Comparative cytotoxic and cytoprotective effects of taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) in HepG2 cell line

• Published in: Biochimica et biophysica acta Vol. 1580; no. 1; pp. 31 - 39
• Main Authors: Carubbi, Francesca, Guicciardi, Maria Eugenia, Concari, Mauro, Loria, Paola, Bertolotti, Marco, Carulli, Nicola
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30-01-2002
• Subjects: Alanine Transaminase - analysis; Aspartate Aminotransferases - analysis; Bile acid; Deoxycholic Acid - antagonists & inhibitors; Dose-Response Relationship, Drug; Erythrocytes - drug effects; Hemolysis; Hepatocyte; Hepatoprotection; Hepatotoxicity; Humans; Hydrophilic–hydrophobic balance; Taurochenodeoxycholic Acid - pharmacology; Taurochenodeoxycholic Acid - toxicity; Taurodeoxycholic Acid - analogs & derivatives; Taurodeoxycholic Acid - pharmacology; Taurodeoxycholic Acid - toxicity; Time Factors; Transglutaminases - analysis; Tumor Cells, Cultured - drug effects; Hepatoprotection; THDCA, taurohyodeoxycholic acid; CDCA, chenodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; DCA, deoxycholic acid; AST, aspartate transaminase; ALT, alanine transaminase; GGT, γ-glutamyltranspeptidase; MEM, minimum essential medium; Hydrophilic–hydrophobic balance; Hepatocyte; Bile acid; CA, cholic acid; UDCA, ursodeoxycholic acid; Hepatotoxicity; CMC, critical micellar concentration
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/S1388-1981(01)00184-6

This study was performed to compare the effects of two hydrophilic bile acids, taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA), on HepG2 cells. Cytotoxicity was evaluated at different times of exposure by incubating cells with increasing concentrations (50–800 μmol/l) of either bile acid, while their cytoprotective effect was tested in comparison with deoxycholic acid (DCA) (350 μmol/l and 750 μmol/l)-induced cytotoxicity. Culture media, harvested at the end of each incubation period, were analyzed to evaluate aspartate transaminase (AST), alanine transaminase and γ-glutamyltranspeptidase release. In addition, the hemolytic effect of THDCA and TUDCA on human red blood cells was also determined. At 24 h of incubation neither THDCA nor TUDCA was cytotoxic at concentrations up to 200 and 400 μmol/l. At 800 μmol/l both THDCA and TUDCA induced a slight increase in AST release. At this concentration and with time of exposure prolonged up to 72 h, THDCA and TUDCA induced a progressive increase of AST release significantly (
P<0.05) higher than that of controls being AST values for THDCA (2.97±0.88 time control value (tcv) at 48 h and 4.50±1.13 tcv at 72 h) significantly greater than those of TUDCA (1.50±0.20 tcv at 48 h and 1.80±0.43 tcv at 72 h) (
P<0.01). In cytoprotection experiments, the addition of 50 μmol/l THDCA decreased only slightly (−5%) AST release induced by 350 μmol/l DCA, while the addition of 50 μmol/l TUDCA was significantly effective (−23%;
P<0.05). Higher doses of THDCA or TUDCA did not reduce toxicity induced by 350 μmol/l DCA, but were much less toxic than an equimolar dose of DCA alone. At the concentration used in this experimental model neither THDCA nor TUDCA was hemolytic; however at a very high concentration (6 mmol/l) both bile acids induced 5–8% hemolysis. We conclude that bile acid molecules with a similar degree of hydrophilicity may show different cytotoxic and cytoprotective properties.