Differential induction and regulation of peroxisomal enzymes: predictive value of peroxisome proliferation in identifying certain nonmutagenic carcinogens

Abstract

Hypolipidemic drugs and certain plasticizers markedly increase the number of peroxisomes in liver parenchymal cells. Continued exposure to peroxisome proliferators has been shown to produce essentially similar pleiotropic responses leading eventually to the development of liver tumors in rats and mice. These agents are not mutagenic in short-term test systems and do not appear to interact with or damage DNA. Accordingly, the events leading to or associated with the induction of peroxisome proliferation have been postulated to play a role in the development of liver tumors. Recent evidence indicates that persistent peroxisome proliferation leads to the formation of 8-hydroxyguanosine in rat liver DNA, which supports the role for oxidative stress. The mRNAs of the three peroxisomal beta-oxidation genes are induced over 20-fold in the livers of rats treated with nafenopin, Wy-14643, BR-931, and other structurally diverse peroxisome proliferators. This increase in beta-oxidation mRNAs is evident within 30 min to 1 hr and was maximal 8 to 16 hr after the administration of a single dose of these agents by gavage. The peroxisomal catalase and urate oxidase mRNAs increase about 2-fold in the livers of rats treated chronically with peroxisome proliferators. These results indicate that peroxisome proliferators differentially regulate different peroxisomal enzymes. The tissue specificity of peroxisomal beta-oxidation gene regulation by xenobiotics supports the contention that the development of liver tumors following exposure to peroxisome proliferators correlates well with the inducibility of peroxisome proliferation and the beta-oxidation genes. Although these agents are known to exert mitogenic response in liver, it is unlikely that stimulation of DNA synthesis alone is responsible for tumor development. Cell proliferation may, however, play a secondary role. The morphological phenomenon of peroxisome proliferation should serve as a simple, sensitive, and valuable biological indicator for the identification of nongenotoxic or nonmutagenic chemicals that may be carcinogenic. An understanding of the cellular and molecular basis of peroxisome proliferation is a prerequisite for the evaluation of toxicological implications of this phenomenon.