URSODEOXYCHOLATE (UDCA) INHIBITS THE MITOCHONDRIAL-MEMBRANE PERMEABILITY TRANSITION INDUCED BY GLYCOCHENODEOXYCHOLATE - A MECHANISM OF UDCACYTOPROTECTION

Ursodeoxycholate (UDCA), a hydrophilic bile salt, ameliorates hepatoce llular injury by toxic bile salts and is used to treat cholestatic liv er disease. However, the mechanisms of bile salt-mediated hepatocyte n ecrosis and UDCA cytoprotection remain unclear. Hepatocyte necrosis is thought to be caused by the mitochondrial membrane permeability trans ition (MMPT). Thus, the aims of our study were to determine if a toxic bile salt, glycochenodeoxycholate (GCDC) induces the MMPT and if so, whether UDCA prevents the bile salt-induced MMPT. The MMPT was assesse d in isolated rat liver mitochondria. Cell viability was measured in i solated rat hepatocytes. GCDC induced the MMPT in a dose-dependent man ner. The GCDC induced MMPT was partially blocked by cyclosporin A plus trifluoperazine, known inhibitors of the MMPT. UDCA also inhibited th e GCDC-induced MMPT, and partially blocked the MMPT by phenylarsene ox ide, an established mediator of the MMPT. UDCA or cyclosporin A plus t rifluoperazine protected against loss of hepatocyte viability during t reatment with GCDC. In conclusion, GCDC induces a MMPT; a finding prov iding a physicochemical explanation for the bioenergetic form of cell necrosis caused by toxic bile salts. UDCA cytoprotection may, in part, be due to inhibition of the bile salt-induced MMPT.