Affinage

SLC22A6

Solute carrier family 22 member 6 · UniProt Q4U2R8

Length
563 aa
Mass
61.8 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC22A6 (OAT1) is the rate-limiting transporter of the classical basolateral organic anion secretory pathway of the renal proximal tubule, mediating uptake of a broad array of anionic drugs, toxins, and endogenous metabolites from blood into tubular cells (PMID:9374486, PMID:16354673). It operates as a tertiary-active α-ketoglutarate/organic anion exchanger: it transports p-aminohippurate with trans-stimulation by glutarate preloading in a probenecid-sensitive, voltage-independent manner (PMID:9374486). Substrate handling extends across antiviral nucleoside and nucleotide analogs (zidovudine, acyclovir, tenofovir, raltegravir), diuretics (furosemide, thiazides), folate/methotrexate, and the imaging substrate d-luciferin (PMID:10945832, PMID:10991988, PMID:21078936, PMID:29273507). Its ligand preference is for planar, anionic structures, distinguishing it from sibling transporters (PMID:27488918), with substrate binding requiring Asn-39 and a translocation pathway lined by Cys-440 in transmembrane helix 10 (PMID:14749323, PMID:21543413). OAT1 is restricted to the basolateral membrane of proximal tubule segments in rat and human kidney (PMID:11912243, PMID:27053689) and is also positioned at the blood-facing membrane of the blood-arachnoid barrier, where it clears organic anions from CSF (PMID:31771948, PMID:29436232). Genetic ablation in mice abolishes PAH secretion and impairs diuretic responsiveness, while protecting against tenofovir-, mercury-, and cisplatin-metabolite-induced nephrotoxicity, defining OAT1 as the gateway for both therapeutic clearance and tubular drug/toxin accumulation (PMID:16354673, PMID:18216144, PMID:21403643, PMID:21652719, PMID:28689374). Beyond xenobiotics, OAT1 governs the renal disposition of gut-microbiome-derived and host metabolites—including indoxyl sulfate, kynurenine, and other tryptophan derivatives—positioning it as an inter-organ remote-sensing hub linking microbial Phase II metabolism to renal clearance (PMID:21476605, PMID:33757768, PMID:36692015). OAT1 activity is dynamically regulated: it constitutively cycles between the plasma membrane and recycling endosomes through dynamin/clathrin-dependent endocytosis, with PKC and RhoA signaling accelerating its internalization and PKCζ (downstream of insulin and EGF→PKA) stimulating surface activity (PMID:18818201, PMID:19028678, PMID:26846716). Expression is transcriptionally controlled by HNF4α during proximal tubule development, by BCL6 and sex hormones generating male-dominant abundance, and by ERα via induction of CBF/HNRNPK, and is repressed by LXR activation and by PGE2/COX1→EP4→PKA signaling (PMID:15010355, PMID:22169006, PMID:22808265, PMID:22530049, PMID:31724834, PMID:16338963, PMID:26277839).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1997 High

    Establishing the molecular identity and transport mechanism of the long-known renal organic anion secretory carrier was the foundational question, answered by cloning OAT1 and demonstrating it is an exchanger.

    Evidence Expression cloning from rat kidney and functional PAH transport assays in Xenopus oocytes with trans-stimulation tests

    PMID:9374486

    Open questions at the time
    • Endogenous physiological substrates not yet defined
    • No structural model of the translocation pathway
  2. 2000 High

    Defining the substrate spectrum addressed whether OAT1 handles clinically important drug classes, showing it transports antiviral nucleoside analogs and diuretics.

    Evidence Xenopus oocyte uptake and kinetic/inhibition assays with antivirals and diuretics

    PMID:10945832 PMID:10991988 PMID:21078936

    Open questions at the time
    • In vitro substrate lists do not establish in vivo clearance contribution
    • Structural determinants of substrate selectivity not yet defined
  3. 2004 High

    Mapping the structural basis of substrate binding versus trafficking distinguished a residue essential for transport from glycosylation needed for surface delivery.

    Evidence Site-directed mutagenesis (N39Q, glycosylation mutants) with transport and surface expression assays in HeLa cells; later C440 cysteine-accessibility mutagenesis with homology modeling

    PMID:14749323 PMID:21543413

    Open questions at the time
    • No experimental high-resolution structure
    • Full translocation cycle conformational mechanism unresolved
  4. 2002 High

    Pinpointing where OAT1 acts required subcellular and tissue localization, confirming exclusive basolateral expression across proximal tubule segments.

    Evidence Confocal immunofluorescence in rat kidney and validated-antibody immunochemistry in human kidney with transfected-cell controls

    PMID:11912243 PMID:27053689

    Open questions at the time
    • Polarized targeting machinery not defined
    • Quantitative segment-level transport contribution not resolved
  5. 2006 High

    Whether OAT1 is the rate-limiting in vivo secretory transporter was settled by knockout mice that lose PAH transport and show metabolite accumulation.

    Evidence OAT1 knockout mice with ex vivo renal slice, in vivo clearance, and plasma metabolite profiling; epistasis with OAT3 knockout

    PMID:16354673 PMID:18216144

    Open questions at the time
    • Compensation by OAT3 complicates substrate-specific attribution
    • Human in vivo validation limited
  6. 2008 High

    How OAT1 surface levels are set acutely was answered by demonstrating constitutive endocytic recycling and PKC/PKCζ/RhoA control of internalization and Vmax.

    Evidence Live-cell imaging, dominant-negative dynamin/Eps15 and RhoA, yeast two-hybrid and co-IP for PKCζ, microtubule disruption, PKC activation in transfected and native cells

    PMID:18818201 PMID:19028678 PMID:26846716 PMID:9827570

    Open questions at the time
    • Direct OAT1 phosphorylation sites not mapped
    • Adaptor proteins linking signaling to endocytosis incomplete
  7. 2011 High

    Defining OAT1's role in nephrotoxicity addressed the mechanism of drug/toxin-induced tubular injury, showing OAT1 mediates uptake of tenofovir, mercury conjugates, and cisplatin metabolites.

    Evidence OAT1 (and MRP4) knockout mice with mitochondrial DNA, histology, biochemical injury endpoints, and metabolite identification

    PMID:15864112 PMID:15914676 PMID:21403643 PMID:21652719 PMID:22027505 PMID:28689374

    Open questions at the time
    • Intracellular toxicity effectors downstream of uptake not fully resolved
    • Human polymorphism phenotypes characterized only in heterologous systems
  8. 2012 Medium

    How OAT1 expression is developmentally and hormonally programmed was addressed by identifying transcriptional regulators governing nephron-stage and sex-dependent abundance.

    Evidence ChIP-qPCR for HNF4α, luciferase promoter assays for BCL6 and ERα/CBF/HNRNPK, gonadectomy and hormone replacement, and LXR/PGE2/COX1-EP4 pharmacological dissection

    PMID:15010355 PMID:16338963 PMID:22169006 PMID:22530049 PMID:22808265 PMID:23389457 PMID:26277839 PMID:31724834

    Open questions at the time
    • Several regulators characterized in single labs or reporter systems
    • Integration of competing transcriptional inputs in vivo unresolved
  9. 2021 High

    Establishing OAT1's endogenous physiological purpose recast it as an inter-organ remote-sensing hub handling gut-microbiome and host metabolites.

    Evidence Knockout metabolomics, in vitro transport and bead-binding assays, microbiome depletion, computational modeling, and human probenecid challenge

    PMID:21476605 PMID:33757768 PMID:36692015

    Open questions at the time
    • Causal physiological consequences of individual metabolite handling not fully dissected
    • Quantitative flux through OAT1 versus other clearance routes incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • An experimental atomic-resolution structure and a complete description of the exchange/translocation cycle remain to be established.
  • No solved 3D structure in the corpus
  • Stoichiometry and conformational coupling of α-ketoglutarate exchange not directly resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 8 GO:0140104 molecular carrier activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-382551 Transport of small molecules 3 R-HSA-9748784 Drug ADME 3
Partners
PRKCZ

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ROAT1 (OAT1/SLC22A6) was expression-cloned from rat kidney and shown to mediate probenecid-sensitive, voltage-independent uptake of p-aminohippurate (PAH); transport was trans-stimulated by glutarate preloading but not by methylsuccinate, establishing OAT1 as a tertiary-active basolateral α-ketoglutarate/PAH exchanger with Km ~70 µM for PAH. Expression cloning in Xenopus laevis oocytes; functional transport assays with radiolabeled PAH; inhibition and trans-stimulation experiments The Journal of biological chemistry High 9374486
1998 Rat OAT1 transports methotrexate and folate but not probenecid; transport activity is down-regulated by phorbol ester-activated protein kinase C (PKC), as the inhibitory effect of PMA was attenuated by the PKC inhibitor staurosporine, placing PKC as a negative regulator of OAT1 activity. Xenopus oocyte expression system; radiolabeled substrate uptake; pharmacological inhibition with staurosporine and phorbol esters FEBS letters Medium 9827570
2000 Rat OAT1 mediates basolateral uptake of multiple antiviral nucleoside analogs (zidovudine, acyclovir, zalcitabine, didanosine, lamivudine, stavudine, trifluridine) in a probenecid-sensitive, glutarate-stimulated manner; foscarnet is not transported. Xenopus laevis oocyte expression system; radiolabeled substrate uptake; kinetic analysis (Km determination for AZT and ACV) The Journal of pharmacology and experimental therapeutics High 10945832
2000 OAT1/NKT transcript appears in the embryonic mouse kidney coinciding with proximal tubule differentiation at midgestation, with expression also detected in fetal brain, demonstrating developmentally regulated expression tied to nephron maturation. Spatiotemporal expression analysis during murine development; transporter function demonstrated in developing tissue American journal of physiology. Renal physiology Medium 10751225
2000 Rat OAT1 transports thiazide diuretics (acetazolamide, hydrochlorothiazide), loop diuretics (furosemide), and acetazolamide via the basolateral membrane of renal proximal tubules; kinetic analysis showed competitive inhibition by acetazolamide (Ki = 1.1 mM) and mixed competitive/noncompetitive inhibition by furosemide. Xenopus laevis oocyte expression system; radiolabeled PAH uptake inhibition; Dixon plot kinetic analysis; trans-stimulation efflux assays The Journal of pharmacology and experimental therapeutics High 10991988
2002 OAT1 (rOAT1) localizes exclusively to the basolateral membrane of proximal tubule segments S1, S2, and S3 in rat kidney cortex, as determined by confocal immunofluorescence microscopy. Confocal immunofluorescence microscopy on frozen rat kidney sections with segment-specific markers Journal of the American Society of Nephrology : JASN High 11912243
2002 OAT1 protein abundance in basolateral membrane vesicles of female rat kidney is ~40% of that in males, correlating with lower PAH secretion in females. Western blot of basolateral membrane vesicles; sex comparison with membrane fluidity measurements Molecular and cellular biochemistry Medium 12083373
2003 Interaction with DMPS (2,3-dimercapto-1-propanesulfonic acid) at OAT1 in isolated rabbit renal proximal tubules: DMPS inhibits OAT1-mediated PAH uptake (Kapp ~405 µM for reduced DMPS) and trans-stimulates PAH efflux, indicating DMPS is transported by OAT1. Isolated perfused rabbit renal proximal tubule segments; radiolabeled PAH uptake and efflux; RT-PCR to confirm transporter expression American journal of physiology. Renal physiology Medium 13129851
2004 Gender differences in rat renal cortical OAT1 expression (male > female) appear after puberty and are determined by a stimulatory effect of androgens (and progesterone) and an inhibitory effect of estrogens, demonstrated by gonadectomy and hormone replacement experiments. Immunocytochemistry; Western blot; gonadectomy and sex hormone replacement in rats American journal of physiology. Renal physiology High 15010355
2004 Asparagine-39 (Asn-39) of OAT1 is critically involved in substrate binding: mutation N39Q abolishes transport activity in both mouse and human OAT1 without affecting cell surface expression, indicating a functional (not trafficking) role. Simultaneous elimination of all N-glycosylation sites impairs OAT1 trafficking to the plasma membrane. Site-directed mutagenesis; transport assays in HeLa cells; cell surface expression analysis The Journal of biological chemistry High 14749323
2005 OAT1 knockout mice show profound loss of organic anion transport (PAH) both ex vivo (isolated renal slices) and in vivo, establishing OAT1 as the rate-limiting transporter of the classical basolateral renal organic anion secretory pathway. Loss of OAT1-mediated furosemide secretion impairs diuretic responsiveness. Multiple endogenous organic anions accumulate in plasma of knockouts. OAT1 knockout mice; ex vivo renal slice transport assays; in vivo clearance studies; plasma metabolite profiling; Xenopus oocyte interaction assays The Journal of biological chemistry High 16354673
2005 SNP R50H in hOAT1 (found in African-origin samples) decreases Km for nucleoside phosphonate analogs (adefovir, cidofovir, tenofovir) compared to wild-type without altering PAH Km; SNP R454Q produces a non-functional transporter for PAH, ochratoxin A, and methotrexate. Xenopus oocyte expression system; kinetic transport assays with multiple substrates; population genetic screening The Journal of pharmacology and experimental therapeutics Medium 15864112 15914676
2008 Both OAT1 and OAT3 contribute to renal secretion of furosemide and bendroflumethiazide in vivo; OAT1 knockout (but not OAT3 knockout) abolishes PAH secretion, while both knockouts similarly impair diuretic secretion and responsiveness, demonstrating non-redundant overlapping roles. OAT1 and OAT3 knockout mice; in vivo renal clearance and natriuresis studies; Xenopus oocyte cRNA expression; dose-response curves American journal of physiology. Renal physiology High 18216144
2008 OAT1 constitutively traffics between the plasma membrane and recycling endosomes through a dynamin- and clathrin-dependent endocytic pathway. PKC activation accelerates OAT1 internalization (decreasing Vmax without changing Km) without affecting recycling. OAT1 colocalizes with transferrin at the cell surface and in EEA1-positive early endosomes. Live cell imaging; dominant-negative dynamin-2 and Eps15 transfection; concanavalin A and K+ depletion; colocalization with endocytic markers; PKC activation assays in transfected cells The Journal of biological chemistry High 18818201
2008 Atypical protein kinase Cζ (PKCζ) binds OAT3 (identified by yeast two-hybrid) and up-regulates both OAT3 and OAT1 transport activity (increasing Vmax). Insulin activates PKCζ to stimulate OAT transport; PKCζ acts downstream of EGF→PKA signaling; stimulation requires intact microtubules, suggesting transporter trafficking to the plasma membrane. Yeast two-hybrid; immunoprecipitation; rat renal cortical slices from OAT3-null mice; PKCζ pseudosubstrate inhibitor; microtubule disruption; radiolabeled substrate uptake The Journal of biological chemistry High 19028678
2011 OAT1 is the primary mediator of tenofovir uptake into renal proximal tubule cells; OAT1 knockout mice are protected from TDF-induced mitochondrial DNA depletion and ultrastructural mitochondrial damage in proximal tubules, while MRP4 knockout mice show increased TDF toxicity. OAT1 and MRP4 knockout mice; laser-capture microdissection of proximal tubules; mitochondrial DNA quantification; electron microscopy Laboratory investigation High 21403643
2011 OAT1 knockout mice accumulate gut microbiome-derived metabolites including indoxyl sulfate, kynurenine, and xanthurenic acid in plasma; indoxyl sulfate, kynurenine, and xanthurenic acid directly interact with OAT1 in vitro (IC50 values 18, 12, and 50 µM respectively), establishing OAT1 as a transporter of uremic toxins derived from enteric Phase II metabolism. Untargeted metabolomics on OAT1 knockout mouse plasma/urine; in vitro competitive inhibition assays; pharmacophore modeling with NCI database validation Journal of proteome research High 21476605
2011 OAT1 deletion abolishes mercury-induced renal injury (histological and biochemical) in vivo, demonstrating that OAT1 mediates uptake of nephrotoxic Hg²⁺-conjugated organic anions into proximal tubule cells. OAT1 knockout mice; HgCl₂ treatment; histological analysis; BUN and creatinine measurements The Journal of biological chemistry High 21652719
2011 OAT1 (rOAT1) mediates uptake of aristolochic acid I (AAI) into renal cells; rOAT1-transfected HEK293 cells accumulate more AAI and show higher apoptosis rates than controls; PAH competitively reduces AAI accumulation; chronic AAI in vivo reduces OAT1 basolateral membrane expression and PAH clearance. rOAT1-transfected HEK293 cells; radiolabeled/unlabeled substrate competition; apoptosis assays; in vivo rat model with Western blot and clearance studies Human & experimental toxicology Medium 22027505
2011 Liver X receptor (LXR) activation down-regulates hOAT1 activity in renal S2 cells (decreasing Jmax but not Kt) and reduces OAT1 protein expression; effect is enhanced by RXR agonist 9-cis retinoic acid and confirmed in mouse kidney cortical slices. hOAT1-expressing renal S2 cells; radiolabeled PAH transport assay; Western blot; LXR agonists and antagonists; mouse kidney cortical slices American journal of physiology. Renal physiology Medium 22169006
2012 HNF4α occupies the Oat1 proximal promoter in the in vivo differentiating rat kidney (ChIP-qPCR), and Oat1 gene expression is strongly co-expressed with Hnf4α during metanephric mesenchyme differentiation, identifying Hnf4α as a transcriptional regulator of Oat1 during proximal tubule development. ChIP-qPCR; time-series microarray bioinformatics; ex vivo metanephric mesenchyme culture PloS one Medium 22808265
2012 The transcription factor BCL6 activates promoter constructs of Oat1 and Oat3 in luciferase assays; BCL6 is male-dominantly expressed in rat proximal tubule cells; predicted androgen response elements in the Oat1/Oat3 promoters are not functional, indicating BCL6 (not direct androgen receptor signaling) mediates male-dominant OAT1 expression. Luciferase reporter assays; microarray expression profiling in sex-separated rat proximal tubule cells; promoter deletion analysis PloS one Medium 22530049
2013 mOat3 protein in mouse kidney colocalizes exclusively with mOat1 at the basolateral membrane of proximal tubules (not in other nephron segments as previously reported with nonspecific antibodies); mOat3 is female-dominant (androgen-inhibited) while mOat1 is male-dominant (androgen-stimulated), showing opposite sex-dependent patterns at the protein level. Oat3 knockout mouse validation of antibody specificity; immunofluorescence; Western blot; castration and testosterone treatment experiments American journal of physiology. Renal physiology High 23389457
2016 OAT1 localizes to the basolateral membrane of cortical proximal tubules (S1/S2 more intense than S3; S3 outer stripe negative) in human kidney, established side-by-side with NaDC3, OAT2, and OAT3 using antibodies validated in OAT-transfected HEK293 cells. Immunochemical analysis on human kidney cryosections and isolated membranes; antibody validation in stably transfected HEK293 cells American journal of physiology. Renal physiology High 27053689
2010 Raltegravir is a substrate of SLC22A6 (OAT1) in Xenopus oocyte expression system with Km = 150 µM and Vmax = 36 pmol/oocyte/h; raltegravir and tenofovir compete for SLC22A6 transport, providing a molecular mechanism for their pharmacokinetic drug-drug interaction. Xenopus laevis oocyte expression system; kinetic transport assays; competitive inhibition studies Antimicrobial agents and chemotherapy Medium 21078936
2011 OAT1 and OAT3 are expressed in rat choroid plexus; ex vivo choroid plexus from Oat1(-/-) and Oat3(-/-) mice each still mediate probenecid-inhibitable transport of 6-carboxyfluorescein, confirming independent function of each transporter. All antivirals tested (zidovudine, acyclovir, tenofovir, lamivudine) inhibit both Oat1 and Oat3 in choroid plexus; stavudine does not significantly inhibit Oat1. Ex vivo choroid plexus preparations from OAT1 and OAT3 knockout mice; fluorescent substrate uptake inhibition assays Neuroscience letters Medium 23196129
2016 OAT1 (SLC22A6) mediates uptake of a mercapturic acid metabolite of cisplatin into renal proximal tubule cells, contributing to cisplatin nephrotoxicity via an OCT2-independent pathway; tyrosine kinase inhibitor nilotinib inhibits OAT1 (and OAT3) by non-competitive mechanisms without affecting cisplatin's anticancer activity. Transporter-deficient mouse models; in vitro transport assays; pharmacological inhibition with nilotinib; metabolite identification Clinical and translational science High 28689374
2016 Machine-learning and pharmacophore analysis of ~250 drugs identified that OAT1 ligands preferentially have planar structures and anionic character, distinguishing them from OAT3 (more zwitterionic/cationic) and OCT substrates; predictions were validated by in vitro transport assays and drug/metabolite handling in knockout animals. Statistical analysis of physicochemical descriptors; machine-learning; pharmacophore modeling; in vitro transport assays; knockout animal metabolomics validation The Journal of pharmacology and experimental therapeutics Medium 27488918
2016 Uric acid crystals activate RhoA in proximal tubule cells, causing OAT1 internalization from the plasma membrane surface; dominant-negative RhoA N19 blocks MSU-induced OAT1 internalization; folic acid reverses OAT1 internalization by inhibiting the RhoA signaling pathway. HEK cell model with monosodium urate crystal treatment; dominant-negative RhoA transfection; OAT1 surface expression analysis; rat UAN model Molecular medicine reports Medium 26846716
2017 OAT1 transports d-luciferin with saturable kinetics (Km = 0.23 µM) in HEK293 cells; OAT1-mediated d-luciferin uptake is the rate-limiting step in the d-luciferin-luciferase bioluminescence reaction, enhancing signal in vitro and in vivo in subcutaneous tumors. Transient transfection of OAT1 in HEK293 cells; intracellular d-luciferin accumulation assays; competitive inhibition with 6-carboxyfluorescein; in vivo bioluminescence imaging Biochemical and biophysical research communications Medium 29273507
2019 Estrogen receptor α (ERα) activates hOAT1 transcription indirectly (without direct binding to the OAT1 promoter) by inducing transcription factors CBF (CCAAT-box-binding transcription factor) and HNRNPK, which then bind and activate the OAT1 promoter. Luciferase reporter assays in OK cells; transcription factor array; proteomic analysis; ERα expression vectors with 17β-estradiol treatment Physiological reports Medium 31724834
2019 OAT1 and OAT3 are localized at the blood (dura)-facing plasma membrane of the pig blood-arachnoid barrier, where OAT1 showed the greatest expression among organic anion transporters detected only at leptomeninges; OAT1 mediates PAH clearance from CSF at the arachnoid membrane (confirmed in rat intracisternal injection model with inhibitors). Quantitative targeted absolute proteomics (QTAP); membrane fractionation; in vivo intracisternal injection with selective inhibitors cephalothin and selective oat3 inhibitor Drug metabolism and disposition / Molecular pharmaceutics High 29436232 31771948
2021 OAT1 (Oat1 knockout) regulates tryptophan metabolism systemically and in the kidney; loss of OAT1 depletes kynurenine, kynurenate, anthranilate, and N-formylanthranilate from kidney cells, triggering upregulation of intrinsic tryptophan biosynthetic pathways; human probenecid treatment elevates circulating tryptophan metabolites, confirming in vivo relevance. Oat1 and Oat3 knockout mouse metabolomics; cell-based transport assays; computational metabolic task modeling; human probenecid treatment with metabolite measurement The Journal of biological chemistry High 33757768
2023 OAT1 is an in vivo intermediary between the host and gut microbiome: 40 of 162 microbiome-dependent metabolites are also affected by Oat1 knockout; gut-derived metabolites (including indoxyl sulfate, p-cresol sulfate, deoxycholate) directly interact with OAT1 in vitro (transport and magnetic bead binding assays), defining a gut microbe → liver Phase II metabolism → renal OAT1 transport pathway. Gut microbiome depletion in Oat1-KO and WT mice; metabolomics; in vitro transport assays; magnetic bead binding assays; chemoinformatic analysis JCI insight High 36692015
2011 Cysteine 440 (C440) in transmembrane helix 10 of OAT1 is accessible from the extracellular space and lines the substrate translocation pathway; C440A mutation reduces OAT1 sensitivity to HgCl₂ and thiol-reactive reagents, and homology modeling places C440 in the aqueous translocation pathway. Site-directed mutagenesis (C440A); thiol-reactive reagent reactivity; cell surface biotinylation assays; homology modeling; inhibition studies in CHO cells expressing OAT1 and OAT3 American journal of physiology. Renal physiology Medium 21543413
2005 Prostaglandin E2 (PGE2) dose- and time-dependently down-regulates OAT1 (rOAT1) and OAT3 expression and basolateral organic anion uptake in NRK-52E proximal tubular cells, without affecting general tubular transport systems or counter-ion recirculation, establishing a negative feedback loop where PGE2 inhibits its own renal secretion. NRK-52E rat proximal tubular cell line; fluorescein organic anion uptake assay; Western blot; dose-response PGE2 treatment Journal of the American Society of Nephrology : JASN Medium 16338963
2015 Ischemia/reperfusion-induced down-regulation of OAT1 transport occurs via COX1 metabolites acting through EP4 prostanoid receptors and PKA/PLC signaling, leading to transcriptional repression of OAT1; this was demonstrated using selective COX inhibitors and EP receptor antagonists on OAT1 promoter reporter constructs and in a cellular I/R model. Fluorescein organic anion uptake in proximal tubular cells; hOAT1 promoter luciferase reporter assay in HEK cells; selective COX1/COX2 inhibitors; EP2 and EP4 receptor antagonists and agonists; PKA and PLC inhibitors Cellular physiology and biochemistry Medium 26277839

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. The Journal of biological chemistry 359 9374486
2002 Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. Journal of the American Society of Nephrology : JASN 178 11912243
2005 Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. The Journal of biological chemistry 175 16354673
2011 Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). Journal of proteome research 153 21476605
2004 Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. American journal of physiology. Renal physiology 132 15010355
2011 Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Laboratory investigation; a journal of technical methods and pathology 129 21403643
1998 Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney. FEBS letters 117 9827570
2004 Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1-3; Slc22a6-8) mRNA levels. Drug metabolism and disposition: the biological fate of chemicals 111 15155553
2008 Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. American journal of physiology. Renal physiology 106 18216144
2000 Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. The Journal of pharmacology and experimental therapeutics 96 10945832
2004 Role of glycosylation in the organic anion transporter OAT1. The Journal of biological chemistry 95 14749323
2005 Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6). The Journal of pharmacology and experimental therapeutics 93 15914676
2008 Organic anion transporter OAT1 undergoes constitutive and protein kinase C-regulated trafficking through a dynamin- and clathrin-dependent pathway. The Journal of biological chemistry 89 18818201
2000 Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. American journal of physiology. Renal physiology 87 10751225
2007 Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. American journal of physiology. Renal physiology 79 17244891
2003 Decreased activity of basolateral organic ion transports in hyperuricemic rat kidney: roles of organic ion transporters, rOAT1, rOAT3 and rOCT2. Biochemical pharmacology 74 12963498
1999 Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. Kidney international 73 10594788
2005 Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenetics and genomics 72 15864112
2000 Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1. The Journal of pharmacology and experimental therapeutics 69 10991988
2011 Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. The Journal of biological chemistry 64 21652719
2016 Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach. The Journal of pharmacology and experimental therapeutics 62 27488918
2005 Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney international 61 16164626
2007 The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. The Journal of pharmacology and experimental therapeutics 59 17585018
2010 Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir. Antimicrobial agents and chemotherapy 53 21078936
2005 Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction. Kidney international 53 16316345
2016 P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate. Toxicology and applied pharmacology 50 27377006
2006 Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction. Hepatology (Baltimore, Md.) 49 16628676
2002 Sex differences in p-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1. Molecular and cellular biochemistry 48 12083373
2006 Renal elimination of p-aminohippurate (PAH) in response to three days of biliary obstruction in the rat. The role of OAT1 and OAT3. Biochimica et biophysica acta 47 16844357
2005 Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharmaceutical research 47 15846470
2012 Renal uptake of substrates for organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2 is altered in rats with adenine-induced chronic renal failure. Journal of pharmaceutical sciences 46 23280877
2012 Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11). Biochemical pharmacology 44 22877817
2013 Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. American journal of physiology. Renal physiology 43 23389457
2017 Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity. Clinical and translational science 42 28689374
2012 Changes in expression of renal Oat1, Oat3 and Mrp2 in cisplatin-induced acute renal failure after treatment of JBP485 in rats. Toxicology and applied pharmacology 42 22992436
2008 Activation of protein kinase Czeta increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated transport. The Journal of biological chemistry 42 19028678
2013 JBP485 improves gentamicin-induced acute renal failure by regulating the expression and function of Oat1 and Oat3 in rats. Toxicology and applied pharmacology 40 23707770
2021 Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3. The Journal of biological chemistry 39 33757768
2005 Prostaglandin E2 inhibits its own renal transport by downregulation of organic anion transporters rOAT1 and rOAT3. Journal of the American Society of Nephrology : JASN 39 16338963
2016 An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network. The Journal of biological chemistry 38 27440044
2012 Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neuroscience letters 37 23196129
2019 Abundant Expression of OCT2, MATE1, OAT1, OAT3, PEPT2, BCRP, MDR1, and xCT Transporters in Blood-Arachnoid Barrier of Pig and Polarized Localizations at CSF- and Blood-Facing Plasma Membranes. Drug metabolism and disposition: the biological fate of chemicals 36 31771948
2014 Flavonoids are inhibitors of human organic anion transporter 1 (OAT1)-mediated transport. Drug metabolism and disposition: the biological fate of chemicals 36 25002746
2021 Regulation of solute carriers oct2 and OAT1/3 in the kidney: a phylogenetic, ontogenetic, and cell dynamic perspective. Physiological reviews 33 34486394
2016 Distribution of organic anion transporters NaDC3 and OAT1-3 along the human nephron. American journal of physiology. Renal physiology 32 27053689
2018 A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery. Archives of toxicology 31 30155723
2012 Organic anion and cation SLC22 "drug" transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule. PloS one 31 22808265
2021 Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2. Scientific reports 30 33790363
2006 Analyses of 5' regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). Journal of human genetics 30 16648942
2005 Restored expression and activity of organic ion transporters rOAT1, rOAT3 and rOCT2 after hyperuricemia in the rat kidney. Biochemical pharmacology 29 15748710
2020 Hypouricemic Effects of Extracts from Urtica hyperborea Jacq. ex Wedd. in Hyperuricemia Mice through XOD, URAT1, and OAT1. BioMed research international 28 32083126
2018 Hypouricemic Effects of Ganoderma applanatum in Hyperuricemia Mice through OAT1 and GLUT9. Frontiers in pharmacology 27 29379442
2018 Drug Clearance from Cerebrospinal Fluid Mediated by Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8) at Arachnoid Membrane of Rats. Molecular pharmaceutics 27 29436232
2013 OAT1 and OAT3: targets of drug-drug interaction between entecavir and JBP485. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 27 23313623
2022 Drug transporters OAT1 and OAT3 have specific effects on multiple organs and gut microbiome as revealed by contextualized metabolic network reconstructions. Scientific reports 25 36316339
2002 Rat renal organic anion transporter rOAT1 mediates transport of urinary-excreted cephalosporins, but not of biliary-excreted cefoperazone. Drug metabolism and pharmacokinetics 24 15618660
2018 From the Cover: Identification of Natural Products as Inhibitors of Human Organic Anion Transporters (OAT1 and OAT3) and Their Protective Effect on Mercury-Induced Toxicity. Toxicological sciences : an official journal of the Society of Toxicology 22 29045746
2018 Puerarin improves methotrexate-induced renal damage by up-regulating renal expression of Oat1 and Oat3 in vivo and in vitro. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 29710508
2011 Organic anion transporter 1 (OAT1) involved in renal cell transport of aristolochic acid I. Human & experimental toxicology 21 22027505
2009 Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome. American journal of physiology. Renal physiology 21 19794109
2006 The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3. American journal of physiology. Regulatory, integrative and comparative physiology 21 16857889
2023 The kidney drug transporter OAT1 regulates gut microbiome-dependent host metabolism. JCI insight 20 36692015
2010 Expression of OAT1 and OAT3 in differentiating proximal tubules of the mouse kidney. Histology and histopathology 20 19924639
2009 Expression and function of Oat1 and Oat3 in rat kidney exposed to mercuric chloride. Archives of toxicology 20 19533102
2015 Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 26277839
2012 Male-dominant activation of rat renal organic anion transporter 1 (Oat1) and 3 (Oat3) expression by transcription factor BCL6. PloS one 19 22530049
2009 5-Hydroxy-L-tryptophan alters gaboxadol pharmacokinetics in rats: involvement of PAT1 and rOat1 in gaboxadol absorption and elimination. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 19 19900542
2011 Liver X receptor activation downregulates organic anion transporter 1 (OAT1) in the renal proximal tubule. American journal of physiology. Renal physiology 18 22169006
2003 Interaction of the metal chelator DMPS with OAT1 and OAT3 in intact isolated rabbit renal proximal tubules. American journal of physiology. Renal physiology 18 13129851
2019 Estrogen receptor α (ERα) indirectly induces transcription of human renal organic anion transporter 1 (OAT1). Physiological reports 17 31724834
2014 Oat1/3 restoration protects against renal damage after ischemic AKI. American journal of physiology. Renal physiology 17 25391897
2022 Functional Characterization of Rare Variants in OAT1/SLC22A6 and OAT3/SLC22A8 Urate Transporters Identified in a Gout and Hyperuricemia Cohort. Cells 16 35406626
2011 Differences in the substrate binding regions of renal organic anion transporters 1 (OAT1) and 3 (OAT3). American journal of physiology. Renal physiology 16 21543413
2008 Upregulation of rat renal cortical organic anion transporter (OAT1 and OAT3) expression in response to ischemia/reperfusion injury. American journal of nephrology 16 18441523
2021 PahT regulates carbon fluxes in Novosphingobium sp. HR1a and influences its survival in soil and rhizospheres. Environmental microbiology 15 33817928
2020 Nano Ellagic Acid Counteracts Cisplatin-Induced Upregulation in OAT1 and OAT3: A Possible Nephroprotection Mechanism. Molecules (Basel, Switzerland) 15 32630784
2019 Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2. Acta pharmacologica Sinica 14 31341258
2014 PAH clearance after renal ischemia and reperfusion is a function of impaired expression of basolateral Oat1 and Oat3. Physiological reports 14 24744908
2023 Inhibition of OAT1/3 and CMPF uptake attenuates myocardial ischemia-induced chronic heart failure via decreasing fatty acid oxidation and the therapeutic effects of ruscogenin. Translational research : the journal of laboratory and clinical medicine 13 37315712
2016 Generation and Characterisation of a Pax8-CreERT2 Transgenic Line and a Slc22a6-CreERT2 Knock-In Line for Inducible and Specific Genetic Manipulation of Renal Tubular Epithelial Cells. PloS one 13 26866916
2015 Arsenic and Mercury Containing Traditional Chinese Medicine (Realgar and Cinnabar) Strongly Inhibit Organic Anion Transporters, Oat1 and Oat3, In Vivo in Mice. BioMed research international 13 26788513
2019 Zebrafish (Danio rerio) Oat1 and Oat3 transporters and their interaction with physiological compounds. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 12 31255699
2019 Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3. Cancer chemotherapy and pharmacology 12 31691080
2015 Bezafibrate-mizoribine interaction: Involvement of organic anion transporters OAT1 and OAT3 in rats. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 12 26474691
2012 Effect of JBP485 on obstructive jaundice is related to regulation of renal Oat1, Oat3 and Mrp2 expression in ANIT-treated rats. Peptides 12 22521734
2012 Renal expression and function of oat1 and oat3 in rats with vascular calcification. Pharmacology 12 22759781
2009 Identification of genetic polymorphisms of human OAT1 and OAT2 genes and their relationship to hOAT2 expression in human liver. Clinica chimica acta; international journal of clinical chemistry 12 19854166
2006 Relative contribution of OAT1 and OAT3 transport activities in isolated perfused rabbit renal proximal tubules. Biochimica et biophysica acta 12 16815243
2019 Impaired renal organic anion transport 1 (SLC22A6) and its regulation following acute myocardial infarction and reperfusion injury in rats. Biochimica et biophysica acta. Molecular basis of disease 11 31125610
2018 Hypouricemic Effects of Armillaria mellea on Hyperuricemic Mice Regulated through OAT1 and CNT2. The American journal of Chinese medicine 11 29595077
2005 [Tubular transporters OAT1 and MRP2 and clearance of adefovir]. Nephrologie & therapeutique 11 16895698
2017 Organic anion transporters, OAT1 and OAT3, are crucial biopterin transporters involved in bodily distribution of tetrahydrobiopterin and exclusion of its excess. Molecular and cellular biochemistry 10 28534121
2017 Apigenin, a novel candidate involving herb-drug interaction (HDI), interacts with organic anion transporter 1 (OAT1). Pharmacological reports : PR 10 29128807
2021 Estimation of Ontogeny Functions for Renal Transporters Using a Combined Population Pharmacokinetic and Physiology-Based Pharmacokinetic Approach: Application to OAT1,3. The AAPS journal 9 33948771
2017 Impact of the induced organic anion transporter 1 (Oat1) renal expression by furosemide on the pharmacokinetics of organic anions. Nephrology (Carlton, Vic.) 9 27282888
2017 Organic anion transporter 1 (OAT1/SLC22A6) enhances bioluminescence based on d-luciferin-luciferase reaction in living cells by facilitating the intracellular accumulation of d-luciferin. Biochemical and biophysical research communications 9 29273507
2013 Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney. Drug metabolism and drug interactions 9 24166669
2008 Time course of organic anion excretion in rats with bilateral ureteral obstruction: role of organic anion transporters (Oat1 and Oat3). Nephron. Physiology 9 18953184
2005 Characterization of the oat1 gene of Penicillium chrysogenum encoding an omega-aminotransferase: induction by L-lysine, L-ornithine and L-arginine and repression by ammonium. Molecular genetics and genomics : MGG 9 16163487
2016 Folic acid reverses uric acid crystal-induced surface OAT1 internalization by inhibiting RhoA activity in uric acid nephropathy. Molecular medicine reports 8 26846716

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