Toxicity of peroxisomal C27-bile acid intermediates

Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the β-oxidation system located inside peroxisomes. As a consequence, C27-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C27-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C27-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C27-bile acids on cell viability, mitochondrial respiratory chain function and production of oxygen radicals in the rat hepatoma cell line McA-RH7777. Cell viability decreased progressively after incubation with increasing concentrations of different bile acids with dihydroxycholestanoic acid (DHCA) being clearly the most cytotoxic bile acid. In addition, the different bile acids caused a dose-dependent decrease in ATP synthesis by isolated mitochondria oxidizing malate and glutamate. Finally, there was a dose-dependent stimulation of ROS generation in the presence of C27-bile acids. In conclusion, our studies showed that C27-bile acids are more cytotoxic than mature C24-bile acids. In addition, C27-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.