Toxicity of Peroxisome Proliferators

Peroxisome proliferators (PPs) are an important group of chemicals that include certain hypolipidemic drugs, plasticizers and pollutants. Chemicals that are classified as PPs are known rodent liver tumor promoters, although there is debate whether humans are at increased cancer risk upon exposure. The effects observed upon long-term treatment of rodents to PPs include hepatic peroxisome proliferation, hepatomegaly, regulation of gene expression, alteration in cell cycle control and ultimately, carcinogenesis. The majority of the physiological, toxicological and carcinogenic effects induced by PPs are mediated by a nuclear hormone receptor, Peroxisome Proliferator-Activated Receptor-α (PPARα). Although humans respond to PPs via PPARα activation resulting in altered lipid metabolism, there is little evidence for peroxisome proliferation or liver cancer. In the present chapter, the current understanding of how PPARs are involved in tumorigenesis, and what this may mean to human risk assessment, will be discussed.