Mechanistic Understanding of Idiosyncratic Drug-Induced Hepatotoxicity Using Co-Cultures of Hepatocytes and Macrophages
| Autor: | Estela Villanueva-Badenas, M. Teresa Donato, Laia Tolosa |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Antioxidants, Vol 12, Iss 7, p 1315 (2023) |
| Druh dokumentu: | article |
| ISSN: | 12071315 2076-3921 |
| DOI: | 10.3390/antiox12071315 |
| Popis: | Hepatotoxicity or drug-induced liver injury (DILI) is a major safety issue in drug development as a primary reason for drug failure in clinical trials and the main cause for post-marketing regulatory measures like drug withdrawal. Idiosyncratic DILI (iDILI) is a patient-specific, multifactorial, and multicellular process that cannot be recapitulated in current in vitro models; thus, our major goal is to develop and fully characterize a co-culture system and to evaluate its suitability for predicting iDILI. For this purpose, we used human hepatoma HepG2 cells and macrophages differentiated from a monocyte cell line (THP-1) and established the appropriate co-culture conditions for mimicking an inflammatory environment. Then, mono-cultures and co-cultures were treated with model iDILI compounds (trovafloxacin, troglitazone) and their parent non-iDILI compounds (levofloxacin, rosiglitazone), and the effects on viability and the mechanisms implicated (i.e., oxidative stress induction) were analyzed. Our results show that co-culture systems including hepatocytes (HepG2) and other cell types (THP-1-derived macrophages) help to enhance the mechanistic understanding of iDILI, providing better hepatotoxicity predictions. |
| Databáze: | Directory of Open Access Journals |
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