Toxicity of peroxisomal C sub(27)-bile acid intermediates

Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta -oxidation system located inside peroxisomes. As a consequence, C sub(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested...

Full description

Saved in:
Bibliographic Details
Published in:Molecular genetics and metabolism 2009-03, Vol.96 (3), p.121-128
Main Authors: Ferdinandusse, Sacha, Denis, Simone, Dacremont, Georges, Wanders, Ronald JA
Format: Article
Language:English
Subjects:
ATP
Bile acids
Cytotoxicity
Electron transport
Glutamic acid
Hepatoma
Liver diseases
Mitochondria
Oxidative phosphorylation
Peroxisomes
Reactive oxygen species
Toxicity
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta -oxidation system located inside peroxisomes. As a consequence, C sub(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C sub(27)-bile acids are especially toxic and contribute to the liver disease associated with peroxisomal disorders. For this reason, we investigated the toxicity of C sub(27)-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C sub(27)-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 C sub(27)-bile acids. In conclusion, our studies showed that C sub(27)-bile acids are more cytotoxic than mature C sub(24)-bile acids. In addition, C sub(27)-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.
ISSN:1096-7192
DOI:10.1016/j.ymgme.2008.11.165