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Research ArticleArticle

Interaction between Two Sulfate-Conjugated Uremic Toxins, p-Cresyl Sulfate and Indoxyl Sulfate, during Binding with Human Serum Albumin

Hiroshi Watanabe, Tsuyoshi Noguchi, Yohei Miyamoto, Daisuke Kadowaki, Shunsuke Kotani, Makoto Nakajima, Shigeyuki Miyamura, Yu Ishima, Masaki Otagiri and Toru Maruyama
Drug Metabolism and Disposition July 2012, 40 (7) 1423-1428; DOI: https://doi.org/10.1124/dmd.112.045617
Hiroshi Watanabe
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Tsuyoshi Noguchi
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Yohei Miyamoto
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Daisuke Kadowaki
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Shunsuke Kotani
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Makoto Nakajima
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Shigeyuki Miyamura
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Yu Ishima
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Masaki Otagiri
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Toru Maruyama
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Abstract

Recently, p-cresyl sulfate (PCS) has been identified as a protein-bound uremic toxin. Moreover, the serum-free concentration of PCS, which is associated with its efficacy of hemodialysis, appears to be a good predictor of survival in chronic kidney disease (CKD). We previously found that PCS interacts with indoxyl sulfate (IS), another sulfate-conjugated uremic toxin, during renal excretion via a common transporter. The purpose of this study was to further investigate the interaction between PCS and IS on the binding to human serum albumin (HSA). Here, we used ultrafiltration to show that there is only one high-affinity binding site for PCS, with a binding constant on the order of 105 M−1 (i.e., comparable to that of IS). However, a binding constant of the low-affinity binding site for PCS is 2.5-fold greater than that for IS. Displacement of a fluorescence probe showed that PCS mainly binds to site II, which is the high-affinity site for PCS, on HSA. This finding was further supported by experiments using mutant HSA (R410A/Y411A) that displayed reduced site II ligand binding. A Klotz analysis showed that there could be competitive inhibition between PCS and IS on HSA binding. A similar interaction between PCS and IS on HSA was also observed under the conditions mimicking CKD stage 4 to 5. The present study suggests that competitive interactions between PCS and IS in both HSA binding and the renal excretion process could contribute to fluctuations in their free serum concentrations in patients with CKD.

Footnotes

  • This work was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research KAKENHI 23790187]; and the Kidney Foundation, Japan.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045617.

  • ABBREVIATIONS:

    CKD
    chronic kidney disease
    PCS
    p-cresyl sulfate
    IS
    indoxyl sulfate
    OAT
    organic anion transporter
    HSA
    human serum albumin
    HA
    hippurate
    IA
    indoleacetic acid
    CMPF
    3-carboxy-4-methyl-5-propyl-2-furan propionate
    PBS
    phosphate-buffered saline
    HPLC
    high-performance liquid chromatography.

  • Received March 12, 2012.
  • Accepted April 18, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

INTERACTION BETWEEN PCS AND IS ON HUMAN SERUM ALBUMIN

Hiroshi Watanabe, Tsuyoshi Noguchi, Yohei Miyamoto, Daisuke Kadowaki, Shunsuke Kotani, Makoto Nakajima, Shigeyuki Miyamura, Yu Ishima, Masaki Otagiri and Toru Maruyama
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1423-1428; DOI: https://doi.org/10.1124/dmd.112.045617

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Research ArticleArticle

INTERACTION BETWEEN PCS AND IS ON HUMAN SERUM ALBUMIN

Hiroshi Watanabe, Tsuyoshi Noguchi, Yohei Miyamoto, Daisuke Kadowaki, Shunsuke Kotani, Makoto Nakajima, Shigeyuki Miyamura, Yu Ishima, Masaki Otagiri and Toru Maruyama
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1423-1428; DOI: https://doi.org/10.1124/dmd.112.045617
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