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A Plant-Derived Hydrolysable Tannin Inhibits CFTR Chloride Channel: A Potential Treatment of Diarrhea

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Abstract

Purpose

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).

Materials and 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 ∼ 10 µM) 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.

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Abbreviations

CFTR:

cystic fibrosis transmembrane conductance regulator

CFTRinh-172:

3-[(3-trifluoromethyl) phenyl]-5-[(4-carboxyphenyl) methylene]-2-thioxo-4-thiazolidinone

DMSO:

dimethyl sulfoxide

CPT-cAMP:

8-cholorophenyl-thio-cAMP

FRT:

Fisher rat thyroid

MTT:

3-(4, 5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

PBS:

phosphate-buffered saline

PDG:

penta- m- digalloyl- glucose

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Acknowledgements

This work was supported by the Thailand Research Fund (grant RMU5180029 to VC), the National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand National Science and Technology Development Agency (Grant 3-2548) and Center for Environmental Health, Toxicology and Management of Chemicals, Commission for Higher Education, Ministry of Education, Thailand.

We thank Prof. Alan S. Verkman (University of California, San Francisco, CA, USA) for providing the FRT cells and highly appreciate Prof. Prapon Wilairat (Department of Biochemistry, Mahidol University) for his valuable comments and corrections of this manuscript.

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Authors and Affiliations

  1. Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand

    Nisa Wongsamitkul & Lalida Sirianant

  2. Department of Physiology, Faculty of Science, Mahidol University, 272 Rama VI Road, Ratchathewi District, Bangkok, 10400, Thailand

    Chatchai Muanprasat & Varanuj Chatsudthipong

Authors
  1. Nisa Wongsamitkul
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  2. Lalida Sirianant
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  3. Chatchai Muanprasat
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  4. Varanuj Chatsudthipong
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Correspondence to Chatchai Muanprasat or Varanuj Chatsudthipong.

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Wongsamitkul, N., Sirianant, L., Muanprasat, C. et al. A Plant-Derived Hydrolysable Tannin Inhibits CFTR Chloride Channel: A Potential Treatment of Diarrhea. Pharm Res 27, 490–497 (2010). https://doi.org/10.1007/s11095-009-0040-y

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  • DOI: https://doi.org/10.1007/s11095-009-0040-y

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