β-eudesmol but not atractylodin exerts an inhibitory effect on CFTR-mediated chloride transport in human intestinal epithelial cells.

Abstract

Oriental herbal medicine with the two bioactive constituents, β-eudesmol (BE) and atractylodin (AT), has been used as a remedy for gastrointestinal disorders. There was no scientific evidence reporting their antidiarrheal effect and underpinning mechanisms. Therefore, we aimed to investigate the anti-secretory activity of these two compounds in vitro. The inhibitory effect of BE and AT on cAMP-induced Cl- secretion was evaluated by Ussing chamber in human intestinal epithelial (T84) cells. Short-circuit current (ISC) and apical Cl- current (ICl-) were measured after adding indirect and direct cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activator. MTT assay was used to determine cellular cytotoxicity. Protein-ligand interaction was investigated by in silico molecular docking analysis. BE, but not AT concentration-dependently (IC50 of ~1.05 µM) reduced cAMP-mediated, CFTRinh-172 inhibitable Cl- secretion as determined by transepithelial ISC across a monolayer of T84 cells. Potency of CFTR-mediated ICl- inhibition by BE did not change with the use of different CFTR activators suggesting a direct blockage of the channel active site(s). Pretreatment with BE completely prevented cAMP-induced ICl-. Furthermore, BE at concentrations up to 200 µM (24 h) had no effect on T84 cell viability. In silico studies indicated that BE could best dock onto dephosphorylated structure of CFTR at ATP-binding pockets in nucleotide-binding domain (NBD) 2 region. These findings provide the first evidence for the anti-secretory effect of BE involving inhibition of CFTR function. BE represents a promising candidate for the therapeutic or prophylactic intervention of diarrhea resulted from intestinal hypersecretion of Cl.

• Authors: Phuntila Tharabenjasin, Ronaldo P Ferraris, Kiattawee Choowongkomon, Pawin Pongkorpsakol, Nichakorn Worakajit, Sutthipong Sawasvirojwong, Noel Pabalan, Kesara Na-Bangchang, Chatchai Muanprasat
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 142 Pg. 112030 (Oct 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34426253 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Antidiarrheals
• CFTR protein, human
• Chloride Channels
• Chlorides
• Furans
• Sesquiterpenes, Eudesmane
• Cystic Fibrosis Transmembrane Conductance Regulator
• beta-eudesmol
• atractylodin
• Cyclic AMP

Topics

• Antidiarrheals (administration & dosage, pharmacology)
• Biological Transport (drug effects)
• Cell Line
• Chloride Channels (metabolism)
• Chlorides (metabolism)
• Cyclic AMP (metabolism)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Epithelial Cells (drug effects, metabolism)
• Furans (administration & dosage, pharmacology)
• Humans
• Inhibitory Concentration 50
• Intestinal Mucosa (cytology, drug effects)
• Molecular Docking Simulation
• Sesquiterpenes, Eudesmane (administration & dosage, pharmacology)