Hydroxyxanthone as an inhibitor of cAMP-activated apical chloride channel in human intestinal epithelial cell.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
This study revealed that hydroxyxanthone represents another chemical class of polyphenolic compounds that may hold promise as anti-secretory therapy for cholera.
Graduate Program in Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Wachiraporn
W
Luerang
Thongchai
T
Khammee
Watinee
W
Kumpum
Sunit
S
Suksamrarn
Varanuj
V
Chatsudthipong
Chatchai
C
Muanprasat
D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D011916:Rats, Inbred F344; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
D018118:Chloride Channels; D044004:Xanthones; D000242:Cyclic AMP