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Fungus‐Derived Zearalenone as an Inhibitor of cAMP‐Dependent Chloride Secretion in Human Colonic Epithelial T84 Cells
Author(s) -
Muangnil Paradorn,
Tadpetch Kwanruthai,
Rukachaisirikul Vatcharin,
Chatsudthipong Varanuj,
Muanprasat Chatchai
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.703.17
Subject(s) - cystic fibrosis transmembrane conductance regulator , secretion , chloride channel , apical membrane , zearalenone , intracellular , chemistry , mucus , biochemistry , medicine , endocrinology , biology , ecology , food science , membrane , aflatoxin , gene
Secretory diarrhea remains a major health problem caused by either intestinal infection or side‐effect of many drugs. An elevation in intracellular cAMP activates transepithelial Cl − secretion, which provides the driving force for secretory diarrhea. Therefore, inhibition of cAMP‐activated transepithelial Cl − secretion in intestinal mucosa is regarded as a potential therapeutic strategy for secretory diarrhea. This study aimed to identify fungus‐derived compounds that inhibit cAMP‐activated transepithelial Cl − secretion and investigate its underlying mechanism(s). From the screening of compounds derived from fungi, zearalenone (β‐resorcyclic acid lactone produced by Fusarium fungi) was found to inhibit cAMP‐activated Cl − secretion across human intestinal epithelial (T84) cell monolayers as measured by short‐circuit current (I sc ) analysis with half maximal inhibitory concentration (IC 50 ) of ~ 0.5 μM. This effect was observed only when zearalenone was added into apical side, but not basolateral side, suggesting that zearalenone affects mainly apical transport processes. We further demonstrated that zearalenone reversibly inhibited cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated apical Cl − transport with IC 50 ~ 0.8 μM, indicating that zearalenone inhibits cAMP‐acivated Cl − secretion in T84 cell, at least in part, by inhibiting CFTR Cl − channel activity. The mechanisms of zearalenone‐induced CFTR inhibition involved neither phosphodiesterase‐mediated cAMP degradation, multi‐drug resistance protein 4‐mediated cAMP efflux nor protein phosphatase‐mediated CFTR dephosphorylation. In addition, the CFTR inhibitory effect of zearalenone was not affected by co‐treatment with β‐estradiol, indicating that the CFTR inhibition by this compound did not result from its binding to estrogen binding site on the CFTR. Zearalenone at concentrations up to 50 μM did not produce the cytotoxic effect on T84 cells. This study revealed that zearalenone represents the first class of CFTR inhibitors derived from fungi, which may be useful in the treatment of secretory diarrhea resulting from overactivation of cAMP‐dependent chloride secretion. Support or Funding Information This work was supported by the NSTDA Chair Professor grant (the Fourth Grant) of the Crown Property Bureau Foundation and the National Science and Technology Development Agency and BRG5890008 grant from the Thailand Research Fund and Mahidol University