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ToxSci Advance Access originally published online on December 1, 2005
Toxicological Sciences 2006 90(2):269-295; doi:10.1093/toxsci/kfj062
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Published by Oxford University Press 2005.

REVIEW

The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR)

Marjorie A. Peraza*, Andrew D. Burdick*, Holly E. Marin*, Frank J. Gonzalez{dagger} and Jeffrey M. Peters*,1

* Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802; and {dagger} Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892

Received September 21, 2005; accepted November 28, 2005

Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors that modulate target gene expression in response to endogenous and exogenous ligands. Ligands for the PPARs have been widely developed for the treatment of various diseases including dyslipidemias and diabetes. While targeting selective receptor activation is an established therapeutic approach for the treatment of various diseases, a variety of toxicities are known to occur in response to ligand administration. Whether PPAR ligands produce toxicity via a receptor-dependent and/or off-target-mediated mechanism(s) is not always known. Extrapolation of data derived from animal models and/or in vitro models, to humans, is also questionable. The different toxicities and mechanisms associated with administration of ligands for the three PPARs will be discussed, and important data gaps that could increase our current understanding of how PPAR ligands lead to toxicity will be highlighted.

Key Words: peroxisome proliferator-activated receptors (PPAR); toxicity; carcinogenesis; receptor-mediated toxicology.


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