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Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based
Merrie Mosedale1, Yanwei Cai2, J Scott Eaddy1
1Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, 27599, United States.
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.
Insights
A novel preclinical approach using Collaborative Cross mice identified genetic risk factors and human-relevant mechanisms for drug-induced liver injury (DILI). This method aids in predicting and preventing DILI for future drugs.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- TAK-875 development halted due to serious drug-induced liver injury (DILI) in clinical trials.
- Mechanisms of TAK-875 DILI involve oxidative stress, mitochondrial dysfunction, and immune response, with genetic factors contributing to susceptibility.
- Human genome-wide association studies (GWAS) have implicated genetic risk factors in DILI.
Purpose of the Study:
- To test a preclinical approach using gene pathway analysis in Collaborative Cross (CC) mice to identify human-relevant mechanisms and genetic risk factors for TAK-875 DILI.
- To assess the utility of CC mice in uncovering hepatocyte-level toxicity mechanisms and genetic predispositions.
Main Methods:
- Forty-five Collaborative Cross mouse lines were treated with TAK-875 or vehicle.
- Liver gene expression profiling was performed to identify drug-responsive transcripts.
- Pathway-based phenotypes were developed for genetic mapping to identify candidate risk genes.
Main Results:
- TAK-875 treatment altered immune response and bile acid homeostasis gene expression across all strains.
- Interactions between treatment and strain revealed oxidative stress and mitochondrial dysfunction.
- Genetic mapping identified candidate genes associated with TAK-875 toxicity susceptibility at the hepatocyte level.
Conclusions:
- A gene pathway-based approach in CC mice successfully identified human-relevant mechanisms and genetic risk factors for TAK-875 DILI.
- This novel preclinical strategy can inform sensitive strains and aid in understanding, predicting, and preventing clinical DILI for other drugs.
