Publications

• Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3.

  Uwai Y., Honjo H., Iwamoto K.

  Kynurenic acid, a catabolite of tryptophan, is suggested to be involved in schizophrenia, and is known to be a uremic toxin, although there is little information about the mechanism of its disposition. In this study, we performed uptake experiment using Xenopus laevis oocyte expression system to e ... >> More

  Kynurenic acid, a catabolite of tryptophan, is suggested to be involved in schizophrenia, and is known to be a uremic toxin, although there is little information about the mechanism of its disposition. In this study, we performed uptake experiment using Xenopus laevis oocyte expression system to examine the transport of kynurenic acid by human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8), which mediate the transport of organic anions in the brain and kidney. The uptake of p-aminohippurate in hOAT1-expressing oocytes and of estrone sulfate in hOAT3-expressing oocytes was strongly inhibited by kynurenic acid, and other tryptophan catabolites, kynurenine and quinolinic acid, showed moderate and no inhibition, respectively. The apparent 50% inhibitory concentrations of kynurenic acid were estimated to be 12.9 μM for hOAT1, and 7.76 μM for hOAT3. Both hOAT1 and hOAT3 markedly stimulated the uptake of kynurenic acid into oocytes, and the K(m) values of the transport were calculated to be 5.06 μM and 4.86 μM, respectively. The transport efficiencies of kynurenic acid by hOAT1 and hOAT3 were comparable to those of p-aminohippurate and estrone sulfate, respectively. Probenecid inhibited kynurenic acid transport by hOAT1 and hOAT3. These findings show the interaction of kynurenic acid with hOAT1 and hOAT3, and that kynurenic acid is their substrate. It is suggested that these transporters are involved in the disposition of kynurenic acid. << Less

  Pharmacol. Res. 65:254-260(2012) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites.

  Bahn A., Ljubojevic M., Lorenz H., Schultz C., Ghebremedhin E., Ugele B., Sabolic I., Burckhardt G., Hagos Y.

  Tryptophan metabolites such as kynurenate (KYNA), xanthurenate (XA), and quinolinate are considered to have an important impact on many physiological processes, especially brain function. Many of these metabolites are secreted with the urine. Because organic anion transporters (OATs) facilitate th ... >> More

  Tryptophan metabolites such as kynurenate (KYNA), xanthurenate (XA), and quinolinate are considered to have an important impact on many physiological processes, especially brain function. Many of these metabolites are secreted with the urine. Because organic anion transporters (OATs) facilitate the renal secretion of weak organic acids, we investigated whether the secretion of bioactive tryptophan metabolites is mediated by OAT1 and OAT3, two prominent members of the OAT family. Immunohistochemical analyses of the mouse kidneys revealed the expression of OAT1 to be restricted to the proximal convoluted tubule (representing S1 and S2 segments), whereas OAT3 was detected in almost all parts of the nephron, including macula densa cells. In the mouse brain, OAT1 was found to be expressed in neurons of the cortex cerebri and hippocampus as well as in the ependymal cell layer of the choroid plexus. Six tryptophan metabolites, including the bioactive substances KYNA, XA, and the serotonin metabolite 5-hydroxyindol acetate inhibited [(3)H]p-aminohippurate (PAH) or 6-carboxyfluorescein (6-CF) uptake by 50-85%, demonstrating that these compounds interact with OAT1 as well as with OAT3. Half-maximal inhibition of mOAT1 occurred at 34 muM KYNA and 15 muM XA, and it occurred at 8 muM KYNA and 11.5 muM XA for mOAT3. Quinolinate showed a slight but significant inhibition of [(3)H]PAH uptake by mOAT1 and no alteration of 6-CF uptake by mOAT3. [(14)C]-Glutarate (GA) uptake was examined for both transporters and demonstrated differences in the transport rate for this substrate by a factor of 4. Trans-stimulation experiments with GA revealed that KYNA and XA are substrates for mOAT1. Our results support the idea that OAT1 and OAT3 are involved in the secretion of bioactive tryptophan metabolites from the body. Consequently, they are crucial for the regulation of central nervous system tryptophan metabolite concentration. << Less

  Am. J. Physiol. 289:C1075-C1084(2005) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.