Administration Of Tauroursodeoxycholic Acid Research Articles

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

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+.

Effect of tauroursodeoxycholic acid on serum liver enzyme and serum lipid levels in patients with chronic active hepatitis

Tauroursodeoxycholic acid (TUDCA) is a new natural bile acid amidate being investigated as a gallstone-dissolving agent in humans. We report herein the results of a multicenter, cooperative study that involved 12 hospitals throughout Italy, aimed at evaluating the effects of long-term oral administration of TUDCA (500 mg/d for 3 months) on serum liver enzymes, total bilirubin, and serum lipid levels in patients with biopsy-proven chronic hepatitis due to hepatitis C virus (HCV) or hepatitis B virus (HBV) infection. The study population included 134 anti-HCV—positive and 28 hepatitis B surface antigen-positive patients. TUDCA was well tolerated and safe and was associated with a significant ( P < 0.001) decrease in all serum liver enzyme levels. Aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase levels decreased by a mean of 29.7 ± 14.5%, 24.1 ± 15.9%, and 26.6 ± 19.9%, respectively, after 1 month of therapy and by an additional 5% to 10% by the end of 3 months of therapy. A slight improvement in total bilirubin levels was also observed. In addition, TUDCA caused a slight, but significant, improvement in serum lipid profiles (decreased total cholesterol [ P < 0.001] and triglycerides [ P < 0.05] and increased high-density lipoprotein cholesterol [NS]). These favorable changes were similar in HCV and HBV hepatitis and were independent of age, sex, body weight, and alcohol consumption. These results indicate that TUDCA may have a place in the treatment of patients with chronic hepatitis, a possibility that needs to be verified by means of long-term, prospective, placebo-controlled, double-blind studies

Tauroursodeoxycholate and tauro-β-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content

Cytoprotection by tauroursodeoxycholic acid and tauro-beta-muricholic acid against taurochenodeoxycholic acid-induced toxicity was examined with reference to intracellular bile acid content in primary cultured rat hepatocytes. In comparison with levels in the group administered taurochenodeoxycholic acid 1 mmol/L alone, lactate dehydrogenase levels in the culture medium decreased significantly in groups simultaneously administered taurochenodeoxycholic acid 1 mmol/L and tauroursodeoxycholic acid 0.5 to 2 mmol/L or tauro-beta-muricholic acid. Results of the trypan blue uptake test indicated that the lactate dehydrogenase release was indeed caused by cell damage. After the administration of tauroursodeoxycholic acid 2 mmol/L or tauro-beta-muricholic acid 2 mmol/L, intracellular taurochenodeoxycholic acid content was consistently reduced to half of that after administration of taurochenodeoxycholic acid alone. Simultaneous administration of dibutyl cyclic AMP also reduced intracellular taurochenodeoxycholic acid content and lactate dehydrogenase release. Being rinsed with tauroursodeoxycholic acid and tauro-beta-muricholic acid after being precultured in taurochenodeoxycholic acid 1 mmol/L also markedly reduced their taurochenodeoxycholic acid content. Taurocholic acid caused limited reduction of intracellular taurochenodeoxycholic acid but not suppression of lactate dehydrogenase release. Taurodehydrocholic acid showed no reduction of taurochenodeoxycholic acid content and no decrease of lactate dehydrogenase release. Although only small amounts of tauroursodeoxycholic acid or tauro-beta-muricholic acid were found to accumulate in hepatocytes, taurocholic acid increased as if replacing taurochenodeoxycholic acid. The results suggest that tauroursodeoxycholic acid or tauro-beta-muricholic acid may exert cytoprotective effects by lowering intracellular taurochenodeoxycholic acid levels associated with their optimal hydrophilicity.

Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes

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+.