Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury
Open accessAbstract
Drug-induced liver injury (DILI) remains a challenge and a leading risk for drug discovery. Three-dimensional liver spheroids made from primary human hepatocytes (PHHs) with, or without, other liver cell types can provide more physiological relevance. In comparison to conventional 2-dimensional monolayer culture, our tests with 100 drugs of known DILI status indicate that PHH spheroids are significantly more sensitive in detecting drug-induced hepatotoxicity. To evaluate the role of Kupffer cells (KCs) in drug-induced liver toxicity, we have established conditions for generating co-culture spheroids with PHH and KCs. Inflammatory responses as shown by interleukin 6 secretion can be recapitulated in co-culture spheroids when treated with endotoxin lipopolysaccharides. KCs potentiated the cytotoxicity induced by trovafloxacin in co-culture spheroids at 48 h, but the differences between PHH spheroids and co-culture spheroids became less obvious after a 5-day treatment. Interestingly, a protective role of KCs was shown in co-culture spheroids treated with both acetaminophen and lipopolysaccharides. Additional tests with 14 DILI compounds comparing PHH spheroids and co-culture spheroids showed differential roles of KCs that were compound dependent. In summary, these 3-dimensional liver spheroid models are useful tools to understand the complex mechanisms underlying DILI.
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3D hepatic spheroids correctly identified 8 out of the 19 toxic drugs in the set.
“a preclinical model that is currently widely used in pharma and was only able to correctly identify 8 out of the 19 toxic drugs in the set (Table 5).”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [48]
The sensitivity of 80% was almost double the sensitivity of 3D hepatic spheroids for the same drug set (42%) based on previously published data.
“This was almost double the sensitivity of 3D hepatic spheroids for the same drug set (42%) based on previously published data31,47,48”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [48]
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Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology
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- Authors
- Li, F., Cao, L., Parikh, S., & Zuo, R.
- Corresponding author
- Li, Feng
- ORCID
- Li, Feng
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 109
- Issue
- 6
- Pages
- 1912-1923
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W3010228584
- Cited by
- 72
- References
- 8
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 10 · 2023: 9 · 2022: 14 · 2021: 15 · 2020: 4
- FWCI
- 9.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- drug-induced liver injury, primary human hepatocytes, Kupffer cells, hepatotoxicity, co-culture spheroids, drug safety testing, lipopolysaccharide, interleukin-6, inflammation, trovafloxacin, paracetamol, hepatoprotection
- MeSH terms
- Humans, Kupffer Cells, Liver, Spheroids, Cellular, Coculture Techniques, Hepatocytes, Chemical and Drug Induced Liver Injury
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