title: In vitro evidence for involvement of CoA thioesters in peroxisome proliferation and hypolipidaemia.
abstract: The mechanisms of peroxisomal induction and hypolipidaemia caused by treatment with peroxisome proliferators, such as nafenopin and clofibrate, remain to be elucidated. Proposed mechanisms include receptor-mediated processes or adaptations resulting from disruption of hepatic lipid metabolism. The latter mechanism was investigated in a series of in vitro studies. Incubation of primary rat hepatocytes with various carboxyl-containing compounds revealed no clear common factor which imparted potency as a peroxisomal inducer. Inhibitors of fatty acyl-CoA synthetase, norepinephrine and desulpho-CoA, however, decreased the level of peroxisomal induction by nafenopin in rat hepatocytes, suggesting that activation of carboxyl-containing compounds to their CoA thioesters may be a necessary step in initiating peroxisome proliferation. Coenzyme A thioesters of nafenopin, clofibric acid and other carboxyl-containing chemicals were synthesised and found to inhibit the activity of acetyl-CoA carboxylase to varying degrees. The CoA thioester of nafenopin was the most potent inhibitor among this group (Ki = 1.45 x 10(-5) M), but weaker than palmitoyl-CoA (Ki = 2.22 x 10(-6) M), the feedback inhibitor of acetyl-CoA carboxylase. Hypolipidaemia caused by treatment with peroxisome proliferators may, therefore, be related to inhibition of fatty-acid synthesis by the corresponding CoA thioester derivative.
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
authors.forename: K E
authors.initials: KE
authors.lastname: Tomaszewski
authors.forename: R L
authors.initials: RL
authors.lastname: Melnick
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003065:Coenzyme A / Q000494:pharmacology; D004952:Esters / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008830:Microbodies / Q000187:drug effects*; D009255:Nafenopin / Q000031:analogs & derivatives* / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats
chemical_list: D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D004952:Esters; D005227:Fatty Acids; D009255:Nafenopin; C051513:clofibric acid-coenzyme A; C051515:nafenopin-coenzyme A; D002995:Clofibric Acid; C035999:desulfo-coenzyme A; D000103:Acetyl-CoA Carboxylase; D003065:Coenzyme A; D009638:Norepinephrine