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  • 1
    ISSN: 1432-2013
    Keywords: Oxalate ; Succinate ; Glutarate ; 2-Oxoglutarate ; Citrate ; Sulfate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to study the specificity for contraluminal para-aminohippurate (PAH) transport, the inhibitory potency of aliphatic dicarboxylates on3H-PAH influx, as well as the inhibitory effect on35SO 4 2− - and3H-succinate influx, from the interstitium into cortical tubular cells in situ has been determined. The following was found: 1. Testing a homologous series of dicarboxylates-ranging from the 2 C oxalate to the 10 C sebacate — PAH transport was inhibited by succinate (app.K i 1.35 mmol/l), and all longer dicarboxylates, with high potency (app.K i 0.05–0.35 mmol/l). Sulfate transport was inhibited only by oxalate (app.K i 1.1 mmol/l), while dicarboxylate transport was inhibited by succinate, glutarate, adipate and pimelate with decreasing potency (app.K i 0.04, 0.24, 0.91, 4.0 mmol/l, respectively). 2. PAH transport was inhibited by succinate and glutarate with high potency (app.K i 1.35 and 0.05 mmol/l), by the correspondent monomethylester to a lesser extent (app.K i 1.7 and 0.74 mmol/l), but not by the dimethylester. On the other hand, the semialdehyde of succinate with aK i-value of 1.2 mmol/l, had the same inhibitory potency as succinate itself, while the dialdehyde of glutarate (app.K i 1.4 mmol/l) was much less potent as glutarate. 3. Introduction of an oxo-, methyl- or sulfhydroxylgroup onto the 2-position of succinate, or of an oxo-group onto the 2-position of glutarate moderately augmented the inhibitory potency against PAH-uptake. However, introduction of a 2-hydroxy group onto succinate or glutarate in thel-position reduced the inhibitory potency more than in thed-position. Introduction of two methyl-, sulfhydryl- or hydroxyl-groups in the 2–3-position of succinate reduced or abolished its inhibitory potency. The introduction of a 2-amino group onto succinate or glutarate abolished its effect on PAH transport. However, N-acetylation or N-benzoylation led to a restitution in inhibitory potency. 4. The trans-isomers fumarate and mesaconate inhibited PAH- and methylsuccinate transport, while the cis-isomers maleate and citraconate did so to a lesser extent or not at all. The effect was reversed with the tricarboxylic aconitates, because cis-aconitate bears a CH2-extended COOH-group in trans-position and trans-aconitate in cis-position. The data indicate that there exist three different anion transport systems at the contraluminal cell side of the proximal renal tubule: 1. a sulfate-oxalate transporter, 2. a sodium-dependent dicarboxylate transporter, and 3. a paraaminohippurate transporter. The PAH transport system accepts dicarboxylates with chain length higher than 7.5 Å (=distance between the terminal oxygen atoms), while the dicarboxylate transport interacts with dicarboxylates with a chain length between 6.5 and 10 Å. Both transport systems prefer the transconfiguration. The effect of side groups on the interaction of dicarboxylates with the PAH-transport system is due mainly to hydrophobicity and electron configuration.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1440
    Keywords: Transport interaction ; Organic anions ; Organic cations ; Sulfate ; Dicarboxylates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Using the stopped flow tubular lumen or peritubular capillary microperfusion method, the apparent Ki values of a large number of organic anions and cations against the respective transport systems were evaluated. Thereby the luminal transport system for monocarboxylates (lactate), the contraluminal and luminal transport systems for dicarboxylates (succinate), sulfate, and hydrophobic organic cations (tetraethylammonium or N 1-methyl-nicotinamide), as well as contraluminal transport system for hydrophobic organic anions (para-aminohippurate, PAH) were characterized and their specificity determined. There is a partially overlapping substrate specificity between the PAH, dicarboxylate, and sulfate transport systems but also between the PAH and organic cation transport system. Xenobiotics and their metabolites are transported mainly by the organic anion (PAH) and organic cation transport systems. To test the complicated interactions possible a shot injection/urinary excretion method with simultaneous measurement of the intracellular concentration was developed. With this approach it is possible to evaluate (a) whether a substrate is net secreted or net reabsorbed, (b) whether interference with other substrates occurs, (c) whether interference takes place at the luminal or contraluminal cell side, and (d) whether cis-inhibition or trans-stimulation is the predominant mode of interaction. Finally, it will be discussed which ability a substrate must have to penetrate the cell membrane via a transporter, through the lipid bilayer, or both.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0005-2736
    Keywords: Anion transport ; Contraluminal membrane ; Hydrophobicity ; Molecular charge distribution ; Sulfate
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Type of Medium: Electronic Resource
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