Taurodeoxycholate Modulates Apical Cl−/OH− Exchange Activity in Caco2 Cells

Seema Saksena; Sangeeta Tyagi; Ravinder Gill; Krishnamurthy Ramaswamy; Pradeep Dudeja
May 2007
Digestive Diseases & Sciences;May2007, Vol. 52 Issue 5, p1270
Academic Journal
Abstract  Bile acid malabsorption has been shown to be associated with diarrhea in cases such as ileal resection Crohn’s disease of the ileum, and radiation enteritis. The mechanisms of bile acid-induced diarrhea are not fully understood. Although the induction of colonic chloride secretion in response to bile acids has been extensively investigated, to date the direct effect of bile acids on intestinal chloride absorption has not been well defined. Therefore, the current studies were undertaken to investigate the effect of bile acids on the apical Cl−/OH− exchange process utilizing Caco2 monolayers as an in vitro cellular model. Cl−/OH− exchange activity was measured as DIDS-sensitive pH gradient-driven 36Cl uptake. The results are summarized as follows: (i) short-term exposure (20 min) of Caco2 cells to taurodeoxycholate (TDC; 200 μM) and glycochenodeoxycholate (GCDC; 200 μM) acids significantly inhibited apical Cl−/OH− exchange (by ∼60–70%); (ii) the Ca2+ chelator BAPTA-AM blocked the inhibition by TDC; (iii) the reduction in Cl−/OH− exchange by TDC was reversed by the PKC inhibitor, chelerythrine chloride; (iv) functional and inhibitor studies indicated that TDC induced inhibition of Cl−/OH− exchange was mediated via the activation of the PKCβI isoform; (v) the effect of TDC on apical Cl−/OH− exchange was completely blocked by the PI3 kinase inhibitor LY294002 (5 μM); and (vi) the PKA inhibitor, RpcAMP, had no effect on TDC induced inhibition of Cl−/OH− exchange. In conclusion, our studies provide direct evidence for inhibition of human intestinal apical Cl−/OH− exchange activity by bile acids via Ca2+-, PI3 kinase-, and PKCβI-dependent pathways in Caco2 cells.


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