Ferdinandusse Sacha, Denis Simone, Dacremont Georges, Wanders Ronald J A
Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, Amsterdam, The Netherlands.
Mol Genet Metab. 2009 Mar;96(3):121-8. doi: 10.1016/j.ymgme.2008.11.165. Epub 2009 Jan 10.
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(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that C(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(27)-bile acids and the underlying mechanisms. We studied the effects of conjugated and unconjugated C(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(27)-bile acids. In conclusion, our studies showed that C(27)-bile acids are more cytotoxic than mature C(24)-bile acids. In addition, C(27)-bile acids are potent inhibitors of oxidative phosphorylation and enhance mitochondrial ROS production by inhibiting the respiratory chain.
过氧化物酶体在胆汁酸生物合成中发挥重要作用，因为合成途径的最后几步是由位于过氧化物酶体内的β-氧化系统完成的。因此，C(27) -胆汁酸中间体在几种过氧化物酶体疾病中积累。有人提出，C(27) -胆汁酸具有特别的毒性，并导致与过氧化物酶体疾病相关的肝脏疾病。基于这个原因，我们研究了C(27) -胆汁酸的毒性及其潜在机制。我们研究了结合型和非结合型C(27) -胆汁酸对大鼠肝癌细胞系McA-RH7777的细胞活力、线粒体呼吸链功能和氧自由基产生的影响。用不同胆汁酸的浓度递增孵育后，细胞活力逐渐下降，其中二羟基胆甾烷酸（DHCA）显然是细胞毒性最大的胆汁酸。此外，不同的胆汁酸使分离的线粒体氧化苹果酸和谷氨酸时的ATP合成呈剂量依赖性下降。最后，在存在C(27) -胆汁酸的情况下，活性氧生成受到剂量依赖性刺激。总之，我们的研究表明，C(27) -胆汁酸比成熟的C(24) -胆汁酸具有更强的细胞毒性。此外，C(27) -胆汁酸是氧化磷酸化的有效抑制剂，并通过抑制呼吸链增强线粒体活性氧的产生。
