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Tytuł:
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Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes.
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Autorzy:
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Tolosa L; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain. .
Jiménez N; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain.
Pelechá M; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain.
Castell JV; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain.; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain.
Gómez-Lechón MJ; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain.
Donato MT; Unidad de Hepatología Experimental, Torre A. Instituto Investigación Sanitaria La Fe, Av Fernando Abril Martorell 106, 46026, Valencia, Spain. donato_.; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010, Valencia, Spain. donato_.
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Źródło:
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Archives of toxicology [Arch Toxicol] 2019 Feb; Vol. 93 (2), pp. 519-532. Date of Electronic Publication: 2018 Nov 13.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Berlin, New York, Springer-Verlag.
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MeSH Terms:
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Cell Culture Techniques/*methods
Chemical and Drug Induced Liver Injury/*pathology
Hepatocytes/*drug effects
Toxicity Tests/*methods
Adult ; Chemical and Drug Induced Liver Injury/etiology ; Child ; Dose-Response Relationship, Drug ; Enzymes/drug effects ; Enzymes/genetics ; Enzymes/metabolism ; Female ; Hep G2 Cells ; Hepatocytes/cytology ; High-Throughput Screening Assays/methods ; Humans ; Inactivation, Metabolic ; Middle Aged ; Time Factors
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Grant Information:
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PI16/00333 International Instituto de Salud Carlos III; CP16/00097 International Instituto de Salud Carlos III
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Contributed Indexing:
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Keywords: Cell model; Chronic toxicity; Hepatotoxicity; Mechanisms; Preclinical evaluation
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Substance Nomenclature:
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0 (Enzymes)
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Entry Date(s):
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Date Created: 20181115 Date Completed: 20200518 Latest Revision: 20200518
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Update Code:
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20240105
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DOI:
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10.1007/s00204-018-2349-y
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PMID:
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30426164
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Drug-induced liver injury (DILI) constitutes one of the most frequent reasons of restricted-use warnings as well as withdrawals of drugs in postmarketing and poses an important concern for the pharmaceutical industry. The current hepatic in vivo and in vitro models for DILI detection have shown clear limitations, mainly for studies of long-term hepatotoxicity. For this reason, we here evaluated the potential of using Upcytes human hepatocytes (UHH) for repeated-dose long-term exposure to drugs. The UHH were incubated with 15 toxic and non-toxic compounds for up to 21 days using a repeated-dose approach, and, in addition to conventional examination of effects on viability, the mechanisms implicated in cell toxicity were also assessed by means of high-content screening. The UHH maintained the expression and activity levels of drug-metabolizing enzymes for up to 21 days of culture and became more sensitive to the toxic compounds after extended exposures, showing inter-donor differences which would reflect variability among the population. The assay also allowed to detect the main mechanisms implicated in the toxicity of each drug as well as identifying special susceptibilities depending on the donor. UHH can be used for a long-term repeated detection of DILI at clinically relevant concentrations and also offers key mechanistic features of drug-induced hepatotoxicity. This system is therefore a promising tool in preclinical testing of human relevance that could help to reduce and/or replace animal testing for drug adverse effects.