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
Affiliations
Manon C. Bouwmeester
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
Yu Tao
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
Susana Proença
Division of Toxicology, Wageningen University, 6700 EA Wageningen, The Netherlands
Frank G. van Steenbeek
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
Roos-Anne Samsom
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
Sandra M. Nijmeijer
Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
Theo Sinnige
Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
Luc J. W. van der Laan
Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands
Juliette Legler
Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands
Kerstin Schneeberger
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
Nynke I. Kramer
Division of Toxicology, Wageningen University, 6700 EA Wageningen, The Netherlands
Bart Spee
Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands
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.
