AN UPSTREAM REGION OF THE ENOYL-COENZYME-A HYDRATASE 3-HYDROXYACYL-COENZYME-A DEHYDROGENASE GENE DIRECTS LUCIFERASE EXPRESSION IN LIVER IN RESPONSE TO PEROXISOME PROLIFERATORS IN TRANSGENIC MICE/

Peroxisome proliferators, which are structurally diverse nonmutagenic agents, induce hepatocarcinogenesis in rats and mice. Exposure to thes e xenobiotics leads to a rapid and coordinated transcriptional activat ion of the genes for the peroxisomal beta-oxidation enzyme system path way in the liver. We have previously identified a peroxisome prolifera tor-responsive element in the 5'-flanking region of the rat peroxisoma l hydratase/dehydrogenase (PBE) gene, the second enzyme in the beta-ox idation pathway. The peroxisome proliferator-responsive element in the PBE gene was shown to direct the induction of a luciferase reporter g ene in vitro. We have now used this 3.2-kilobase 5'-flanking region of the PBE gene fused to the coding region of luciferase to generate tra nsgenic mice. Three independent lines of transgenic mice expressed luc iferase in response to ciprofibrate, a peroxisome proliferator. The in duction of luciferase is specific to the liver; this agrees with the t issue-specific induction of PBE. Two other hypolipidemic drugs, nafeno pin and Wy-14,643, were also capable of inducing luciferase activity i n the liver. This study suggests that the PBE upstream element can be used to direct and modulate the expression of cloned genes by changing the levels of peroxisome proliferators. Also, the PBE-luciferase tran sgenic mouse should be an excellent model system for screening xenobio tics for potential peroxisome proliferator property.