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ToxSci Advance Access published online on August 4, 2005
Toxicological Sciences, 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
Received June 23, 2005
Accepted June 27, 2005

Safety Evaluation

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

Neal F. Cariello 1*, Elizabeth H. Romach 1, Heidi M. Colton 1, Hong Ni 1, Lawrence Yoon 1, J. Greg Falls 1, Warren Casey 1, Donald Creech 1, Steven P. Anderson 2, Gina R. Benavides 3, Debie J. Hoivik 1, Roger Brown 1, and Richard T. Miller 1

1 GlaxoSmithKline Inc., Safety Assessment, Research Triangle Park, NC 27709
2 GlaxoSmithKline Inc., Safety Assessment, Research Triangle Park, NC 27709; Current Address: Bayer HealthCare LLC, 85 T.W. Alexander Drive, Research Triangle Park, NC 27709
3 GlaxoSmithKline Inc., Human Biomarker Center, Research Triangle Park, NC 27709

* To whom correspondence should be addressed.
Neal F. Cariello, E-mail: Neal.F.Cariello{at}gsk.com


  Abstract

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. Clinical administration of fibrates increases the expression and activity of fatty acid {beta}-oxidation genes, and causes a decrease in plasma triglycerides and an increase in high-density lipoproteins.

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.

Hepatic transcriptional profiling has been reported for a variety of PPAR agonists in the rodent, but to our knowledge, this report is the first in the primate. 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, (i) many genes related to ribosome and proteasome biosynthesis were upregulated, (ii) a large number of genes downregulated were in the complement and coagulation cascades, (iii) 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, (iv) no transcriptional signal for DNA damage or oxidative stress was observed and (v) 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 {beta}-oxidation pathways was substantially greater in the rodent than the primate.


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