title: Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone.
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.
authors.affiliation: Department of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Woodville, South Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Kennedy
authors.forename: S A
authors.initials: SA
authors.lastname: Unger
authors.forename: J D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D010480:Perhexiline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013381:Subtilisins / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002317:Cardiovascular Agents; D002334:Carnitine O-Palmitoyltransferase; D013381:Subtilisins; D010480:Perhexiline; D000638:Amiodarone