Perfluorodecanoic acid noncompetitively inhibits the peroxisomal enzymes enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase.
The mechanisms of the inhibition of hepatic peroxisomal beta-oxidation by the peroxisome proliferator PFDA3 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 beta-oxidation pathway. Similarly, treatment of rats with ciprofibrate greatly increased total peroxisomal beta-oxidation, but peroxisomal beta-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 enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase. The Ki of the inhibition was approximately 5 microM. 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 beta-oxidation by noncompetitively inhibiting the peroxisomal bifunctional enzyme.
Borges
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Graduate Center for Toxicology, University of Kentucky, Lexington 40506-0054.
Glauert
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HP
Robertson
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LW
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology*; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors*; D005260:Female; D005466:Fluorocarbons / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D003652:Decanoic Acids; D005466:Fluorocarbons; C036567:perfluorodecanoic acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D004746:Enoyl-CoA Hydratase