The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut–liver– kidney axis

Journal of Biological Chemistry

Volumn 292, Issue 38, 2017, Pages 15789-15803

  Bush, Kevin T ^a   Wu, Wei ^b   Lun, Christina ^c   Nigam, Sanjay K ^a  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; BIOMOLECULES; METABOLISM; MOLECULES; NEGATIVE IONS; PHYSICOCHEMICAL PROPERTIES; REMOTE SENSING; SIGNALING; SUBSTRATES;

ENDOGENOUS METABOLITES; MOLECULAR COMPLEXITY; PATHWAY ANALYSIS; PHYSICOCHEMICAL FEATURES; REMOTE COMMUNICATION; SIGNALING MOLECULES; SIGNALING PATHWAYS; SUBSTRATE SPECIFICITY;

METABOLITES;

BENZOIC ACID; BETA MURICHOLATE; BILE ACID; CHENODEOXYCHOLIC ACID; CHOLIC ACID; EQUOL; GLYCOCHOLIC ACID; INDOLE; ORGANIC ANION TRANSPORTER 1; ORGANIC ANION TRANSPORTER 3; PHENYLALANINE; PHOSPHOLIPID; PYRIDOXINE; SPHINGOLIPID; TAUROCHOLIC ACID; TAURODEOXYCHOLIC ACID; TAUROURSODEOXYCHOLIC ACID; TRYPTOPHAN; TYROSINE; UNCLASSIFIED DRUG; AMINO ACID; LIGAND; ORGANIC ANION TRANSPORTER; SLC22A6 PROTEIN, MOUSE; XENOBIOTIC AGENT;

ADULT; AMINO ACID METABOLISM; ARTICLE; BILE ACID METABOLISM; BLOOD LEVEL; CHEMICAL STRUCTURE; CONTROLLED STUDY; ENERGY METABOLISM; ENZYME SPECIFICITY; HYDROPHOBICITY; INTESTINE FLORA; KIDNEY; KIDNEY METABOLISM; KIDNEY PROXIMAL TUBULE; LIPID METABOLISM; LIVER; MALE; METABOLITE; METABOLOMICS; MOUSE; NONHUMAN; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TRANSPORT ASSAY; WILD TYPE; XENOBIOTIC METABOLISM; ANIMAL; C57BL MOUSE; DEFICIENCY; DIET; GENE INACTIVATION; GENETICS; INTESTINE; METABOLISM; MICROBIOLOGY;

AMINO ACIDS; ANIMALS; BILE ACIDS AND SALTS; DIET; ENERGY METABOLISM; GASTROINTESTINAL MICROBIOME; GENE KNOCKOUT TECHNIQUES; INTESTINES; KIDNEY; LIGANDS; LIPID METABOLISM; LIVER; MALE; METABOLOMICS; MICE; MICE, INBRED C57BL; ORGANIC ANION TRANSPORT PROTEIN 1; ORGANIC ANION TRANSPORTERS, SODIUM-INDEPENDENT; SUBSTRATE SPECIFICITY; XENOBIOTICS;

EID: 85029764069     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M117.796516     Document Type: Article

References (86)

1. Food and Drug Administration and Center for Drug Evaluation and Research (2012) Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. United States Department of Health and Human Services, Silver Spring, MD
2. Nigam, S. K. (2015) What do drug transporters really do? Nat. Rev. Drug Discov. 14, 29 – 44
3. Nigam, S. K., Bush, K. T., Martovetsky, G., Ahn, S. Y., Liu, H. C., Richard, E., Bhatnagar, V., and Wu, W. (2015) The organic anion transporter (OAT) family: a systems biology perspective. Physiol. Rev. 95, 83–123
4. VanWert, A. L., Gionfriddo, M. R., and Sweet, D. H. (2010) Organic anion transporters: discovery, pharmacology, regulation and roles in pathophys-iology. Biopharm. Drug Dispos. 31, 1–71
5. You, G. F., and Morris, M. E. (eds) (2014) Drug Transporters: Molecular Characterization and Role in Drug Disposition, John Wiley & Sons, Inc, Hoboken, NJ
6. López-Nieto, C. E., and Nigam, S. K. (1996) Selective amplification of protein-coding regions of large sets of genes using statistically designed primer sets. Nat. Biotechnol. 14, 857– 861
7. Lopez-Nieto, C. E., You, G., Barros, E. J. G., Beier, D. R., and Nigam, S. K. (1996) Molecular cloning and characterization of a novel transport protein with very high expression in the kidney. J. Am. Soc. Nephrol. 7, 1301 (abstr.)
8. Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney. J. Biol. Chem. 272, 6471– 6478
9. Brady, K. P., Dushkin, H., Förnzler, D., Koike, T., Magner, F., Her, H., Gullans, S., Segre, G. V., Green, R. M., and Beier, D. R. (1999) A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56, 254 –261
10. Sweet, D. H., Miller, D. S., Pritchard, J. B., Fujiwara, Y., Beier, D. R., and Nigam, S. K. (2002) Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J. Biol. Chem. 277, 26934 –26943
11. Eraly, S. A., Vallon, V., Vaughn, D. A., Gangoiti, J. A., Richter, K., Nagle, M., Monte, J. C., Rieg, T., Truong, D. M., Long, J. M., Barshop, B. A., Kaler, G., and Nigam, S. K. (2006) Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J. Biol. Chem. 281, 5072–5083
12. Eraly, S. A., Vallon, V., Rieg, T., Gangoiti, J. A., Wikoff, W. R., Siuzdak, G., Barshop, B. A., and Nigam, S. K. (2008) Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol. Genomics 33, 180 –192
13. Vallon, V., Rieg, T., Ahn, S. Y., Wu, W., Eraly, S. A., and Nigam, S. K. (2008) Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am. J. Physiol. Renal Physiol. 294, F867–F873
14. Vanwert, A. L., Srimaroeng, C., and Sweet, D. H. (2008) Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol. Pharmacol. 74, 122–131
15. Vanwert, A. L., Bailey, R. M., and Sweet, D. H. (2007) Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am. J. Physiol. Renal Physiol. 293, F1332–F1341
16. VanWert, A. L., and Sweet, D. H. (2008) Impaired clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm. Res. 25, 453– 462
17. Vallon, V., Eraly, S. A., Wikoff, W. R., Rieg, T., Kaler, G., Truong, D. M., Ahn, S. Y., Mahapatra, N. R., Mahata, S. K., Gangoiti, J. A., Wu, W., Barshop, B. A., Siuzdak, G., and Nigam, S. K. (2008) Organic anion transporter 3 contributes to the regulation of blood pressure. J. Am. Soc. Nephrol. 19, 1732–1740
18. Truong, D. M., Kaler, G., Khandelwal, A., Swaan, P. W., and Nigam, S. K. (2008) Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination. J. Biol. Chem. 283, 8654 – 8663
19. Nagle, M. A., Truong, D. M., Dnyanmote, A. V., Ahn, S. Y., Eraly, S. A., Wu, W., and Nigam, S. K. (2011) Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling. J. Biol. Chem. 286, 243–251
20. Wikoff, W. R., Nagle, M. A., Kouznetsova, V. L., Tsigelny, I. F., and Nigam, S. K. (2011) Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J. Proteome Res. 10, 2842–2851
21. Ahn, S. Y., Jamshidi, N., Mo, M. L., Wu, W., Eraly, S. A., Dnyanmote, A., Bush, K. T., Gallegos, T. F., Sweet, D. H., Palsson, B. Ø., and Nigam, S. K. (2011) Linkage of organic anion transporter-1 to metabolic pathways through integrated “omics”-driven network and functional analysis. J. Biol. Chem. 286, 31522–31531
22. Sweeney, D. E., Vallon, V., Rieg, T., Wu, W., Gallegos, T. F., and Nigam, S. K. (2011) Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney. Mol. Pharmacol. 80, 147–154
23. Nagle, M. A., Wu, W., Eraly, S. A., and Nigam, S. K. (2013) Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neurosci. Lett. 534, 133–138
24. Wolman, A. T., Gionfriddo, M. R., Heindel, G. A., Mukhija, P., Witkowski, S., Bommareddy, A., and Vanwert, A. L. (2013) Organic anion transporter 3 interacts selectively with lipophilic -lactam antibiotics. Drug Metab. Dispos. 41, 791– 800
25. Wu, W., Jamshidi, N., Eraly, S. A., Liu, H. C., Bush, K. T., Palsson, B. O., and Nigam, S. K. (2013) Multispecific drug transporter Slc22a8 (Oat3) regulates multiple metabolic and signaling pathways. Drug Metab. Dispos. 41, 1825–1834
26. Torres, A. M., Dnyanmote, A. V., Bush, K. T., Wu, W., and Nigam, S. K. (2011) Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. J. Biol. Chem. 286, 26391–26395
27. Wu, W., Bush, K. T., and Nigam, S. K. (2017) Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci. Rep. 7, 4939
28. Zhu, C., Nigam, K. B., Date, R. C., Bush, K. T., Springer, S. A., Saier, M. H., Jr, Wu, W., and Nigam, S. K. (2015) Evolutionary analysis and classification of OATs, OCTs, OCTNs, and other SLC22 transporters: structure-function implications and analysis of sequence motifs. PLoS ONE 10, e0140569
29. Wu, W., Baker, M. E., Eraly, S. A., Bush, K. T., and Nigam, S. K. (2009) Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members. Physiol. Genomics 38, 116 –124
30. Eraly, S. A., Monte, J. C., and Nigam, S. K. (2004) Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol. Genomics 18, 12–24
31. Nigam, S. K., Wu, W., Bush, K. T., Hoenig, M. P., Blantz, R. C., and Bhatnagar, V. (2015) Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin. J. Am. Soc. Nephrol. 10, 2039 –2049
32. Pavlova, A., Sakurai, H., Leclercq, B., Beier, D. R., Yu, A. S., and Nigam, S. K. (2000) Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am. J. Physiol. Renal Physiol. 278, F635–F643
33. Kaler, G., Truong, D. M., Sweeney, D. E., Logan, D. W., Nagle, M., Wu, W., Eraly, S. A., and Nigam, S. K. (2006) Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem. Biophys. Res. Commun. 351, 872– 876
34. Monte, J. C., Nagle, M. A., Eraly, S. A., and Nigam, S. K. (2004) Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem. Biophys. Res. Commun. 323, 429 – 436
35. Wu, W., Bush, K. T., Liu, H. C., Zhu, C., Abagyan, R., and Nigam, S. K. (2015) Shared ligands between organic anion transporters (OAT1 and OAT6) and odorant receptors. Drug Metab. Dispos. 43, 1855–1863
36. Ahn, S. Y., and Nigam, S. K. (2009) Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol. Pharmacol. 76, 481– 490
37. Liu, H. C., Jamshidi, N., Chen, Y., Eraly, S. A., Cho, S. Y., Bhatnagar, V., Wu, W., Bush, K. T., Abagyan, R., Palsson, B. O., and Nigam, S. K. (2016) An organic anion transporter 1 (OAT1)-centered metabolic network. J. Biol. Chem. 291, 19474 –19486
38. Wu, W., Dnyanmote, A. V., and Nigam, S. K. (2011) Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. Mol. Pharmacol. 79, 795– 805
39. Kaler, G., Truong, D. M., Khandelwal, A., Nagle, M., Eraly, S. A., Swaan, P. W., and Nigam, S. K. (2007) Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members. J. Biol. Chem. 282, 23841–23853
40. Prentice, K. J., Luu, L., Allister, E. M., Liu, Y., Jun, L. S., Sloop, K. W., Hardy, A. B., Wei, L., Jia, W., Fantus, I. G., Sweet, D. H., Sweeney, G., Retnakaran, R., Dai, F. F., and Wheeler, M. B. (2014) The furan fatty acid metabolite CMPF is elevated in diabetes and induces beta cell dysfunction. Cell Metab. 19, 653– 666
41. Saito, H. (2010) Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol. Ther. 125, 79 –91
42. Sharma, K., Karl, B., Mathew, A. V., Gangoiti, J. A., Wassel, C. L., Saito, R., Pu, M., Sharma, S., You, Y. H., Wang, L., Diamond-Stanic, M., Linden-meyer, M. T., Forsblom, C., Wu, W., Ix, J. H., et al. (2013) Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901–1912
43. Bhatnagar, V., Richard, E. L., Wu, W., Nievergelt, C. M., Lipkowitz, M. S., Jeff, J., Maihofer, A. X., and Nigam, S. K. (2016) Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling. Clin. Kidney J. 9, 444 – 453
44. Liu, H. C., Goldenberg, A., Chen, Y., Lun, C., Wu, W., Bush, K. T., Balac, N., Rodriguez, P., Abagyan, R., and Nigam, S. K. (2016) Molecular properties of drugs interacting with SLC22 transporters OAT1, OAT3, OCT1, and OCT2: a machine-learning approach. J. Pharmacol. Exp. Ther. 359, 215–229
45. Ahn, S. Y., Eraly, S. A., Tsigelny, I., and Nigam, S. K. (2009) Interaction of organic cations with organic anion transporters. J. Biol. Chem. 284, 31422–31430
46. Chiang, J. Y. (2013) Bile acid metabolism and signaling. Compr. Physiol. 3, 1191–1212
47. Ridlon, J. M., Kang, D. J., Hylemon, P. B., and Bajaj, J. S. (2014) Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338
48. Rechner, A. R., Kuhnle, G., Bremner, P., Hubbard, G. P., Moore, K. P., and Rice-Evans, C. A. (2002) The metabolic fate of dietary polyphenols in humans. Free Radic. Biol. Med. 33, 220 –235
49. Gibson, D. T. (1967) Microbial degradation of aromatic compounds. Science 161, 1093–1097
50. Nicholson, J. K., and Wilson, I. D. (2003) Opinion: understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nat. Rev. Drug Discov. 2, 668 – 676
51. Beebe, K., and Pappan, K. (2016) Metabolomics–a key technology for microbiome research. Metabolon http://metabolomics.metabolon.com/acton/media/17033/microbiome-ebook
52. Mazerska, Z., Mróz, A., Pawl owska, M., and Augustin, E. (2016) The role of glucuronidation in drug resistance. Pharmacol. Ther. 159, 35–55
53. Legette, L. L., Prasain, J., King, J., Arabshahi, A., Barnes, S., and Weaver, C. M. (2014) Pharmacokinetics of equol, a soy isoflavone metabolite, changes with the form of equol (dietary versus intestinal production) in ovariectomized rats. J. Agric. Food Chem. 62, 1294 –1300
54. Lennerz, B. S., Vafai, S. B., Delaney, N. F., Clish, C. B., Deik, A. A., Pierce, K. A., Ludwig, D. S., and Mootha, V. K. (2015) Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. Mol. Genet. Metab. 114, 73–79
55. Badenhorst, C. P., Erasmus, E., van der Sluis, R., Nortje, C., and van Dijk, A. A. (2014) A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. Drug Metab. Rev. 46, 343–361
56. Keszthelyi, D., Troost, F. J., and Masclee, A. A. (2009) Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function. Neurogastroenterol. Motil. 21, 1239 –1249
57. Badawy, A. A. (2017) Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. Int. J. Tryptophan Res. 10, 1178646917691938
58. Bender, D. A. (1983) Biochemistry of tryptophan in health and disease. Mol. Aspects Med. 6, 101–197
59. Peters, J. C. (1991) Tryptophan nutrition and metabolism: an overview. Adv. Exp. Med. Biol. 294, 345–358
60. Namkung, J., Kim, H., and Park, S. (2015) Peripheral serotonin: a new player in systemic energy homeostasis. Mol. Cells 38, 1023–1028
61. Konishi, Y., and Kobayashi, S. (2004) Microbial metabolites of ingested caffeic acid are absorbed by the monocarboxylic acid transporter (MCT) in intestinal Caco-2 cell monolayers. J. Agric. Food Chem. 52, 6418 – 6424
62. Flydal, M. I., and Martinez, A. (2013) Phenylalanine hydroxylase: function, structure, and regulation. IUBMB Life 65, 341–349
63. Ney, D. M., Blank, R. D., and Hansen, K. E. (2014) Advances in the nutritional and pharmacological management of phenylketonuria. Curr. Opin. Clin. Nutr. Metab. Care 17, 61– 68
64. Deng, H., Hu, H., and Fang, Y. (2012) Multiple tyrosine metabolites are GPR35 agonists. Sci. Rep. 2, 373
65. Martinot, E., Sèdes, L., Baptissart, M., Lobaccaro, J. M., Caira, F., Beau-doin, C., and Volle, D. H. (2017) Bile acids and their receptors. Mol. Aspects Med. 56, 2–9
66. Chu, L., Zhang, K., Zhang, Y., Jin, X., and Jiang, H. (2015) Mechanism underlying an elevated serum bile acid level in chronic renal failure patients. Int. Urol. Nephrol. 47, 345–351
67. van Berge Henegouwen, G. P., Brandt, K. H., Eyssen, H., and Parmentier, G. (1976) Sulphated and unsulphated bile acids in serum, bile, and urine of patients with cholestasis. Gut 17, 861– 869
68. Chen, J., Terada, T., Ogasawara, K., Katsura, T., and Inui, K. (2008) Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis. Am. J. Physiol. Renal Physiol. 295, F247–F252
69. Jimenez, F., Monte, M. J., El-Mir, M. Y., Pascual, M. J., and Marin, J. J. (2002) Chronic renal failure-induced changes in serum and urine bile acid profiles. Dig. Dis. Sci. 47, 2398 –2406
70. Sahu, M., Sinha, S. K., and Pandey, K. K. (2013) Computer aided drug design: the most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Comp. Engineer Intell Systems 4, 22–26
71. Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A., and Schwartz, T. W. (2017) GPCR-mediated signaling of metabolites. Cell Metab. 25, 777–796
72. Tan, J. K., McKenzie, C., Mariño, E., Macia, L., and Mackay, C. R. (2017) Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation. Annu. Rev. Immunol. 35, 371– 402
73. Thorburn, A. N., Macia, L., and Mackay, C. R. (2014) Diet, metabolites, and “Western-lifestyle” inflammatory diseases. Immunity 40, 833– 842
74. Mackenzie, A. E., and Milligan, G. (2017) The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113, 661– 671
75. Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J., and Schoonjans, K. (2008) Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678 – 693
76. Guo, C., Chen, W. D., and Wang, Y. D. (2016) TGR5, not only a metabolic regulator. Front. Physiol. 7, 646
77. Pritchard, J. B. (1988) Coupled transport of p-aminohippurate by rat kidney basolateral membrane vesicles. Am. J. Physiol. 255, F597–F604
78. Shimada, H., Moewes, B., and Burckhardt, G. (1987) Indirect coupling to Na of p-aminohippuric acid uptake into rat renal basolateral membrane vesicles. Am. J. Physiol. 253, F795–F801
79. Pritchard, J. B. (1995) Intracellular -ketoglutarate controls the efficacy of renal organic anion transport. J. Pharmacol. Exp. Ther. 274, 1278–1284
80. Martovetsky, G., Tee, J. B., and Nigam, S. K. (2013) Hepatocyte nuclear factors 4a and 1a regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters. Mol. Pharmacol. 84, 808 – 823
81. Martovetsky, G., Bush, K. T., and Nigam, S. K. (2016) Kidney versus liver specification of SLC and ABC drug transporters, tight junction molecules, and biomarkers. Drug Metab. Dispos. 44, 1050 –1060
82. Gallegos, T. F., Martovetsky, G., Kouznetsova, V., Bush, K. T., and Nigam, S. K. (2012) Organic anion and cation SLC22 “drug” transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule. PLoS One 7, e40796
83. Evans, A. M., DeHaven, C. D., Barrett, T., Mitchell, M., and Milgram, E. (2009) Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal. Chem. 81, 6656 – 6667
84. Ohta, T., Masutomi, N., Tsutsui, N., Sakairi, T., Mitchell, M., Milburn, M. V., Ryals, J. A., Beebe, K. D., and Guo, L. (2009) Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer 344 male rats. Toxicol. Pathol. 37, 521–535
85. Xia, J., Sinelnikov, I. V., Han, B., and Wishart, D. S. (2015) MetaboAnalyst 3.0 –making metabolomics more meaningful. Nucleic Acids Res. 43, W251–W257
86. Vallon, V., Eraly, S. A., Rao, S. R., Gerasimova, M., Rose, M., Nagle, M., Anzai, N., Smith, T., Sharma, K., Nigam, S. K., and Rieg, T. (2012) A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am. J. Physiol. Renal Physiol. 302, F1293–F1299