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Linkage of organic anion transporter-1 to metabolic pathways through integrated "omics"-driven network and functional analysis.
Ahn SY
,
Jamshidi N
,
Mo ML
,
Wu W
,
Eraly SA
,
Dnyanmote A
,
Bush KT
,
Gallegos TF
,
Sweet DH
,
Palsson BØ
,
Nigam SK
.
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The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478). Targeted metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many important metabolites, including intermediates in carbohydrate, fatty acid, and amino acid metabolism. This observation raises the possibility that OAT1 helps regulate broader metabolic activities. We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally tested genome-scale reconstruction of human metabolism. A computational approach was used to analyze in vivo metabolomic as well as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of several metabolic pathways, including the citric acid cycle, polyamine, and fatty acid metabolism. Validation by in vitro and ex vivo analysis using Xenopus oocyte, cell culture, and kidneytissue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways, including previously unknown substrates, such as polyamines (e.g. spermine and spermidine). A genome-scale metabolic network reconstruction generated some experimentally supported predictions for metabolic pathways linked to OAT1-related transport. The data support the possibility that the SLC22 and other families of transporters, known to be expressed in many tissues and primarily known for drug and toxin clearance, are integral to a number of endogenous pathways and may be involved in a larger remote sensing and signaling system (Ahn, S. Y., and Nigam, S. K. (2009) Mol. Pharmacol. 76, 481-490, and Wu, W., Dnyanmote, A. V., and Nigam, S. K. (2011) Mol. Pharmacol. 79, 795-805). Drugs may alter metabolism by competing for OAT1 binding of metabolites.
Ahn,
Interaction of organic cations with organic anion transporters.
2009, Pubmed,
Xenbase
Ahn,
Interaction of organic cations with organic anion transporters.
2009,
Pubmed
,
Xenbase
Ahn,
Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis.
2009,
Pubmed
Ahn,
Update on the molecular physiology of organic anion transporters.
2008,
Pubmed
Becker,
Context-specific metabolic networks are consistent with experiments.
2008,
Pubmed
Béery,
Molecular evidence of organic ion transporters in the rat adrenal cortex with adrenocorticotropin-regulated zonal expression.
2003,
Pubmed
,
Xenbase
Burckhardt,
Transport of organic anions across the basolateral membrane of proximal tubule cells.
2003,
Pubmed
Duarte,
Global reconstruction of the human metabolic network based on genomic and bibliomic data.
2007,
Pubmed
Enomoto,
Roles of organic anion transporters in the progression of chronic renal failure.
2007,
Pubmed
Eraly,
Multiple organic anion transporters contribute to net renal excretion of uric acid.
2008,
Pubmed
Eraly,
Novel aspects of renal organic anion transporters.
2003,
Pubmed
Eraly,
Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters.
2004,
Pubmed
Eraly,
Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice.
2006,
Pubmed
,
Xenbase
Feist,
The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli.
2008,
Pubmed
Hasegawa,
Contribution of organic anion transporters to the renal uptake of anionic compounds and nucleoside derivatives in rat.
2003,
Pubmed
Ichida,
Urate transport via human PAH transporter hOAT1 and its gene structure.
2003,
Pubmed
Joyce,
Experimental and computational assessment of conditionally essential genes in Escherichia coli.
2006,
Pubmed
Kaler,
Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions.
2006,
Pubmed
Kaler,
Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members.
2007,
Pubmed
Ketteler,
Cytokines and L-arginine in renal injury and repair.
1994,
Pubmed
Kumar,
GrowMatch: an automated method for reconciling in silico/in vivo growth predictions.
2009,
Pubmed
Levillain,
Ornithine metabolism in male and female rat kidney: mitochondrial expression of ornithine aminotransferase and arginase II.
2004,
Pubmed
Levillain,
Ornithine decarboxylase along the mouse and rat nephron.
1998,
Pubmed
Lopez-Nieto,
Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney.
1997,
Pubmed
,
Xenbase
Mahadevan,
The effects of alternate optimal solutions in constraint-based genome-scale metabolic models.
2003,
Pubmed
Monte,
Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa.
2004,
Pubmed
Mount,
Molecular physiology and the four-component model of renal urate transport.
2005,
Pubmed
Nagle,
Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling.
2011,
Pubmed
,
Xenbase
Nigam,
Drug and toxicant handling by the OAT organic anion transporters in the kidney and other tissues.
2007,
Pubmed
,
Xenbase
Nii-Kono,
Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells.
2007,
Pubmed
Oberhardt,
Applications of genome-scale metabolic reconstructions.
2009,
Pubmed
Price,
Genome-scale models of microbial cells: evaluating the consequences of constraints.
2004,
Pubmed
Reed,
Towards multidimensional genome annotation.
2006,
Pubmed
Sato,
Involvement of uric acid transporters in alteration of serum uric acid level by angiotensin II receptor blockers.
2008,
Pubmed
,
Xenbase
Silva,
Energy and fuel substrate metabolism in the kidney.
1990,
Pubmed
Srimaroeng,
Physiology, structure, and regulation of the cloned organic anion transporters.
2008,
Pubmed
Sugiyama,
Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier.
2001,
Pubmed
Suthers,
Genome-scale gene/reaction essentiality and synthetic lethality analysis.
2009,
Pubmed
Sweet,
Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice.
2002,
Pubmed
,
Xenbase
Thiele,
Candidate metabolic network states in human mitochondria. Impact of diabetes, ischemia, and diet.
2005,
Pubmed
Truong,
Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination.
2008,
Pubmed
,
Xenbase
Uchida,
Substrate specificity to maintain cellular ATP along the mouse nephron.
1988,
Pubmed
Vallon,
Organic anion transporter 3 contributes to the regulation of blood pressure.
2008,
Pubmed
,
Xenbase
Vallon,
Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics.
2008,
Pubmed
,
Xenbase
Vanwert,
Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin.
2008,
Pubmed
,
Xenbase
Wikoff,
Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1).
2011,
Pubmed
,
Xenbase
Wu,
Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis.
2011,
Pubmed
You,
Structure, function, and regulation of renal organic anion transporters.
2002,
Pubmed
Zahedi,
Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest.
2007,
Pubmed
