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Research ArticleArticle

Multispecific Drug Transporter Slc22a8 (Oat3) Regulates Multiple Metabolic and Signaling Pathways

Wei Wu, Neema Jamshidi, Satish A. Eraly, Henry C. Liu, Kevin T. Bush, Bernhard O. Palsson and Sanjay K. Nigam
Drug Metabolism and Disposition October 2013, 41 (10) 1825-1834; DOI: https://doi.org/10.1124/dmd.113.052647
Wei Wu
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Neema Jamshidi
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Satish A. Eraly
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Henry C. Liu
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Kevin T. Bush
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Bernhard O. Palsson
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Sanjay K. Nigam
Departments of Pediatrics (H.C.L., K.T.B., S.K.N.), Medicine, Division of Nephrology and Hypertension (W.W., S.A.E., S.K.N.), Cellular and Molecular Medicine (S.K.N.), and Bioengineering (N.J., B.O.P., S.K.N.), University of California, San Diego, La Jolla, California
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Abstract

Multispecific drug transporters of the solute carrier and ATP-binding 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.

Footnotes

    • Received May 14, 2013.
    • Accepted August 1, 2013.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM88824, GM098449 and GM104098] and Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD07160] (to S.K.N.), and National Heart, Lung, and Blood Institute [Grant HL094728] (to S.A.E.)

  • dx.doi.org/10.1124/dmd.113.052647.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
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Research ArticleArticle

OAT3 Handling of Endogenous Metabolites and Flavonoids

Wei Wu, Neema Jamshidi, Satish A. Eraly, Henry C. Liu, Kevin T. Bush, Bernhard O. Palsson and Sanjay K. Nigam
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1825-1834; DOI: https://doi.org/10.1124/dmd.113.052647

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Research ArticleArticle

OAT3 Handling of Endogenous Metabolites and Flavonoids

Wei Wu, Neema Jamshidi, Satish A. Eraly, Henry C. Liu, Kevin T. Bush, Bernhard O. Palsson and Sanjay K. Nigam
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1825-1834; DOI: https://doi.org/10.1124/dmd.113.052647
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