Untargeted metabolomic profiling as an evaluative tool of fenofibrate-induced toxicology in Fischer 344 male rats.
Peroxisome proliferator-activated receptor-alpha (PPARalpha) 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 beta-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.
Ohta
Tetsuya
T
Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818, Japan.
Masutomi
Naoya
N
Tsutsui
Naohisa
N
Sakairi
Tetsuya
T
Mitchell
Matthew
M
Milburn
Michael V
MV
Ryals
John A
JA
Beebe
Kirk D
KD
Guo
Lining
L
D000140:Acidosis, Lactic / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002853:Chromatography, Liquid; D002952:Citric Acid Cycle / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000008:administration & dosage / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000473:pathology*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D036401:Toxicity Tests, Chronic; D014364:Tryptophan / Q000378:metabolism
D015415:Biomarkers; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014364:Tryptophan; D011345:Fenofibrate