Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes.

Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes. Arch Toxicol. 2018 Nov 13;: Authors: Tolosa L, Jiménez N, Pelechá M, Castell JV, Gómez-Lechón MJ, Donato MT Abstract 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 lo...
Source: Archives of Toxicology - Category: Toxicology Authors: Tags: Arch Toxicol Source Type: research