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|Title:||Hydroxyxanthone as an inhibitor of cAMP-activated apical chloride channel in human intestinal epithelial cell|
Graduate Program in Toxicology
|Keywords:||Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics|
|Citation:||Life Sciences. Vol.90, No.25-26 (2012), 988-994|
|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 ~ 100 μM). 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. © 2012 Elsevier Inc.|
|Appears in Collections:||Scopus 2011-2015|
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