Title:Human Liver Organoid Models for Assessment of Drug Toxicity at the
Preclinical Stage
Volume: 23
Issue: 14
Author(s): Mustafa Karabicici, Soheil Akbari, Ozge Ertem, Mukaddes Gumustekin and Esra Erdal*
Affiliation:
- Izmir Biomedicine and Genome Center (IBG-Izmir), Dokuz Eylul University Health Campus, Izmir, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
- Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
Keywords:
Drug metabolism, DILI, organoids, hepatoxicity, liver, cytochrome.
Abstract: The hepatotoxicity of drugs is one of the leading causes of drug withdrawal from the
pharmaceutical market and high drug attrition rates. Currently, the commonly used hepatocyte
models include conventional hepatic cell lines and animal models, which cannot mimic human
drug-induced liver injury (DILI) due to poorly defined dose-response relationships and/or lack
of human-specific mechanisms of toxicity. In comparison to 2D culture systems from different
cell sources such as primary human hepatocytes and hepatomas, 3D organoids derived from an
inducible pluripotent stem cell (iPSC) or adult stem cells are promising accurate models to
mimic organ behavior with a higher level of complexity and functionality owing to their ability
to self-renewal. Meanwhile, the heterogeneous cell composition of the organoids enables metabolic
and functional zonation of hepatic lobule important in drug detoxification and has the
ability to mimic idiosyncratic DILI as well. Organoids having higher drug-metabolizing enzyme
capacities can culture long-term and be combined with microfluidic-based technologies such as
organ-on-chips for a more precise representation of human susceptibility to drug response in a
high-throughput manner. However, there are numerous limitations to be considered about this
technology, such as enough maturation, differences between protocols and high cost. Herein,
we first reviewed the current preclinical DILI assessment tools and looked at the organoid technology
with respect to in vitro detoxification capacities. Then we discussed the clinically applicable
DILI assessment markers and the importance of liver zonation in the next generation organoid-
based DILI models.
