Peroxisome Proliferators

Abstract

The peroxisome proliferators (PPs) are a group of structurally unrelated chemicals capable of increasing the size and number of peroxisomes. Currently, more than 100 compounds are identified as PPs, including hypolipidemic drugs, plasticizers, herbicides, industrial solvents, and endogenous substances such as steroid hormones and fatty acids. PPs initially induce morphological and biochemical changes, predominantly in hepatocytes. Long-term administration of PPs causes hepatocellular carcinoma in both rats and mice. Ample evidence now shows that the PP-binding protein belongs to the steroid receptor superfamily. Peroxisome proliferation serves as a good indicator for screening chemicals in safety evaluation. Liver peroxisomes are composed of several enzymes, e.g., urate oxidase, d-amine oxidase, catalase, and ATP-dependent acyl-COA synthetase. The function of PPs is mostly mediated by a group of specific receptors, known as peroxisome proliferator-activated receptors (PPARs), which belong to the nuclear receptor superfamily. Upon ligand binding, PPARs dimerize with retinoid receptors, translocate to the nucleus, recognize specific PP-responsive elements on DNA, and transactivate a number of genes. Several processes are regulated by PPARs, such as mitochondrial and peroxisomal fatty acid uptake and β-oxidation, inflammation, intracellular lipid trafficking, and cell proliferation and death. Therefore, PPs and the PPARs are thought to play dominant roles in inducing as well as regulation of a variety of diseases, including Alzheimer's, diabetes, hypertension, and obesity.