Molecular toxicology of peroxisome proliferators.

The rat Reuber hepatoma cell cell line, H4IIEC3, has been used in gene transfection studies to study the molecular mechanisms of induction of the acyl CoA oxidase gene, the first and rate-limiting enzyme of the peroxisomal fatty acid beta-oxidation spiral. cDNAs encoding the peroxisome proliferator activated receptor and the 9-cis retinoic acid receptor were transfected into the cells, either in the presence or absence of their cognate ligands (Wy-14,643 and 9-cis retinoic acid respectively), in addition to the acyl CoA oxides promoter linked to a chloramphenicol acetyltransferase reporter gene construct. The above experimental approach has confirmed that the 9-cis retinoic acid receptor acts cooperatively with the peroxisome receptor in mediating activation of the acyl CoA oxidase gene. In addition, in vivo experiments have demonstrated that treatment of rats with peroxisome proliferators substantially increase the hepatic levels of the peroxisome receptor mRNA itself. Taken collectively, the above data provides a wealth of molecular and mechanistic information on perioxisome proliferation in the rat and is discussed in terms of the safety assessment of peroxisome proliferators in man.