Induction of Hepatic Peroxisome Proliferation by Xenobiotics

Abstract

Significant increase in the number of peroxisomes in liver parenchymal cells and in the activity of H₂O₂ generating peroxisomal fatty acid β-oxidation enzyme system, accompanied by an increase in certain other hepatic enzymes, are produced by the administration of several structurally dissimilar hypolipidemic agents and some other xenobiotics. Continued feeding of these non-mutagenic peroxisome proliferators for extended periods of time results in the development of hepatocellular carcinomas in rats and mice. Available evidence indicates that maximal peroxisome prolfieration is a tissue-specific phenomenon restricted largely to the hepatocyte. The mechanism by which structurally diverse peroxisome proliferators produce a similar pleiotropic response is not known, but the tissue specific biological response and rapid rate of transcription of peroxisomal fatty acid β-oxidation enzyme genes support the hypothesis that these agents act by binding to a specific recognition molecule(s). Identification and molecular characterization of peroxisome proliferator-specific receptor(s) will be necessary to understand the tissue-specific and species-sensitive differences in the induction of peroxisome proliferation. Since hepatocarcinogenicity by peroxisome proliferators is not attributable to their direct effect on DNA, it is postulated that oxidative stress emanating from sustained induction of peroxisome proliferation plays a role in the initiation and/or promotion of carcinogenesis. Whether the oxidative stress or the continued peroxisome proliferator-receptor interactions lead to amplification or rearrangement of the peroxisomal β-oxidation genes or oncogenes remains to be elucidated.