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

Abstract

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.