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Toxicogenomics weight of evidence to demonstrate a CAR-mediated MoA for cyclobutrifluram-related mouse liver tumors

ABSTRACT: Transcriptomics and metabolomics provide useful data to identify the mode of action for chemical-induced murine liver tumors and to exclude alternative modes of action. This data was incorporated into a mode of action assessment, for the murine liver hepatocellular carcinomas associated with 80-week dietary exposure to CD-1 mice of the novel complex II succinate dehydrogenase inhibitor (SDHI), cyclobutrifluram. The assessment was conducted using the framework developed by the International Programme on Chemical Safety (IPCS) and the International Life Science Institute (ILSI), based on activation of the constitutive androstane receptor (CAR) and subsequent downstream events. Cyclobutrifluram activated human and mouse CAR in an in vitro transactivation assay. Dietary administration of cyclobutrifluram was associated with time and/or dose-dependent liver weight increases, minimal to moderate hepatic centrilobular hypertrophy, induction of CAR-related enzyme activity, specifically CYP2B and CYP3A, and hepatocellular proliferation. Transcriptomic assessment of the liver identified gene expression profiles consistent with CAR activation. Metabolomic assessment indicated that cyclobutrifluram induced similar biochemical changes to the known CAR activator phenobarbital. Alternative hypotheses to CAR-induced hepatic tumors were assessed and considered to be non-relevant. The transcriptomic and particularly the metabolomic assessments indicated that cyclobutrifluram did not have activity other than that related to CAR induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE289533 | GEO | 2025/12/31

REPOSITORIES: GEO

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Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver [Mouse Liver Experiments]

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2014-08-29 | E-GEOD-57055 | biostudies-arrayexpress

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