This article explains how microphysiological systems can be used for research on fatty liver disease and assessing the risk of drug-induced liver injury
Sponsored Content by CN-BioReviewed by Andrea SalazarAug 1 2024 There is an increased prevalence of diabetes, metabolic syndrome, and obesity. As a result, Metabolic dysfunction-associated liver disease is now the most common chronic liver disease in developed countries.1
A higher risk of drug-induced acute hepatitis in obesity is associated with the increased activity of numerous cytochromes P450 , which augment the generation of toxic metabolites.2 When excessively generated, reactive metabolites can cause hepatic oxidative stress, cytolysis, and severe mitochondrial dysfunction.
In this model, cells were assessed for fluctuations in CYP activity, and the effects of known hepatotoxicants were evaluated when dosed at or around IC:50 concentrations. Figure 3. Hepatocytes in the MASLD model have altered metabolic activity. PHH were cultured for 14 days under fat conditions and then dosed with probe compounds to assess the metabolic activity of key CYP-450 enzymes. The activity of each enzyme was determined by the production of phase I metabolites over 48 hours. The presence of the metabolites was quantified using LC-MS and a standard curve of the metabolite. All compounds were dosed at day 14 except for CLZX which was dosed at day 7.
Conclusions Using the PhysioMimix® OOC, CN Bio generated a human in vitro model of MASLD. PHH were cultured in a fat-containing medium, which induced important features of early-stage clinical disease, such as intracellular fat loading, changes to the expression of key genes and increased albumin production.
Both Ticlopidine and Acetaminophen caused more extravagant DILI responses in fat-loaded cells, resulting in increased LDH release, reduced albumin production, and decreased CYP3A4 activity . When the compounds were dosed multiple times onto the hepatic tissues the changes were often significantly more prominent.
Fatty Liver Disease Drug-Induced Liver Injury DILI
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