Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing
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
(2023) Molecules (Basel, Switzerland), volume 28, issue 2
(Article)
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)
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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.
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Keywords: drug-induced liver injury, hepatic in vitro model, hepatocyte-like cells, hepatotoxicity, intrahepatic cholangiocyte organoids, Analytical Chemistry, Chemistry (miscellaneous), Molecular Medicine, Pharmaceutical Science, Drug Discovery, Physical and Theoretical Chemistry, Organic Chemistry
ISSN: 1420-3049
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: 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). Publisher Copyright: © 2023 by the authors.
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