Several hypolipidemic drugs and environmental contaminants induce hepatic peroxisome proliferation and hepatocellular carcinomas when administered to rodents. The mechanism by which these agents induce hepatocellular carcinomas is not known, but likely is related to biochemical changes induced by peroxisome proliferators, since most studies have not shown them to be genotoxic. Peroxisome proliferators induce cell proliferation and the increased expression of several genes, including the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family. However, because many genes are expressed, it is difficult to determine which specific gene(s) is responsible for the induction of hepatic tumors. The emergence of technology to insert single genes into mice or rats to create transgenic animals may allow the resolution of this question. We hypothesize that the expression of specific genes is responsible for the induction of hepatic tumors by peroxisome proliferators. We therefore propose to 1) produce transgenic mice and rats with the genes for the peroxisome proliferator-induced proteins fatty acyl CoA oxidase, the peroxisomal bifunctional enzyme, and cytochrome P-450 4A1. The genes for these proteins have been attached to PEPCK control elements and are being used to create transgenic mice and rats with liver-specific expression of these genes; and 2) examine biochemical effects produced by the increased expression of these genes in the liver, including the induction of toxicity and cellular proliferation, and the induction of oxidative damage such as oxidative DNA damage and lipid peroxidation. These studies will show which peroxisome proliferator-induced genes are responsible for the biochemical changes seen after the administration of peroxisome proliferators. Specific genes which produce these changes can then be examined in future studies to determine if their increased expression is sufficient to induce or promote hepatocellular carcinomas.
