Tauroursodeoxycholic acid for the treatment of chronic hepatitis: A dose-response study

Abstract

Background: Tauroursodeoxycholic acid (TUDCA) is of potential benefit in cholestatic disorders. However, the effects of TUDCA on cytosolic free calcium [(Ca2+)i], which regulates hepatocyte secretion, are unknown. Methods: The effect of TUDCA on (Ca2+)i was investigated in groups of isolated rat hepatocytes by microspectrofluorometry and in single cells by confocal line scanning microscopy. Results: Administration of TUDCA (5–50 μmol/L) induced a nearly fourfold increase of basal levels of (Ca2+)i. After a 15 minute treatment period, the TUDCA (10 μmol/L)-induced change in (Ca2+)i was higher than that of other monodi-, and trihydroxy bile acids at equimolar concentrations. Pretreatment with TUDCA (10 μmol/L) markedly reduced or abolished increases in (Ca2+)i induced by phenylephrine (1 μmol/L), the microsomal Ca2+ translocase inhibitor 2,5-di-(tert-butyl)-1,4-benzohydroquinone (25 μmol/L), or taurolithocholic acid (10–25 μmol/L). In Ca2+-free medium, TUDCA caused only a reduced and transient increase in (Ca2+)i. TUDCA (10 μmol/L) induced Ca2+ oscillations in all single cells that responded. However, levels of inositol-1,4,5-trisphosphate (IP3) in hepatocytes were not increased by treatment with TUDCA (10 μmol/L). Conclusions: TUDCA at physiological concentrations potently modulates (Ca2+)i signals in hepatocytes by (1) mobilizing microsomal IP3-sensitive Ca2+ stores by an IP3-independent mechanism, (2) initiating Ca2+ oscillations, and (3) inducing influx of extracellular Ca2+.