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

Manon C BouwmeesterYu TaoSusana ProençaFrank G van SteenbeekRoos-Anne SamsomSandra M NijmeijerTheo SinnigeLuc J W van der LaanJuliette LeglerKerstin SchneebergerNynke I KramerBart Spee
Published in: Molecules (Basel, Switzerland) (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.
Keyphrases
  • drug induced
  • liver injury
  • oxidative stress
  • adverse drug
  • endothelial cells
  • poor prognosis
  • long non coding rna
  • climate change