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

Toxicologic Pathology - Tập 37 Số 4 - Trang 521-535 - 2009
Tetsuya Ohta1, Naoya Masutomi1, Naohisa Tsutsui1, Tetsuya Sakairi1, Matthew Mitchell2, Michael V. Milburn2, John Ryals2, Kirk Beebe2, Lining Guo2
1Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818, Japan
2Metabolon Inc., Durham, NC 27713, USA

Tóm tắt

Peroxisome proliferator-activated receptor-α (PPARα) 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.

Từ khóa


Tài liệu tham khảo

10.1177/096032719401300201

10.2337/diab.46.8.1319

10.1592/phco.27.3.412

10.1136/jcp.28.6.506

10.1146/annurev.med.53.082901.104018

10.1210/endo.137.1.8536636

10.1016/j.amjcard.2006.11.017

10.1093/toxsci/kfi273

10.1080/13547500410001720767

10.1016/j.mrfmmm.2003.12.019

10.1016/j.amjcard.2006.11.016

10.1097/00042737-199510000-00009

10.1007/s00204-004-0625-5

10.1093/jn/128.2.444S

10.1111/j.1432-1033.1988.tb14442.x

Feng Y, 2001, Wiener Klinische Wochenschrift, 113, 477

Fruchart JC, 2006, Drugs Today (Barc), 42, 39, 10.1358/dot.2006.42.1.893618

10.1097/00041433-199906000-00007

10.1186/1471-2105-7-S2-S18

10.1016/S0891-5849(01)00631-1

10.1001/archinte.159.22.2647

10.1093/carcin/bgh182

10.1016/j.amjcard.2007.07.057

10.1186/1471-2105-6-179

10.1093/jb/mvj068

10.1016/j.cmet.2007.10.013

Kumps A, 2002, Clin Chem, 48, 708

Lawrence JW, 1998, Toxicology of the Liver, 2, 125

10.2217/14622416.9.4.383

10.1210/en.2003-0288

10.1002/pmic.200500251

10.1007/s11883-000-0092-2

10.1016/0026-0495(88)90118-7

10.1016/S0021-9258(18)68628-4

10.1016/j.taap.2007.04.008

10.1016/0005-2760(86)90338-3

10.1139/H07-083

10.1093/toxsci/kfm011

10.1007/s00204-007-0278-2

10.1046/j.1523-1755.1998.00944.x

10.1034/j.1600-0773.2002.910101.x

10.1007/s00109-005-0678-9

10.1016/j.jns.2007.01.033

10.1038/sj.bjc.6603164

10.1128/MCB.00317-07

Shin M, 2006, Mol Pharmacol, 70, 1281, 10.1124/mol.106.026294

10.1006/taap.1999.8683

10.1161/01.CIR.98.19.2088

10.1007/s11011-007-9064-3

10.1016/S1567-5688(03)00033-3

10.1080/08860220701573640

10.2131/jts.31.471

10.1093/ndt/13.4.867

10.1007/s11306-007-0052-8

10.1016/j.cccn.2003.11.020

Thông tin
Thông tin xuất bản

Toxicologic Pathology

Tập 37 Số 4

521-535

Thông tin tác giả