Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing
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.
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| Format: | Article/Letter to editor biblioteca |
| Language: | English |
| Subjects: | drug-induced liver injury, hepatic in vitro model, hepatocyte-like cells, hepatotoxicity, intrahepatic cholangiocyte organoids, |
| Online Access: | https://research.wur.nl/en/publications/drug-metabolism-of-hepatocyte-like-organoids-and-their-applicabil |
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dig-wur-nl-wurpubs-6108412025-01-14 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 Article/Letter to editor Molecules 28 (2023) 2 ISSN: 1420-3049 Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing 2023 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. en application/pdf https://research.wur.nl/en/publications/drug-metabolism-of-hepatocyte-like-organoids-and-their-applicabil 10.3390/molecules28020621 https://edepot.wur.nl/587719 drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Wageningen University & Research |
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drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids |
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drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids 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 Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| description |
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. |
| format |
Article/Letter to editor |
| topic_facet |
drug-induced liver injury hepatic in vitro model hepatocyte-like cells hepatotoxicity intrahepatic cholangiocyte organoids |
| author |
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 |
| author_facet |
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 |
| author_sort |
Bouwmeester, Manon C. |
| title |
Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| title_short |
Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| title_full |
Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| title_fullStr |
Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| title_full_unstemmed |
Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing |
| title_sort |
drug metabolism of hepatocyte-like organoids and their applicability in in vitro toxicity testing |
| url |
https://research.wur.nl/en/publications/drug-metabolism-of-hepatocyte-like-organoids-and-their-applicabil |
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