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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of N-Terminal Amino Acids in the Absorption-Enhancing Effects of the C-Terminal Fragment of Clostridium perfringens Enterotoxin

Akane Masuyama, Masuo Kondoh, Hirotoshi Seguchi, Azusa Takahashi, Motoki Harada, Makiko Fujii, Hiroyuki Mizuguchi, Yasuhiko Horiguchi and Yoshiteru Watanabe
Journal of Pharmacology and Experimental Therapeutics August 2005, 314 (2) 789-795; DOI: https://doi.org/10.1124/jpet.105.085399
Akane Masuyama
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Masuo Kondoh
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Hirotoshi Seguchi
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Azusa Takahashi
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Motoki Harada
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Makiko Fujii
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Hiroyuki Mizuguchi
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Yasuhiko Horiguchi
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Yoshiteru Watanabe
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Abstract

We recently found that a polypeptide, the C-terminal of Clostridium perfringens enterotoxin (C-CPE), was a novel type of drug absorption enhancer. The C-terminal of C-CPE is thought to play a role in the binding of C-CPE to its receptor, claudin-4; however, the function of the N-terminal of C-CPE is unclear. In the present study, we evaluated the role of the N-terminal domain of C-CPE in jejunal absorption and claudin-4 binding. The treatment of rat jejunum with C-CPE resulted in enhanced absorption of dextran, with a molecular weight of 4000 Da. However, treatment with C-CPE220, which lacks the 36 N-terminal amino acids of C-CPE, did not enhance jejunal absorption. C-CPE had affinity for claudin-4 in rat jejunum lysates and Caco-2 lysates, but C-CPE220 did not. Interaction of C-CPE with the recombinant extracellular domain 2 of human claudin-4 (EC2hCld-4), which is the putative binding site for C-CPE, was observed, but C-CPE220 had no affinity for EC2hCld-4. To investigate the effect of C-CPE220 on the barrier function of tight junctions, we measured transepithelial electric resistance (TER) in C-CPE- or C-CPE220-treated Caco-2 monolayer cells. Although C-CPE decreased TER in Caco-2 monolayer cells, C-CPE220 did not disrupt the barrier function of tight junctions. Together, these results indicate that the 36 N-terminal amino acids of C-CPE may be necessary for the enhanced absorption mediated by C-CPE and play a partial role in binding to claudin-4.

Footnotes

  • This study is partly supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (Japan).

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

  • doi:10.1124/jpet.105.085399.

  • ABBREVIATIONS: TJ, tight junction; CPE, Clostridium perfringens enterotoxin; C-CPE, C-terminal fragment of Clostridium perfringens enterotoxin; CPE-R, Clostridium perfringens enterotoxin receptor; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; FD-4, fluorescein isothiocyanate-dextran with a molecular mass of 4000 Da; AUC0–4, area under the plasma concentration-time curve from 0 to 4 h; Ab, antibody; GST, glutathione S-transferase; EC2hCld-4, extracellular domain 2 of human claudin-4; aa, amino acid; TER, transepithelial electric resistance; AUC, the area under the plasma concentration-time curve; Ni-NTA, nickel-nitrilotriacetic acid.

  • ↵1 These authors equally contributed to this work.

    • Received February 24, 2005.
    • Accepted April 14, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of N-Terminal Amino Acids in the Absorption-Enhancing Effects of the C-Terminal Fragment of Clostridium perfringens Enterotoxin

Akane Masuyama, Masuo Kondoh, Hirotoshi Seguchi, Azusa Takahashi, Motoki Harada, Makiko Fujii, Hiroyuki Mizuguchi, Yasuhiko Horiguchi and Yoshiteru Watanabe
Journal of Pharmacology and Experimental Therapeutics August 1, 2005, 314 (2) 789-795; DOI: https://doi.org/10.1124/jpet.105.085399

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Role of N-Terminal Amino Acids in the Absorption-Enhancing Effects of the C-Terminal Fragment of Clostridium perfringens Enterotoxin

Akane Masuyama, Masuo Kondoh, Hirotoshi Seguchi, Azusa Takahashi, Motoki Harada, Makiko Fujii, Hiroyuki Mizuguchi, Yasuhiko Horiguchi and Yoshiteru Watanabe
Journal of Pharmacology and Experimental Therapeutics August 1, 2005, 314 (2) 789-795; DOI: https://doi.org/10.1124/jpet.105.085399
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