Effects of chronic administration of the peroxisome proliferator, clofibrate, on cytosolic acetyl-CoA hydrolase in rat liver.

The hypolipidemic drug ethyl chlorophenoxyisobutyrate (clofibrate) is known to induce peroxisome proliferation and to be carcinogenic after long term administration to rats and mice. We examined the effects of treatment with this drug for periods of up to 18 months on cytosolic ATP-stimulated and ADP-inhibited acetyl-CoA hydrolase in rat liver. In male Donryu albino rats on a diet containing 0.5% clofibrate, the enzyme activity increased to about 2- and 3-fold the initial level per milligram liver protein and cytosolic protein, respectively, and 2-fold per milligram DNA in 3 days, and then remained at this level for up to 18 months. The increased activity in rats receiving clofibrate for 3 months returned to control level within a week when clofibrate was withdrawn. The change in enzyme activity paralleled the change in the amount of enzyme protein determined by immunoblotting with antibody against purified acetyl-CoA hydrolase from rat liver cytosol. No liver tumors were detected macroscopically after administration of clofibrate for 18 months. However, our results suggest that cytosolic acetyl-CoA hydrolase could be an extraperoxisomal marker enzyme induced by this type of drug.