Investigation into bile acid effects on the golgi apparatus, cell viability and glucocorticoid receptor distribution in esophageal cells

Abstract

Bile acids are a family of steroidal molecules derived from cholesterol and biosynthesised in the pericentral hepatocytes in the liver. In recent years there has been a renaissance in bile acid based research as it has emerged that bile acids have a wide range of biological effects, which extend beyond their traditional role as solubilising agents in the gut. Bile acids have been shown to activate apoptotic, carcinogenic, inflammatory and anti-inflammatory signalling pathways. Using a chemical biology approach this thesis sought to investigate some of the biological effects of bile acids in an esophageal cancer model. Previous studies have demonstrated the cytotoxicity of bile acids in hepatic, colonic and esophageal cell lines. Bile acid hydrophobicity is believed to be an important cytotoxicity determinant but this relationship is not well characterised. Chapter three of this thesis describes an investigation into the relationship between bile acid hydrophobicity and effects on cell viability. In this study we synthesised new azido and other hydrophobic bile acid derivatives. We assembled a panel of 37 bile acids with a good range of hydrophobicities as determined by reverse phase thin layer chromatography. RMW which is extrapolated retention in 100% aqueous phase was used as a measure of hydrophobicity. The MTT cell viability assay was used to assess cytotoxicity over 24 h in the HET-IA cell line, a normal esophageal cell line.