A plant-derived hydrolysable tannin inhibits CFTR chloride channel: a potential treatment of diarrhea.
OBJECTIVE
The present study examined the effects and mechanisms of actions of penta-m-digalloyl-glucose (PDG), a hydrolysable tannin extracted from Chinese gallnut, on cystic fibrosis transmembrane conductance regulator protein (CFTR).


METHODS
Fisher rat thyroid cells stably expressing human CFTR (FRT cells) and human intestinal T84 cells were used as cell models to investigate the effects of PDG on chloride secretion using short-circuit current analysis. The mechanisms by which PDG affected chloride secretion were also examined. Finally, in vivo antidiarrheal efficacy and effects of PDG on intestinal fluid absorption were evaluated in mouse closed-loop models.


RESULTS
In FRT cells, apical chloride current induced by forskolin, CPT-cAMP and apigenin were reversibly inhibited by PDG (IC50 approximately 10microM) without effects on intracellular cAMP content and cell viability. Similarly, in T84 cells, PDG effectively inhibited chloride secretion induced by forskolin and cholera toxin. However, it had no effect on calcium-induced chloride secretion. In mice, a single intraluminal injection of PDG (0.6 mg/kg) reduced cholera toxin-induced intestinal fluid secretion by 75% with no effect on intestinal fluid absorption.


CONCLUSIONS
PDG represents a new class of CFTR inhibitors. Further development of this class of compounds may provide a new therapeutic intervention for diarrhea.
Wongsamitkul
Nisa
N
Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.
Sirianant
Lalida
L
Muanprasat
Chatchai
C
Chatsudthipong
Varanuj
V
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003967:Diarrhea / Q000188:drug therapy*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010944:Plants / Q000737:chemistry; D051381:Rats
D002712:Chlorides; D004365:Drugs, Chinese Herbal; D047348:Hydrolyzable Tannins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP