Mechanistic Investigation of EMD335823s Hepatotoxicity Using Multiple Omics Profiling Technologies

Abstract

We have used modern omics technologies (including Toxicogenomics, proteomics, metabonomics and profiling from FFPE tissues) to ascertain whether a systems biology approach would improve our understanding of the mechanism of toxicity of a compound. Wistar rats were treated for up to 14 days with a non-toxic dose (15 mg kg−1) or a high dose (350 mg kg−1) of a known hepatotoxic compound (EMD 335823), chosen to ensure significant hepatotoxicity (liver necrosis, fibrosis, and bile duct necrosis/hyperplasia). Genomics, proteomics, and metabonomics identified animals with the most severe effects, in good agreement with pathological findings. Protein expression changes correlated well with gene expression changes, indicating that EMD 335823 regulated PPARα signaling. EMD 335823 is an aldose reductase inhibitor resulting in increased glucose metabolism and alterations in fatty acid metabolism. These disturbances result in lower energy resources, contributing to the pathogenesis of liver damage. Proteomics and metabonomics also showed clear separation of the most severely affected animals, although the limited numbers of molecules identified could not reveal the mechanism of toxicity alone. The combination of omics technologies allowed a more detailed analysis and identification of potential mechanisms of action, improving the overall understanding of the compounds toxicity. Additionally, there are indications that a compound-specific signature was visible earlier, when no histopathological changes occurred. Keywords: cross-omics comparison; genomics; hepatotoxicity; metabonomics; proteomics; systems toxicology