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The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR).

Peraza MA, Burdick AD, Marin HE, Gonzalez FJ, Peters JM

Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.

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.

Published 10 March 2006 in Toxicol Sci, 90(2): 269-95.
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