Hepatic bile acid synthesis and secretion: Comparison of in vitro methods. (15th July 2022)

• Record Type: Journal Article
• Authors: de Bruijn, Véronique M.P.; Wang, Zhenguo; Bakker, Wouter; Zheng, Weijia; Spee, Bart; Bouwmeester, Hans
• Is Part Of: Toxicology letters. Volume 365(2022)
• Page Start: 46
• Page End: 60
• Publication Date: 2022-07-15
• Subjects: Bile acids and salts -- Cholestasis -- New approach methodologies; AOP Adverse Outcome Pathway -- BA bile acid -- ICO-heps hepatocyte-like intrahepatic cholangiocyte organoids -- SCHH sandwich-cultured human hepatocytes -- DILI drug-induced liver injury; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.06.004
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Reliable hepatic in vitro systems are crucial for the safety assessment of xenobiotics. Certain xenobiotics decrease the hepatic bile efflux, which can ultimately result in cholestasis. Preclinical animal models and the currently available in vitro systems poorly predict a xenobiotic's cholestatic potential. Here, we compared the phenotype and capacity of three liver derived in vitro systems to emulate human functionality to synthesize and secrete bile acids (BAs). To this end, basal BA production of sandwich cultured human hepatocytes (SCHHs), HepaRG cells (HepaRGs) and hepatocyte-like intrahepatic cholangiocyte organoids (ICO-heps) were analysed, and the effect of the known BSEP (Bile Salt Export Pump)-inhibitors bosentan and lopinavir on BA disposition in SCHHs and HepaRGs was quantified. RT-qPCR of selected target genes involved in maturation status, synthesis, transport and conjugation of BAs was performed to mechanistically underpin the observed differences in BA homeostasis. ICO-heps produced a (very) low amount of BAs. SCHHs are a powerful tool in cholestasis-testing due to their high basal BA production and high transporter expression compared to the other models tested. HepaRGs were responsive to both selected BSEP-inhibitors and produced a BA profile that is most similar to the human in vivo situation, making them a suitable and practical candidate for cholestasis-testing. Highlights: Hepatocyte-like intrahepatic cholangiocyte organoids (ICO-hep) synthesize bile acids. Sandwich cultured human hepatocytes (SCHHs) and HepaRG cells synthesize more bile acids than ICO-heps. The BA profile produced by HepaRGs is the most similar to the in vivo situation. SCHHs and HepaRGs were responsive to selected BSEP-inhibitors lopinavir and bosentan. SCHHs and HepaRGs are more suitable tools for cholestasis-testing than ICO-heps.