Perfluorodecanoic Acid Noncompetitively Inhibits the Peroxisomal Enzymes Enoyl-CoA Hydratase and 3-Hydroxyacyl-CoA Dehydrogenase

Abstract

The mechanisms of the inhibition of hepatic peroxisomal β-oxidation by the peroxisome proliferator PFDA 3 were studied. Female Sprague Dawley rats were given a single ip injection of either 0, 10, or 40 mg/kg PFDA or were placed on a diet supplemented with the peroxisome proliferator ciprofibrate (0.01%). After 2 weeks, the rats were killed, and hepatic peroxisomes were isolated by discontinuous sucrose gradient centrifugation. Treatment of rats with either PFDA or ciprofibrate increased the individual activities of each of the enzymes in the peroxisomal β-oxidation pathway. Similarly, treatment of rats with ciprofibrate greatly increased total peroxisomal β-oxidation, but peroxisomal β-oxidation was slightly decreased in rats treated with 40 mg/kg PFDA. In vitro inhibition studies found that PFDA was a noncompetitive and reversible inhibitor of both the activities of the peroxisomal bifunctional protein, namely enoylCoA hydratase and 3-hydroxyacyl-CoA dehydrogenase. The K i of the inhibition was approximately 5 μM. PFDA only slightly inhibited the activity of peroxisomal fatty acyl CoA oxidase, and did not inhibit peroxisomal thiolase activity. We therefore conclude that PFDA inhibits peroxisomal β-oxidation by noncompetitively inhibiting the peroxisomal bifunctional enzyme.