Ohta, T, et al., Untargeted Metabolomic Profiling as an Evaluative Tool of Fenofibrate-Induced Toxicology in Fischer 344 Male Rats. Toxicol Pathol, 2009. 37(4): 521-35.
Metabolon results led to:
- Greater insight into the full spectrum of on- and off-target effects of the PPAR-a agonist Fenofibrate
- Numerous potential biomarkers – PD, latent toxicity, overt toxicity
Key metabolomic observations:
- Strong validation of the expected energetic changes (beta-oxidation)
- Dramatic changes in tryptophan metabolism, including a strong inducer of reactive oxygen species, quinolinate
- Changes in bile acids and cholesterol as a likely reflection of impaired liver function
Fenofibrate has been widely used to treat dyslipidemic patients and, although generally regarded as safe, it is known to induce hepatomegaly and promote tumors in rats by an unknown mechanism. Thus, a metabolomics study was undertaken. The results provided a comprehensive picture of the on-target and off-target effects including clear validation of effects on energy metabolism, particularly fatty acid beta-oxidation. In addition to expected pharmacological effects, unique pathways that give potential insight into the toxicological effects were observed including large changes in a tryptophan metabolite that serves as a strong inducer of reactive oxygen species, quinolinate. Also, liver function seemed to be accompanied by changes in cholesterol and bile acid metabolism, resulting in the suggestion that bile acids may be useful hepatotoxicity markers. Collectively, the approach showed that metabolomics may be an ideal way to elucidate fine mechanistic detail about compound action (whether pharmacological or toxicological).