URSODEOXYCHOLATE PROTECTS OXIDATIVE MITOCHONDRIAL METABOLISM FROM BILE-ACID TOXICITY - DOSE-RESPONSE STUDY IN ISOLATED RAT-LIVER MITOCHONDRIA

The effect of ursodeoxycholate and tauroursodeoxycholate on the toxicity of lipophilic bile acids (chenodeoxycholate and lithocholate) on the function of the electron transport chain was investigated in isolated rat liver mitochondria. At a concentration of 30 mu mol/L, both chenodeoxycholate and lithocholate reduced state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. In contrast, ADP/O ratios of these substrates and oxidative metabolism of ascorbate were not significantly affected. Ursodeoxycholate did not impair mitochondrial oxidative metabolism up to concentrations of 100 mu mol/L; at 300 mu mol/L, however, it decreased state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. Tauroursodeoxycholate had no significant inhibitory effect on state 3 oxidation rates of L-glutamate and succinate at concentrations up to 300 mu mol/L, When ursodeoxycholate (final concentration, 30 mu mol/L or 100 mu mol/L) was added to mitochondrial incubations containing chenodeoxycholate or lithocholate, the toxic effects of lipophilic bile acids on mitochondrial oxidative metabolism were partially reversed. However, 300 mu mol/L ursodeoxycholate, in combination with chenodeoxycholate or lithocholate, exhibited greater toxicity compared with incubations containing only the individual bile acids. In contrast to ursodeoxycholate, tauroursodeoxycholate did not reduce the toxic effects of chenodeoxycholate or lithocholate on mitochondrial metabolism. Ursodeoxycholate (100 mu mol/L) significantly decreased the incorporation of chenodeoxycholate into mitochondrial membranes, whereas the decrease in lithocholate incorporation was not statistically significant. These studies demonstrate that ursodeoxycholate, but not tauroursodeoxycholate, decreases the toxicity of lipophilic bile acids on the function of the electron transport chain up to a concentration of 100 mu mol/L but increases bile acid-induced mitochondrial toxicity at higher concentrations. The protective effect of ursodeoxycholate may partially be explained by decreased incorporation of bile acids into mitochondrial membranes.