| Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). | |
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MedLine Citation:
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PMID: 21476605 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Untargeted metabolomics on the plasma and urine from wild-type and organic anion transporter-1 (Oat1/Slc22a6) knockout mice identified a number of physiologically important metabolites, including several not previously linked to Oat1-mediated transport. Several, such as indoxyl sulfate, derive from Phase II metabolism of enteric gut precursors and accumulate in chronic kidney disease (CKD). Other compounds included vitamins (pantothenic acid, 4-pyridoxic acid), urate, and metabolites in the tryptophan and nucleoside pathways. Three metabolites, indoxyl sulfate, kynurenine, and xanthurenic acid, were elevated in the plasma and interacted strongly and directly with Oat1 in vitro with IC50 of 18, 12, and 50 μM, respectively. A pharmacophore model based on several identified Oat1 substrates was used to screen the NCI database and candidate compounds interacting with Oat1 were validated in an in vitro assay. Together, the data suggest a complex, previously unidentified remote communication between the gut microbiome, Phase II metabolism in the liver, and elimination via Oats of the kidney, as well as indicating the importance of Oat1 in the handling of endogenous toxins associated with renal failure and uremia. The possibility that some of the compounds identified may be part of a larger remote sensing and signaling pathway is also discussed. |
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Authors:
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William R Wikoff; Megha A Nagle; Valentina L Kouznetsova; Igor F Tsigelny; Sanjay K Nigam |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-04-22 |
Journal Detail:
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Title: Journal of proteome research Volume: 10 ISSN: 1535-3907 ISO Abbreviation: J. Proteome Res. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-03 Completed Date: 2011-10-24 Revised Date: 2011-10-25 |
Medline Journal Info:
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Nlm Unique ID: 101128775 Medline TA: J Proteome Res Country: United States |
Other Details:
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Languages: eng Pagination: 2842-51 Citation Subset: IM |
Affiliation:
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Genome Center, University of California Davis, CA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Membrane Permeability Fluorescent Dyes Indican / blood Kynurenine / metabolism Metabolome* Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Oocytes / metabolism Organic Anion Transport Protein 1 / antagonists & inhibitors, metabolism* Pantothenic Acid / blood Pyridoxic Acid / blood Sulfuric Acid Esters / blood Uremia / blood*, urine* Urinalysis Xanthurenates / metabolism, urine Xenopus |
| Grant Support | |
ID/Acronym/Agency:
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AI057695/AI/NIAID NIH HHS; DK079784/DK/NIDDK NIH HHS; HL35018/HL/NHLBI NIH HHS; R01 AI057695-05/AI/NIAID NIH HHS; R01 DK079784-04/DK/NIDDK NIH HHS; R01 GM088824-03/GM/NIGMS NIH HHS; R01 NS062156-03/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fluorescent Dyes; 0/Organic Anion Transport Protein 1; 0/Slc22a6 protein, mouse; 0/Sulfuric Acid Esters; 0/Xanthurenates; 343-65-7/Kynurenine; 487-94-5/Indican; 59-00-7/xanthurenic acid; 79-83-4/Pantothenic Acid; 82-82-6/Pyridoxic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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