Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice. (September 2021)

• Record Type: Journal Article
• Authors: Mosedale, Merrie; Cai, Yanwei; Eaddy, J. Scott; Kirby, Patrick J.; Wolenski, Francis S.; Dragan, Yvonne; Valdar, William
• Is Part Of: Toxicology. Volume 461(2021)
• Publication Date: 2021-09
• Subjects: Collaborative cross -- Drug-induced liver injury (DILI) -- Mechanisms -- TAK-875 -- Toxicogenomics; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.152902
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: 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.