Journal du métabolisme des médicaments et de la toxicologie
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Evaluating the Sensitivity of HL-ICOs to Hepatotoxicants: Implications for In Vitro Toxicity Assessment

John Simpson

New developments in in vitro toxicity testing make an effort to
address the demand for trustworthy human-based safety
evaluation in medication development. The term "Intrahepatic
Cholangiocyte Organoids" (ICOs) refers to an in vitro disease
model for regenerative medicine that is developed from a donor.
Here, we investigated the expression and activity of genes
implicated in drug metabolism, a significant factor in druginduced
toxicity, and the exposure of Hepatocyte-like ICOs (HLICOs)
to well-known hepatotoxicants in order to examine the
potential of HL-ICOs in in vitro toxicity testing. In terms of
CYP3A4 expression, HL-ICOs' drug metabolism was equivalent
to that of Preventive Health and Health services (PHHs) and
HepaRGs, while other enzymes, such CYP2B6 and CYP2D6,
were expressed at lower levels. EC50 values for acetaminophen
were also calculated in HL-ICOs (24.0–26.8 mM) Troglitazone
(23.1-90.8 M), diclofenac (475.5–500 M), perhexiline (9.7–31.5
M), and valproic acid (>10 mM). When exposed to the
hepatotoxicants, HL-ICOs had EC50s that were equivalent to
those of PHHs and HepaRGs, although they were less susceptible
to acetaminophen. For the purpose of correctly defining the
potential of HL-ICOs in in vitro toxicity assessment, more
understanding of enzyme and transporter activities in drug
metabolism in HL-ICOs and exposure to a larger chemical
collection are required.