Towards an understanding of organic anion transporters: Structure–function relationships

You, Guofeng

doi:10.1002/med.20014

Cited by 37 publications

(22 citation statements)

References 78 publications

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“…NSAIDs are weak organic acids and are thought to be substrates for organic anion transporters, which interact with a wide variety of anionic drugs (You, 2004). Consistent with this possibility, naproxen transport was competitively inhibited by the organic anion transporter substrates phenol red and penicillin.…”

Section: Discussionmentioning

confidence: 86%

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

2006

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Non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage pain and inflammatory disorders. We hypothesized that gingival fibroblasts actively accumulate NSAIDs and enhance their levels in gingival connective tissue. Using fluorescence to monitor NSAID transport, we demonstrated that cultured gingival fibroblasts transport naproxen in a saturable, temperaturedependent manner with a K m of 127 μg/mL and aV max of 1.42 ng/min/μg protein. At steady state, the intracellular/extracellular concentration ratio was 1.9 for naproxen and 7.2 for ibuprofen. Naproxen transport was most efficient at neutral pH and was significantly enhanced upon cell treatment with TNF-α. In humans, systemically administered naproxen attained steady-state levels of 61.9 μg/mL in blood and 9.4 μg/g in healthy gingival connective tissue, while ibuprofen attained levels of 2.3 μg/mL and 1.5 μg/g, respectively. Thus, gingival fibroblasts possess transporters for NSAIDs that are up-regulated by an inflammatory mediator, but there is no evidence that they contribute to elevated NSAID levels in healthy gingiva.

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Section: Discussionmentioning

confidence: 86%

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

2006

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“…Recently, our laboratory has isolated several hOAT1-interacting proteins. 3 Whether any of these proteins is a substrate for PKC-induced phosphorylation is under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The organic anion transporter (OAT) 2 family mediates the body disposition of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories (1)(2)(3). Therefore, understanding the regulation of these transporters has profound clinical significance.…”

mentioning

confidence: 99%

Organic Anion Transporter OAT1 Undergoes Constitutive and Protein Kinase C-regulated Trafficking through a Dynamin- and Clathrin-dependent Pathway

Zhang

Hong

Duan

et al. 2008

Journal of Biological Chemistry

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121

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Organic anion transporter 1 (OAT1) mediates the body disposition of a diverse array of environmental toxins and clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. We previously demonstrate that OAT1 activity was down-regulated by activation of protein kinase C (PKC), kinetically revealed as a decrease in the maximum transport velocity V max without significant change in the substrate affinity K m of the transporter. In the current study, we showed that OAT1 constitutively internalized from and recycled back to the plasma membrane, and PKC activation accelerated OAT1 internalization without affecting OAT1 recycling. We further showed that treatment of OAT1-expressing cells with concanavalin A, depletion of K ؉ from the cells, or transfection of dominant negative mutants of dynamin-2 or Eps15 into the cells, all of which block the clathrindependent endocytotic pathway, significantly blocked constitutive and PKC-regulated OAT1 internalization. We finally showed that OAT1 colocalized with transferrin, a marker for clathrin-dependent endocytosis, at the cell surface and in the EEA1-positive early endosomes. Together, our findings demonstrated for the first time that (i) OAT1 constitutively traffics between plasma membrane and recycling endosomes, (ii) PKC activation down-regulates OAT1 activity by altering already existent OAT1 trafficking, and (iii) OAT1 internalization occurs partly through a dynamin-and clathrin-dependent pathway.

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“…Organic anion transporter (OAT)3 shares several characteristics with OAT1 (Slc22a6) (Lopez-Nieto et al, 1996 and other related transporters, including the presence of 12 membrane-spanning helices with several consensus extracellular glycolsylation and intracellular protein kinase C sites (Eraly et al, 2004;You, 2004;Klaassen and Aleksunes, 2010;VanWert et al, 2010;Wu et al, 2011); however, OAT3 is phylogenetically and structurally unrelated to other transport proteins, such as the organic anion-transporting polypeptide transporters and the drug-transporting ATP-binding cassette proteins (Hagenbuch and Meier, 2003). Its nearest non-Oat SLC22 relations are the organic cation-and carnitine-transporting OCT and OCTN proteins (Burckhardt and Wolff, 2000;Sweet et al, 2001), as well as the FLIPT proteins (fly-like putative transporters) (Eraly and Nigam, 2002;Enomoto et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Multispecific Drug TransporterSlc22a8(Oat3) Regulates Multiple Metabolic and Signaling Pathways

et al. 2013

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Multispecific drug transporters of the solute carrier and ATPbinding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed "mouse Recon1" supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009;Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants.

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Towards an understanding of organic anion transporters: Structure–function relationships

Cited by 37 publications

References 78 publications

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

Accumulation of Non-steroidal Anti-inflammatory Drugs by Gingival Fibroblasts

Organic Anion Transporter OAT1 Undergoes Constitutive and Protein Kinase C-regulated Trafficking through a Dynamin- and Clathrin-dependent Pathway

Multispecific Drug TransporterSlc22a8(Oat3) Regulates Multiple Metabolic and Signaling Pathways

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