Short-chain fatty acids exert opposite effects on the expression and function of p-glycoprotein and breast cancer resistance protein in rat intestine

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are involved in intestinal barrier. Short-chain fatty acids (SCFAs) play important roles in maintaining intestinal barrier. In this study we explored how SCFAs affected the expression and function of intestinal P-gp and BCRP in rats....

Full description

Saved in:
Bibliographic Details
Published in:Acta pharmacologica Sinica 2021-03, Vol.42 (3), p.470-481
Main Authors: Xie, Qiu-Shi, Zhang, Jia-Xin, Liu, Ming, Liu, Pei-Hua, Wang, Zhong-Jian, Zhu, Liang, Jiang, Ling, Jin, Meng-Meng, Liu, Xiao-Nan, Liu, Li, Liu, Xiao-Dong
Format: Article
Language:English
Subjects:
Acetates - pharmacology
Acetic acid
Animals
ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism
BCRP protein
Breast cancer
Butyrates - pharmacology
Caco-2 Cells
Drinking water
Enterocytes
Fatty acids
Fexofenadine
Glycoproteins
Histone deacetylase
Histone Deacetylase Inhibitors - pharmacology
Humans
Intestinal Mucosa - metabolism
Intestine
Male
Mice
Mice, Inbred BALB C
NF-kappa B - metabolism
NF-κB protein
P-Glycoprotein
PPAR gamma - metabolism
Propionates - pharmacology
Propionic acid
Protein expression
Proteins
Rats
Rats, Sprague-Dawley
Rosuvastatin Calcium - pharmacokinetics
Signal Transduction - drug effects
Terfenadine - analogs & derivatives
Terfenadine - pharmacokinetics
Theophylline
Troglitazone
Tumor necrosis factor-α
Valproic acid
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are involved in intestinal barrier. Short-chain fatty acids (SCFAs) play important roles in maintaining intestinal barrier. In this study we explored how SCFAs affected the expression and function of intestinal P-gp and BCRP in rats. Rats received 150 mM acetate, propionate or butyrate in drinking water for 4 weeks. In SCFA-treated rats, the expression and function of intestinal P-gp were decreased, but those of intestinal BCRP were increased; intestinal p-p65 was also decreased, which was positively related to P-gp protein expression. Among the three SCFAs tested, butyrate exhibited the strongest induction or inhibitory effect, followed by propionate and acetate. Similar results were observed in mouse primary enterocytes and Caco-2 cells treated with acetate (5 mM), propionate (2 mM), or butyrate (1 mM). In Caco-2 cells, addition of butyrate, vorinostat, and valproate (two classic HDAC inhibitors), Bay117082 (selective inhibitor of NF-κB activation) or NF-κB p65 silencing significantly decreased the expression of P-gp and the level of phosphorylated p65 (p-p65). Furthermore, butyrate attenuated the expression of P-gp and p-p65 induced by TNF-α (NF-κB activator) and theophylline (HDAC activator). However, vorinostat, valproate, Bay117082, TNF-α or p65 silencing hardly affected BCRP protein expression. But GW9662 (selective PPARγ antagonist) or PPARγ silencing abolished BCRP induction by butyrate and troglitazone (PPARγ agonist). SCFAs-treated rats showed higher intestinal protein expression of PPARγ, which was positively related to BCRP protein expression. Butyrate increased plasma exposure of fexofenadine but decreased that of rosuvastatin following oral dose to rats. In conclusion, SCFAs exert opposite effects on the expression and function of intestinal P-gp and BCRP; butyrate downregulated P-gp expression and function possibly via inhibiting HDAC/NF-κB pathways; butyrate induced BCRP expression and function partly via PPARγ activation.
ISSN:1671-4083
1745-7254
DOI:10.1038/s41401-020-0402-x