1. Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing
- Author
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Bouwmeester, Manon C, Tao, Yu, Proença, Susana, van Steenbeek, Frank G, Samsom, Roos-Anne, Nijmeijer, Sandra M, Sinnige, Theo, van der Laan, Luc J W, Legler, Juliette, Schneeberger, Kerstin, Kramer, Nynke I, Spee, Bart, CS_STEM, Interne geneeskunde GD, CS_Genetics, IRAS OH Toxicology, CS_STEM, Interne geneeskunde GD, CS_Genetics, IRAS OH Toxicology, and Surgery
- Subjects
hepatotoxicity ,intrahepatic cholangiocyte organoids ,Organic Chemistry ,Pharmaceutical Science ,Toxicology ,Analytical Chemistry ,SDG 3 - Good Health and Well-being ,Chemistry (miscellaneous) ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,hepatic in vitro model ,drug-induced liver injury ,hepatocyte-like cells ,Toxicologie - Abstract
Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.
- Published
- 2023