TY - JOUR
T1 - Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing
AU - Bouwmeester, Manon C
AU - Tao, Yu
AU - Proença, Susana
AU - van Steenbeek, Frank G
AU - Samsom, Roos-Anne
AU - Nijmeijer, Sandra M
AU - Sinnige, Theo
AU - van der Laan, Luc J W
AU - Legler, Juliette
AU - Schneeberger, Kerstin
AU - Kramer, Nynke I
AU - Spee, Bart
N1 - Funding: 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).
PY - 2023/1/7
Y1 - 2023/1/7
N2 - 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.
AB - 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.
U2 - 10.3390/molecules28020621
DO - 10.3390/molecules28020621
M3 - Article
C2 - 36677681
VL - 28
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 2
M1 - 621
ER -
