Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Manon C Bouwmeester, Yu Tao, Susana Proença, Frank G van Steenbeek, Roos-Anne Samsom, Sandra M Nijmeijer, Theo Sinnige, Luc J W van der Laan, Juliette Legler, Kerstin Schneeberger, Nynke I Kramer, Bart Spee

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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.

Original languageEnglish
Article number621
JournalMolecules
Volume28
Issue number2
DOIs
Publication statusPublished - 7 Jan 2023

Bibliographical note

Funding: This work is part of the research program Applied and Engineering Sciences with project
number 15498, which is financed by the Dutch Research Council (NWO).

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