Fozia Noor
Saarland University, Germany
Title: Advanced human in-vitro models for the study of drug induced cholestasis
Biography
Biography: Fozia Noor
Abstract
Cholestasis is among the most common adverse effect leading to drug induced liver injury. Drugs usually disrupt bile acid homeostasis by interfering with their metabolism and transport. Although animals especially rodents have been extensively used in cholestasis research, the clinical translation of this knowledge has been very disappointing. Major reasons are species-specific differences in bile acid composition, metabolism and transport. The purpose of this study was to evaluate the suitability of human HepaRG cells comprising of hepatocytes and cholangiocytes as in-vitro model for screening for cholestatic liver injury. We studied the effects of bosentan which impairs the canalicular excretion of bile acids from the hepatocytes. We also investigated the effects of hydrocortisone as inducer of bile acid metabolism and inhibitor of OATP. Bile acids were analysed by LC-MS. Supplementation of serum concentrations of major bile acids resulted in intracellular accumulation of chenodeoxycholic acid upon Bosentan exposure and glycochenodeoxycholic acid upon hydrocortisone exposure in HepaRG cells. We also investigated the effects of bosentan in 2D and 3D HepaRG cultures for 14 days. Using metabolomics we investigated metabolic and cellular alterations. Repeated dose bosentan exposure resulted in more than 20 fold decrease in the EC50 value. We show that there is a change in cellular metabolism upon 14-day bosentan exposure with metabolome hinting at subcellular changes to adapt to cell stress. In conclusion, such human in vitro models will not only be in valuable in the screening of compounds with cholestatic potential but also in the understanding of the disease.