RT Journal Article
SR Electronic
T1 Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 930
OP 938
VO 272
IS 2
A1 Botla, R
A1 Spivey, J R
A1 Aguilar, H
A1 Bronk, S F
A1 Gores, G J
YR 1995
UL http://jpet.aspetjournals.org/content/272/2/930.abstract
AB Ursodeoxycholate (UDCA), a hydrophilic bile salt, ameliorates hepatocellular injury by toxic bile salts and is used to treat cholestatic liver disease. However, the mechanisms of bile salt-mediated hepatocyte necrosis and UDCA cytoprotection remain unclear. Hepatocyte necrosis is thought to be caused by the mitochondrial membrane permeability transition (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 assessed in isolated rat liver mitochondria. Cell viability was measured in isolated rat hepatocytes. GCDC induced the MMPT in a dose-dependent manner. The GCDC-induced MMPT was partially blocked by cyclosporin A plus trifluoperazine, known inhibitors of the MMPT. UDCA also inhibited the GCDC-induced MMPT, and partially blocked the MMPT by phenylarsene oxide, an established mediator of the MMPT. UDCA or cyclosporin A plus trifluoperazine protected against loss of hepatocyte viability during treatment with GCDC. In conclusion, GCDC induces a MMPT; a finding providing 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.