title: Inhibition of butyrate uptake by the primary bile salt chenodeoxycholic acid in intestinal epithelial cells.
abstract: Colorectal cancer (CRC) is one of the most common cancers worldwide. Epidemiological and experimental studies suggest that bile acids may play a role in CRC etiology. Our aim was to characterize the effect of the primary bile acid chenodeoxycholic acid (CDCA) upon(14) C-BT uptake in tumoral (Caco-2) and non-tumoral (IEC-6) intestinal epithelial cell lines. A 2-day exposure to CDCA markedly and concentration-dependently inhibited (14) C-BT uptake by IEC-6 cells (IC(50) = 120 µM), and, less potently, by Caco-2 cells (IC(50) = 402 µM). The inhibitory effect of CDCA upon (14) C-BT uptake did not result from a decrease in cell proliferation or viability. In IEC-6 cells: (1) uptake of (14) C-BT involves both a high-affinity and a low-affinity transporter, and CDCA acted as a competitive inhibitor of the high-affinity transporter; (2) CDCA inhibited both Na(+)-coupled monocarboxylate cotransporter 1 (SMCT1)- and H(+)-coupled monocarboxylate transporter 1 (MCT1)-mediated uptake of (14) C-BT; (3) CDCA significantly increased the mRNA expression level of SMCT1; (4) inhibition of (14) C-BT uptake by CDCA was dependent on CaM, MAP kinase (ERK1/2 and p38 pathways), and PKC activation, and reduced by a reactive oxygen species scavenger. Finally, BT (5 mM) decreased IEC-6 cell viability and increased IEC-6 cell differentiation, and CDCA (100 µM) reduced this effect. In conclusion, CDCA is an effective inhibitor of (14) C-BT uptake in tumoral and non-tumoral intestinal epithelial cells, through inhibition of both H(+) -coupled MCT1- and SMCT1-mediated transport. Given the role played by BT in the intestine, this mechanism may contribute to the procarcinogenic effect of CDCA at this level.
authors.affiliation: Faculty of Medicine, Department of Biochemistry, U38-FCT, University of Porto, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonçalves
authors.forename: Telmo
authors.initials: T
authors.lastname: Catarino
authors.forename: Inês
authors.initials: I
authors.lastname: Gregório
authors.forename: Fátima
authors.initials: F
authors.lastname: Martel
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D002087:Butyrates / Q000378:metabolism*; D018938:Caco-2 Cells; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D006801:Humans; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D002087:Butyrates; D002635:Chenodeoxycholic Acid; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1