{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:11:01Z","timestamp":1790302261583,"version":"4.1.0"},"reference-count":72,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T00:00:00Z","timestamp":1673049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["15498"],"award-info":[{"award-number":["15498"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u201326.8 mM), diclofenac (475.5\u2013&gt;500 \u00b5M), perhexiline (9.7\u2013&gt;31.5 \u00b5M), troglitazone (23.1\u201390.8 \u00b5M), and valproic acid (&gt;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.<\/jats:p>","DOI":"10.3390\/molecules28020621","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T06:38:27Z","timestamp":1673246307000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-9939","authenticated-orcid":false,"given":"Manon C.","family":"Bouwmeester","sequence":"first","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1544-4686","authenticated-orcid":false,"given":"Susana","family":"Proen\u00e7a","sequence":"additional","affiliation":[{"name":"Division of Toxicology, Wageningen University, 6700 EA Wageningen, The Netherlands"},{"name":"Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-6540","authenticated-orcid":false,"given":"Frank G.","family":"van Steenbeek","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"},{"name":"Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roos-Anne","family":"Samsom","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra M.","family":"Nijmeijer","sequence":"additional","affiliation":[{"name":"Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Sinnige","sequence":"additional","affiliation":[{"name":"Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0651-5334","authenticated-orcid":false,"given":"Luc J. W.","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, 3015 CN Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6321-1567","authenticated-orcid":false,"given":"Juliette","family":"Legler","sequence":"additional","affiliation":[{"name":"Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8109-7657","authenticated-orcid":false,"given":"Kerstin","family":"Schneeberger","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3281-1815","authenticated-orcid":false,"given":"Nynke I.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Division of Toxicology, Wageningen University, 6700 EA Wageningen, The Netherlands"},{"name":"Institute for Risk Assessment Sciences, Utrecht University, 3584 CM Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-0560","authenticated-orcid":false,"given":"Bart","family":"Spee","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences, Faculty of Veterinary Medicine, Regenerative Medicine Center Utrecht, Utrecht University, 3584 CT Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2174\/1389200218666170316093301","article-title":"Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools","volume":"18","author":"Issa","year":"2017","journal-title":"Curr. 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