Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.
Toxicology
; 461: 152902, 2021 09.
Article
em En
| MEDLINE
| ID: mdl-34418498
ABSTRACT
Development of TAK-875 was discontinued when a small number of serious drug-induced liver injury (DILI) cases were observed in Phase 3 clinical trials. Subsequent studies have identified hepatocellular oxidative stress, mitochondrial dysfunction, altered bile acid homeostasis, and immune response as mechanisms of TAK-875 DILI and the contribution of genetic risk factors in oxidative response and mitochondrial pathways to the toxicity susceptibility observed in patients. We tested the hypothesis that a novel preclinical approach based on gene pathway analysis in the livers of Collaborative Cross mice could be used to identify human-relevant mechanisms of toxicity and genetic risk factors at the level of the hepatocyte as reported in a human genome-wide association study. Eight (8) male mice (4 matched pairs) from each of 45 Collaborative Cross lines were treated with a single oral (gavage) dose of either vehicle or 600 mg/kg TAK-875. As expected, liver injury was not detected histologically and few changes in plasma biomarkers of hepatotoxicity were observed. However, gene expression profiling in the liver identified hundreds of transcripts responsive to TAK-875 treatment across all strains reflecting alterations in immune response and bile acid homeostasis and the interaction of treatment and strain reflecting oxidative stress and mitochondrial dysfunction. Fold-change expression values were then used to develop pathway-based phenotypes for genetic mapping which identified candidate risk factor genes for TAK-875 toxicity susceptibility at the level of the hepatocyte. Taken together, these findings support our hypothesis that a gene pathway-based approach using Collaborative Cross mice could inform sensitive strains, human-relevant mechanisms of toxicity, and genetic risk factors for TAK-875 DILI. This novel preclinical approach may be helpful in understanding, predicting, and ultimately preventing clinical DILI for other drugs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonas
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Benzofuranos
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Estresse Oxidativo
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Hepatócitos
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Doença Hepática Induzida por Substâncias e Drogas
Tipo de estudo:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Toxicology
Ano de publicação:
2021
Tipo de documento:
Article