Data from: Human-relevant mechanisms and risk factors for TAK-875-induced liver injury identified via a gene pathway-based approach in collaborative cross mice

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.