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ToxSci Advance Access originally published online on August 4, 2005
Toxicological Sciences 2005 88(1):250-264; doi:10.1093/toxsci/kfi273
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Gene Expression Profiling of the PPAR-alpha Agonist Ciprofibrate in the Cynomolgus Monkey Liver

Neal F. Cariello*,1, Elizabeth H. Romach*, Heidi M. Colton*, Hong Ni*, Lawrence Yoon*, J. Greg Falls*, Warren Casey*, Donald Creech*, Steven P. Anderson*,2, Gina R. Benavides{dagger}, Debie J. Hoivik*, Roger Brown* and Richard T. Miller*

* GlaxoSmithKline Inc., Safety Assessment, Research Triangle Park, North Carolina 27709, and {dagger} GlaxoSmithKline Inc., Human Biomarker Center, Research Triangle Park, North Carolina 27709

Received June 23, 2005; accepted July 27, 2005

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPAR{alpha} agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NF{kappa}B families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPAR{alpha} agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPAR{alpha}-treated rodents, which showed that the magnitude of induction in ß-oxidation pathways was substantially greater in the rodent than the primate.

Key Words: ciprofibrate; PPAR{alpha}.


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