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Toxicologic Pathology
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Articles

Untargeted Metabolomic Profiling as an Evaluative Tool of Fenofibrate-Induced Toxicology in Fischer 344 Male Rats

Tetsuya Ohta1
Naoya Masutomi1
Naohisa Tsutsui1
Tetsuya Sakairi1
Matthew Mitchell2
Michael V. Milburn2
John A. Ryals2
Kirk D. Beebe2
Lining Guo2

1 Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818, Japan
2 Metabolon Inc., Durham, NC 27713, USA

Correspondence: Lining Guo, Metabolon Inc., 800 Capitola Drive, Suite 1, Durham, NC 27713, USA; e-mail:lguo{at}metabolon.com.

Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) agonists such as fenofibrate are used to treat dyslipidemia. Although fenofibrate is considered safe in humans, it is known to cause hepatocarcinogenesis in rodents. To evaluate untargeted metabolic profiling as a tool for gaining insight into the underlying pharmacology and hepatotoxicology, Fischer 344 male rats were dosed with 300 mg/kg/day of fenofibrate for 14 days and the urine and plasma were analyzed on days 2 and 14. A combination of liquid and gas chromatography mass spectrometry returned the profiles of 486 plasma and 932 urinary metabolites. Aside from known pharmacological effects, such as accelerated fatty acid β-oxidation and reduced plasma cholesterol, new observations on the drug’s impact on cellular metabolism were generated. Reductions in TCA cycle intermediates and biochemical evidence of lactic acidosis demonstrated that energy metabolism homeostasis was altered. Perturbation of the glutathione biosynthesis and elevation of oxidative stress markers were observed. Furthermore, tryptophan metabolism was up-regulated, resulting in accumulation of tryptophan metabolites associated with reactive oxygen species generation, suggesting the possibility of oxidative stress as a mechanism of nongenotoxic carcinogenesis. Finally, several metabolites related to liver function, kidney function, cell damage, and cell proliferation were altered by fenofibrate-induced toxicity at this dose.

Key Words: metabolomics • metabonomics • PPAR alpha • fenofibrate • biomarkers • energy metabolism • oxidative stress

Abbreviations: PPAR{alpha}, peroxisome proliferator-activated receptor-{alpha}; • ROS, reactive oxygen species.

Toxicologic Pathology, Vol. 37, No. 4, 521-535 (2009)
DOI: 10.1177/0192623309336152
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