In vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assay

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dc.contributor.authorBrecklinghaus, Tim
dc.contributor.authorAlbrecht, Wiebke
dc.contributor.authorDuda, Julia
dc.contributor.authorKappenberg, Franziska
dc.contributor.authorGruendler, Lisa
dc.contributor.authorEdlund, Karolina
dc.contributor.authorMarchan, Rosemarie
dc.date.accessioned2024-04-24T16:18:30Z
dc.date.available2024-04-24T16:18:30Z
dc.date.issued2022
dc.departmentDicle Üniversitesien_US
dc.description.abstractThe accumulation of lipid droplets in hepatocytes is a key feature of drug-induced liver injury (DILI) and can be induced by a subset of hepatotoxic compounds. In the present study, we optimized and evaluated an in vitro technique based on the fluorescent dye Nile Red, further named Nile Red assay to quantify lipid droplets induced by the exposure to chemicals. The Nile Red assay and a cytotoxicity test (CTB assay) were then performed on cells exposed concentration-dependently to 60 different compounds. Of these, 31 were known to induce hepatotox-icity in humans, and 13 were reported to also cause steatosis. In order to compare in vivo relevant blood con-centrations, pharmacokinetic models were established for all compounds to simulate the maximal blood concentrations (Cmax) at therapeutic doses. The results showed that several hepatotoxic compounds induced an increase in lipid droplets at sub-cytotoxic concentrations. To compare how well (1) the cytotoxicity test alone, (2) the Nile Red assay alone, and (3) the combination of the cytotoxicity test and the Nile Red assay (based on the lower EC10 of both assays) allow the differentiation between hepatotoxic and non-hepatotoxic compounds, a previously established performance metric, the Toxicity Separation Index (TSI) was calculated. In addition, the Toxicity Estimation Index (TEI) was calculated to determine how well blood concentrations that cause an increased DILI risk can be estimated for hepatotoxic compounds. Our findings indicate that the combination of both assays improved the TSI and TEI compared to each assay alone. In conclusion, the study demonstrates that inclusion of the Nile Red assay into in vitro test batteries may improve the prediction of DILI compounds.en_US
dc.description.sponsorshipEuropean Union [681002, 031L0119]; BMBF [161L0114B, 161L0243C, 031L0114A]; Research Training Group Biostatistical Methods for High-Dimensional Data in Toxicology - Deutsche Forschungsgemeinschaft (DFG, German Research Foundation [RTG 2624, 427806116]; German Research Foundation (DFG) [GH 276/1-1, 457840828]; 2219-TUBITAK International Post Doctoral Research Fellowship Program; DFG [ZE1037/1-3]; SteatoTox-2 [16LW0116k]en_US
dc.description.sponsorshipThis work received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 681002 (EU-ToxRisk) and LivSysTransfer (BMBF, 031L0119) and the BMBF projects SteatoTox (161L0114B) and SysBioTop-Moving (161L0243C). This work has been supported (in part) by the Research Training Group Biostatistical Methods for High-Dimensional Data in Toxicology (RTG 2624, Project P1 and P2) funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation -Project Number 427806116). AG is funded by the German Research Foundation (DFG; GH 276/1-1; Project Number 457840828). Ozlem Demirci Turgunbayer was supported by the 2219-TUBITAK International Post Doctoral Research Fellowship Program. This work was financially supported by the DFG Grant ZE1037/1-3, the BMBF Grants SteatoTox 031L0114A and SteatoTox-2 16LW0116k to A.Zen_US
dc.identifier.doi10.1016/j.toxlet.2022.08.006
dc.identifier.endpage46en_US
dc.identifier.issn0378-4274
dc.identifier.issn1879-3169
dc.identifier.pmid35963427
dc.identifier.scopus2-s2.0-85136110735
dc.identifier.scopusqualityQ1
dc.identifier.startpage33en_US
dc.identifier.urihttps://doi.org/10.1016/j.toxlet.2022.08.006
dc.identifier.urihttps://hdl.handle.net/11468/16141
dc.identifier.volume368en_US
dc.identifier.wosWOS:000848176400002
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherElsevier Ireland Ltden_US
dc.relation.ispartofToxicology Letters
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectSteatosisen_US
dc.subjectDilien_US
dc.subjectAlternative Methodsen_US
dc.subjectNaflden_US
dc.subjectLipid Dropletsen_US
dc.titleIn vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assayen_US
dc.titleIn vitro/in silico prediction of drug induced steatosis in relation to oral doses and blood concentrations by the Nile Red assay
dc.typeArticleen_US

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