Abstract | AIMS: Previous investigation showed that polyphenols abundantly found in many plants could inhibit Cl(-) secretion. The present study was aimed to investigate the effect of phenol containing xanthone derivatives on cAMP-activated intestinal Cl(-) secretion and evaluate potential benefits of these compounds in the treatment of cholera. MAIN METHODS: Four hydroxy xanthones were synthesized via oxidative coupling reaction of the corresponding ortho- hydroxybenzoic acids and hydroxyphenols. Short-circuit current and apical Cl(-) current measurements across monolayers of human intestinal epithelial (T84) cell and Fisher rat thyroid cells transfected with human CFTR (FRT-hCFTR cell) were performed to determine the effect of hydroxyxanthones on cAMP-activated Cl(-) secretion. Intracellular cAMP was measured by immunoassay methods. Anti-diarrheal efficacy was evaluated using closed loop model of cholera. KEY FINDINGS: Among the tested xanthones, 1,3,6-trihydroxyxanthone (THX-001) was found to be the most potent derivative in the inhibition of cAMP-activated Cl(-) secretion across T84 cell monolayers (IC(50)~100μM). Electrophysiological analysis of T84 cells and FRT-hCFTR cells revealed that THX-001 targeted two distinct cAMP-activated Cl(-) channels in the apical membrane of T84 cells, namely, CFTR and inward rectifying Cl(-) channel (IRC). In contrast, THX-001 had no effect on intracellular cAMP levels in these cells. Importantly, THX-001 completely abolished cholera toxin-induced Cl(-) secretion across T84 cell monolayers and significantly inhibited cholera toxin-induced intestinal fluid secretion in mouse closed loop models. SIGNIFICANCE: This study revealed that hydroxyxanthone represents another chemical class of polyphenolic compounds that may hold promise as anti-secretory therapy for cholera.
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Authors | Wachiraporn Luerang, Thongchai Khammee, Watinee Kumpum, Sunit Suksamrarn, Varanuj Chatsudthipong, Chatchai Muanprasat |
Journal | Life sciences
(Life Sci)
Vol. 90
Issue 25-26
Pg. 988-94
(Jun 27 2012)
ISSN: 1879-0631 [Electronic] Netherlands |
PMID | 22634581
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- Chloride Channels
- Xanthones
- Cyclic AMP
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Topics |
- Animals
- Cells, Cultured
- Chloride Channels
(antagonists & inhibitors, metabolism)
- Cyclic AMP
(antagonists & inhibitors, metabolism)
- Epithelial Cells
(drug effects, metabolism)
- Humans
- Intestinal Mucosa
(cytology, drug effects, metabolism)
- Mice
- Mice, Inbred ICR
- Rats
- Rats, Inbred F344
- Xanthones
(chemistry, pharmacology)
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