Benzoic acid and specific 2-oxo acids activate hepatic efflux of glutamate at OAT2

Pfennig, Till; Herrmann, Beate; Bauer, Tim; Schömig, Edgar; Gründemann, Dirk

doi:10.1016/j.bbamem.2012.08.026

Cited by 13 publications

(11 citation statements)

References 29 publications

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“…Glutamate was able to trans-stimulate efflux of intracellular [ 14 C]glutamate via OAT4, but we did not see clear evidence for trans-stimulation of glutamate efflux via OATP2B1. This provides indirect evidence that glutamate is taken up by OAT4 but as we did not observe uptake directly we cannot exclude the possibility that glutamate was acting as a trans-activator, as has been observed to occur for benzoic acid and OAT2 (Pfennig et al 2013). Direct uptake studies are also required to determine whether or not OATP2B1 mediates glutamate uptake.…”

Section: Discussionmentioning

confidence: 64%

“…This provides indirect evidence that glutamate is taken up by OAT4 but as we did not observe uptake directly we cannot exclude the possibility that glutamate was acting as a trans‐activator, as has been observed to occur for benzoic acid and OAT2 (Pfennig et al . ). Direct uptake studies are also required to determine whether or not OATP2B1 mediates glutamate uptake.…”

Section: Discussionmentioning

confidence: 97%

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Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Lofthouse

Brooks

Cleal

et al. 2015

The Journal of Physiology

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Key points The placenta removes waste products, drugs and environmental toxins from the fetal circulation and two of the transport proteins responsible for this are OAT4 and OATP2B1 localised to the basal membrane of placental syncytiotrophoblast.We provide evidence that OAT4 and OATP2B1 mediate glutamate efflux when expressed in Xenopus oocytes and that in the perfused placenta, bromosulphothalein (an OAT4 and OATP2B1 substrate) stimulates glutamate efflux.Furthermore the efflux of glutamate can only be seen in the presence of aspartate, which will block glutamate reuptake by the placenta, consistent with cycling of glutamate across the basal membrane.We propose that glutamate efflux down its transmembrane gradient drives placental uptake via OAT4 and OATP2B1 from the fetal circulation and that reuptake of glutamate maintains this driving gradient. AbstractThe organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter‐ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter‐ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans‐stimulated by an OAT4 and OATP2B1 substrate (bromosulphothalein). Exchange of glutamate for bromosulphothalein was only observed when glutamate reuptake was inhibited (by addition of aspartate). To determine if OAT4 and/or OATP2B1 mediate glutamate exchange, uptake and efflux of glutamate were investigated in Xenopus laevis oocytes. Our data demonstrate that in Xenopus oocytes expressing either OAT4 or OATP2B1 efflux of intracellular [14C]glutamate could be stimulated by conditions including extracellular glutamate (OAT4), estrone‐sulphate and bromosulphothalein (both OAT4 and OATP2B1) or pravastatin (OATP2B1). Cycling of glutamate across the placenta involving efflux via OAT4 and OATP2B1 and subsequent reuptake will drive placental uptake of organic anions from the fetal circulation.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 97%

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Lofthouse

Brooks

Cleal

et al. 2015

The Journal of Physiology

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“…2D ). SLC7A11 has been shown to be involved in glutamate transport, an essential requirement for glutamaine metabolism, and therefore ammoniagenesis 24 . Additionally, excretion of HAVCR1 was monitored across all culturing conditions as a “baseline” measurement for injury or stress to the tubular culture.…”

Section: Resultsmentioning

confidence: 99%

Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip

Sakolish

Weber

Kelly

et al. 2018

Sci Rep

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The adoption of a new technology into basic research, and industrial and clinical settings requires rigorous testing to build confidence in the reproducibility, reliability, robustness, and relevance of these models. Tissue chips are promising new technology, they have the potential to serve as a valuable tool in biomedical research, as well as pharmaceutical development with regards to testing for efficacy and safety. The principal goals of this study were to validate a previously established proximal tubule tissue chip model in an independent laboratory and to extend its utility to testing of nephrotoxic compounds. Here, we evaluated critical endpoints from the tissue chip developer laboratory, focusing on biological relevance (long-term viability, baseline protein and gene expression, ammoniagenesis, and vitamin D metabolism), and toxicity biomarkers. Tissue chip experiments were conducted in parallel with traditional 2D culture conditions using two different renal proximal tubule epithelial cell sources. The results of these studies were then compared to the findings reported by the tissue chip developers. While the overall transferability of this advanced tissue chip platform was a success, the reproducibility with the original report was greatly dependent on the cell source. This study demonstrates critical importance of developing microphysiological platforms using renewable cell sources.

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“…This is surprising since OAT2 was recently identified as a bidirectional glutamate transporter leading to glutamate accumulation (28). Thus, OAT2 most likely does not contribute to hepatic uptake of NCG.…”

Section: Discussionmentioning

confidence: 95%

Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency

Schwob

Hagos

Burckhardt

et al. 2014

American Journal of Physiology-Renal Physiology

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Inborn defects in N-acetylglutamate (NAG) synthase (NAGS) cause a reduction of NAG, an essential cofactor for the initiation of the urea cycle. As a consequence, blood ammonium concentrations are elevated, leading to severe neurological disorders. The orphan drug N-carbamoylglutamate (NCG; Carbaglu), efficiently overcomes NAGS deficiency. However, not much is known about the transporters involved in the uptake, distribution, and elimination of the divalent organic anion NCG. Organic anion-transporting polypeptides (OATPs) as well as organic anion transporters (OATs) working in cooperation with sodium dicarboxylate cotransporter 3 (NaDC3) accept a wide variety of structurally unrelated drugs. To test for possible interactions with OATPs and OATs, the impact of NCG on these transporters in stably transfected human embryonic kidney-293 cells was measured. The two-electrode voltage-clamp technique was used to monitor NCG-mediated currents in Xenopus laevis oocytes that expressed NaDC3. Neither OATPs nor OAT2 and OAT3 interacted with NCG, but OAT1 transported NCG. In addition, NCG was identified as a high-affinity substrate of NaDC3. Preincubation of OAT4-transfected human embryonic kidney-293 cells with NCG showed an increased uptake of estrone sulfate, the reference substrate of OAT4, indicating efflux of NCG by OAT4. In summary, NaDC3 and, to a lesser extent, OAT1 are likely to be responsible for the uptake of NCG from the blood. Efflux of NCG across the luminal membrane into the tubular lumen probably occurs by OAT4 completing renal secretion of this drug.

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Benzoic acid and specific 2-oxo acids activate hepatic efflux of glutamate at OAT2

Cited by 13 publications

References 29 publications

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Technology Transfer of the Microphysiological Systems: A Case Study of the Human Proximal Tubule Tissue Chip

Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency

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