Skip Navigation


ToxSci Advance Access originally published online on August 4, 2005
Toxicological Sciences 2005 88(1):250-264; doi:10.1093/toxsci/kfi273
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
88/1/250    most recent
kfi273v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (14)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Cariello, N. F.
Right arrow Articles by Miller, R. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cariello, N. F.
Right arrow Articles by Miller, R. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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}.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
Q. Yang, T. Nagano, Y. Shah, C. Cheung, S. Ito, and F. J. Gonzalez
The PPAR{alpha}-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPAR{alpha}
Toxicol. Sci., January 1, 2008; 101(1): 132 - 139.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
T. L. Horn, K. E. O. Torres, J. M. Naylor, M. J. Cwik, C. J. Detrisac, I. M. Kapetanovic, R. A. Lubet, J. A. Crowell, and D. L. McCormick
Subchronic Toxicity and Toxicogenomic Evaluation of Tamoxifen Citrate + Bexarotene in Female Rats
Toxicol. Sci., October 1, 2007; 99(2): 612 - 627.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn
Genomic Profiling in Nuclear Receptor-Mediated Toxicity
Toxicol Pathol, June 1, 2007; 35(4): 474 - 494.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.