Inhibition of butyrate uptake by the primary bile salt chenodeoxycholic acid in intestinal epithelial cells

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) upon14C-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 14C-BT uptake by IEC-6 cells (IC50 = 120 µM), and, less potently, by Caco-2 cells (IC50 = 402 µM). The inhibitory effect of CDCA upon 14C-BT uptake did not result from a decrease in cell proliferation or viability. In IEC-6 cells: (1) uptake of 14C-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 14C-BT; (3) CDCA significantly increased the mRNA expression level of SMCT1; (4) inhibition of 14C-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 14C-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. J. Cell. Biochem. 113: 2937–2947, 2012. © 2012 Wiley Periodicals, Inc.