Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: In vitro studies in rat hepatocytes and human erythrocytes

Abstract

Intraduodenal infusion of hydrophobic bile salts to bile-fistula rats leads within hours to severe hepatocellular necrosis and cholestasis; simultaneous administration of conjugates of ursodeoxycholate, either intraduodenally or intravenously, reduces or prevents liver injury. To evaluate the short-term protective effects of ursodeoxycholate at the cellular level, we incubated primary monolayer cultures of adult rat hepatocytes or freshly isolated washed human erythrocytes for 1 to 240 min with varying defined concentrations of different bile salts in the presence or absence of ursodeoxycholate. Cytolysis was quantified by measuring the release into the medium of cytosolic lactate dehydrogenase (hepatocytes) or hemoglobin (erythrocytes). In both systems, cytolysis increased sigmoidally with increasing bile salt concentration, and the relative toxicity of different bile salts proceeded in the following order: tauroursodeoxycholate was less toxic than taurocholate, which was less toxic than taurodeoxycholate. Taurochenodeoxycholate was more toxic to erythrocytes than taurodeoxycholate; the two were equally toxic to rat hepatocytes. Unconjugated bile salts were more toxic than their conjugates. The addition of tauroursodeoxycholate to taurochenodeoxycholate or taurodeoxycholate led to time-dependent and concentration-dependent reduction or elimination of the toxicity of the more hydrophobic component. Protection was evident within minutes. With respect to hemolysis, at pH 8.5 glyco was less protective than tauroursodeoxycholate, and free ursodeoxycholate was only minimally protective. We conclude that the hepatocytotoxicity of hydrophobic bile salts at millimolar concentrations is markedly reduced in the presence of tauroursodeoxycholate. Conjugates of ursodeoxycholate also prevented disruption of erythrocytes by bile salts, suggesting that protection does not depend on liver-specific pathways of bile salt uptake, compartmentation, transport or metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

“…However, this study was aimed at evaluating the immediate effects of therapeutic bile acids at the cellular level. Primary monolayer cultures of adult rat hepatocytes were incubated for 1-240 min with varying concentrations of the different bile acids (Heuman et al, 1991). This contrasts with the much more prolonged exposure of the present investigation.…”

“…2A, B). In a previous report, Heuman et al (1991) described that the hepatotoxicity of lipophilic bile acids was reduced in the presence of TUDC. However, this study was aimed at evaluating the immediate effects of therapeutic bile acids at the cellular level.…”

Fibrates suppress chenodeoxycholic acid-induced RANTES expression through inhibition of NF-κB activation

“…Ursodeoxycholic acid, which is a 7 isomer of chenodeoxycholic acid, is considered to be a nonhepatotoxic hydrophilic bile acid that may reverse potential hepatotoxicity of endogenous bile acids (Heuman et al, 1991), and is often used in patients with cholestasis to improve liver dysfunction (Lindor and Burnes, 1991;O'Brien et al, 1991;Bouchard et al, 1993). Notably, a beneficial effect of ursodeoxycholic acid in patients with primary biliary cirrhosis has been demonstrated in double-blind controlled studies (Leuschner et al, 1989;Poupon et al, 1991;Corpechot et al, 2000).…”

Differences in the Metabolism and Disposition of Ursodeoxycholic Acid and of Its Taurine–Conjugated Species in Patients With Primary Biliary Cirrhosis

“…11 Therefore, the action of UDCA in PBC appears to be mediated by biotransformation to these more polar bile acid conjugates. Tauroursodeoxycholic acid (TUDCA), for example, has been shown in vitro and in vivo to have greater cytoprotective effects than UDCA [12][13][14][15][16][17] and has been in clinical use for several years. Data from animal studies 18 and from a pilot study of patients with PBC 19 suggest that TUDCA induces more favorable changes in the composition of the bile acid pool and undergoes reduced biotransformation when compared with UDCA.…”