Extraperoxisomal targets of peroxisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease

Abstract

Peroxisome proliferators are a structurally diverse group of compounds that include the fibrate hypolipidemic drugs, the phthalate ester industrial plasticizers, the phenoxy acid herbicides, and the anti-wetting corrosion inhibitors perfluorinated straight-chain monocarboxylic fatty acids. Administration of these chemicals to rodents results in a number of effects, the most prominent being hepatomegaly and induction of peroxisomal enzyme activities. Several of these compounds have also been associated with the production of liver tumors in rodents and are classified as nongenotoxic hepatocarcinogens. Experimental evidence suggests that humans are not susceptible to these effects following exposure to peroxisome-proliferating compounds. This has led to the proposal that an "actual threat to humans" from exposure to one of these compounds seems "rather unlikely". Indeed, recent reports suggest that peroxisome proliferators may prove valuable as antitumor agents in humans. However, this assessment is preliminary given that peroxisome proliferators also produce a myriad of extraperoxisomal effects in livers and other tissues of experimental animals. Such effects include both stimulation and inhibition of mitochondrial and microsomal metabolism and alteration of the activities of various cytosolic enzymes. These responses may be directly or indirectly related to the effects on peroxisomes or may be totally independent of these events. Whether the extraperoxisomal effects of these compounds occur in humans is not known and their potential impact on human health remains to be investigated.