hepatocytes (sinusoidal), and proximal tubule cells (basolateral), hOCT3 does not appear to contribute significantly to FQ disposition. However, hOCT1 in the sinusoidal membrane of hepatocytes, and potentially the basolateral membrane of proximal tubule cells, is likely to play a role in the disposition of these antimicrobial agents.

Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule

2009 ◽  
Vol 296 (6) ◽  
pp. F1504-F1513 ◽  
Author(s):  
Wing-Kee Lee ◽  
Markus Reichold ◽  
Bayram Edemir ◽  
Giuliano Ciarimboli ◽  
Richard Warth ◽  
...  
Keyword(s):  
Organic Cation ◽  
Fluorescent Dyes ◽  
Mouse Kidney ◽  
Proximal Tubules ◽  
Facilitated Diffusion ◽  
Organic Cation Transporters ◽  
High Affinity ◽  
Cation Transporters ◽  
Safety Guidelines ◽  
Positively Charged

The positively charged fluorescent dyes ethidium (Et+) and propidium (Pr2+) are widely used as DNA and necrosis markers. Et+is cytotoxic and mutagenic. The polyspecific organic cation transporters OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3) mediate electrogenic facilitated diffusion of small (≤500 Da) organic cations with broad specificities. In humans, OCT2 mediates basolateral uptake by kidney proximal tubules (PT), whereas in rodents OCT1/2 are involved. In mouse kidney, perfused Et+accumulated predominantly in the S2/S3 segments of the PT, but not Pr2+. In cells stably overexpressing human OCTs (hOCTs), Et+uptake was observed with Kmvalues of 0.8 ± 0.2 μM (hOCT1), 1.7 ± 0.5 μM (hOCT2), and 2.0 ± 0.5 μM (hOCT3), whereas Pr2+was not transported. Accumulation of Et+was inhibited by OCT substrates quinine, 3-methyl-4-phenylpyridinium (MPP+), cimetidine, and tetraethylammonium (TEA+). For hOCT1 and hOCT2, the IC50values for MPP+, TEA+, and cimetidine were higher than for inhibition of previously tested transported substrates. For hOCT2, the inhibition of Et+uptake by MPP+and cimetidine was shown to be competitive. Et+also inhibited transport of 0.1 μM [3H]MPP+by all hOCT isoforms with IC50values between 0.4 and 1.3 μM, and the inhibition of hOCT1-mediated uptake of MPP+by Et+was competitive. In Oct1/2−/−mice, Et+uptake in the PT was almost abolished. The data demonstrate that Et+is taken up avidly by the PT, which is mediated by OCT1 and/or OCT2. Considering the high affinity of OCTs for Et+and their strong expression in various organs, strict safety guidelines for Et+handling should be reinforced.

Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia

2008 ◽  
Vol 584 (2-3) ◽  
pp. 390-397 ◽  
Author(s):  
Suzanne Heemskerk ◽  
Alfons C. Wouterse ◽  
Frans G.M. Russel ◽  
Rosalinde Masereeuw
Keyword(s):  
Nitric Oxide ◽  
Organic Cation ◽  
Rat Kidney ◽  
Organic Cation Transporters ◽  
Cation Transporters

scholarly journals Organic Cation Transporters (OCTs) in EpiAirway™, a Cellular Model of Normal Human Bronchial Epithelium

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 127 ◽  
Author(s):  
Amelia Barilli ◽  
Rossana Visigalli ◽  
Francesca Ferrari ◽  
Maria Di Lascia ◽  
Benedetta Riccardi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Organic Cation ◽  
Quantitative Polymerase Chain Reaction ◽  
Basolateral Membrane ◽  
Physiological Role ◽  
Bronchial Epithelium ◽  
Organic Cation Transporters ◽  
Basolateral Side ◽  
Cation Transporters ◽  
Transformed Cell Lines

Organic cation transporters (OCTs) and novel organic cation transporters (OCTNs) are responsible for drug delivery in the intestine and kidney; in the lung, OCTs mediate inhaled drugs’ transport, although their physiological role in airways remains poorly understood. The studies addressing OCTs/OCTNs in human airways were mostly performed in immortal or transformed cell lines; here, we studied OCTs in EpiAirway™, a recently developed in vitro model of normal bronchial epithelium. Calu-3 monolayers were used for comparison. The activity of OCTs was evaluated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP+) at the apical and basolateral side of monolayers and protein expression through Western Blot analysis. OCTs and OCTNs expression, along with that of Amino acid Transporter B0,+ (ATB0,+)transporter, was determined by measuring the number of mRNA molecules through quantitative Polymerase Chain Reaction (qPCR). The interaction of the transporters with bronchodilators was also assessed. Results highlight significant differences between Calu-3 cells and EpiAirway™, since, in the latter, OCTs are active only on the basolateral membrane where they interact with the bronchodilator ipratropium. No activity of OCTs is detectable at the apical side; there, the most abundant carrier is, instead, SLC6A14/ATB0,+, that can thus be potentially listed among organic cation transporters responsible for drug delivery in the lung.

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

2008 ◽  
Vol 37 (2) ◽  
pp. 424-430 ◽  
Author(s):  
Xin Ming ◽  
Wujian Ju ◽  
Huali Wu ◽  
Richard R. Tidwell ◽  
James E. Hall ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters
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