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Hydroxyxanthone as an inhibitor of cAMP-activated apical chloride channel in human intestinal epithelial cell.
MedLine Citation:
PMID:  22634581     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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-current current and apical Cl(-) current measurements across monolayers of human intestinal epithelial (T84) cell and Fisher rat thyroid cells transfected with human CFTR (FRT-CFTR cell) were performed to determine effect of hydroxy xanthones 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) ~100 μM). Electrophysiological analysis of T84 cells and FRT-CFTR 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 a promise as anti-secretory therapy of cholera.
Authors:
Wachiraporn Luerang; Thongchai Khammee; Watinee Kumpum; Sunit Suksamrarn; Varanuj Chatsudthipong; Chatchai Muanprasat
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-24
Journal Detail:
Title:  Life sciences     Volume:  -     ISSN:  1879-0631     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375521     Medline TA:  Life Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Research Center of Transport Proteins for Medical Innovation (TMED), Mahidol University, Bangkok, Thailand; Graduate Program in Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand.
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