Do Human Epidemiologic Data on Fibrates Offer an Indirect Test of the PPAR-α Activation MOA Hypothesis?
Human exposures to exogenous and endogenous PPAR-α agonists encompass a broad group of chemicals, including environmental contaminants known to activate the receptor, as well as a number of therapeutic agents whose molecular target is one or more receptors in the PPAR family. Indeed, fibrate drugs were developed using rodent models to treat hyperlipidemia in humans before the receptor was identified. These agents have varying degrees of affinity for PPAR-α (Shearer and Hoekstra 2003), and some have multiple mechanisms of action. Drugs that have PPAR-α agonist activity include fibrates or fibric acid derivatives (which are primarily PPAR-α agonists), bezafibrate (which also shows PPAR-γ activity), dual PPAR-α/γ agonists currently under development, the glitazones, and nonsteriod anti-inflammatory drugs (e.g., ibuprofen) (Sertznig et al. 2007). Some human data on PPAR-α agonist effects are available from fibrate clinical trials and population case–control studies of site-specific cancer
