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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 3, 2005; DOI: 10.1124/jpet.105.085399

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Received for publication February 24, 2005.
Revised April 13, 2005.
Accepted for publication April 14, 2005.

Role of N-terminal amino acids in the absorption- enhancing effects of the C-terminal fragment of Clostridium Perfringens enterotoxin

Akane Masuyama 1, Masuo Kondoh 1*, Hirotoshi Seguchi 1, Azusa Takahashi 1, Motoki Harada 1, Makiko Fujii 1, Hiroyuki Mizuguchi 2, Yasuhiko Horiguchi 3, Yoshiteru Watanabe 1

1 Showa Pharmaceutical University 2 National Institute of Biomedical Innovation 3 Osaka University

* Address correspondence to: E-mail: masuo{at}ac.shoyaku.ac.jp

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. But, 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 4,000 Da. But, 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. Taken 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.


Key words: caco-2, claudin-4, clostridium perfringens enterotoxin, dextran, jejunal absorption, transepithelial electric resistance


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