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|Title:||Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone.|
|Citation:||Biochemical Pharmacology, 1996; 52(2):273-280|
|Publisher:||PERGAMON-ELSEVIER SCIENCE LTD|
|Abstract:||The mechanism of the anti-anginal effect of perhexiline is unclear but appears to involve a shift in cardiac metabolism from utilization of fatty acid to that of carbohydrate. We tested the hypothesis that perhexiline inhibits the enzyme carnitine palmitoyltransferase-1 (CPT-1), which controls access of long chain fatty acids to the mitochondrial site of beta-oxidation. Perhexiline produced a concentration-dependent inhibition of CPT-1 in rat cardiac and hepatic mitochondria in vitro, with half-maximal inhibition (IC50) at 77 and 148 mumol/L, respectively. Amiodarone, another drug with anti-anginal properties, also inhibited cardiac CPT-1 (IC50 = 228 mumol/L). The rank order of potency for inhibition was malonyl-CoA > 4-hydroxyphenylglyoxylate (HPG) = perhexiline > amiodarone = monohydroxy-perhexiline. Kinetic analysis revealed competitive inhibition of cardiac and hepatic CPT-1 by perhexiline with respect to palmitoyl-CoA but non-competitive inhibition with respect to carnitine. Curvilinear Dixon plots generated "apparent inhibitory constant (Ki)" values for perhexiline, which indicated a greater sensitivity of the cardiac than the hepatic enzyme to inhibition by perhexiline. Perhexiline inhibition of CPT-1, unlike that of malonyl-CoA and HPG, was unaffected by pretreatment with the protease nagarse. These data establish for the first time that two agents with proven anti-anginal effects inhibit cardiac CPT-1. This action is likely to contribute to the anti-ischaemic effects of both perhexiline and amiodarone.|
|Keywords:||Mitochondria, Liver; Mitochondria, Heart; Animals; Rats; Rats, Sprague-Dawley; Perhexiline; Amiodarone; Subtilisins; Carnitine O-Palmitoyltransferase; Cardiovascular Agents; Anti-Arrhythmia Agents; Male|
|Appears in Collections:||Medicine publications|
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