title: Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.
abstract: In an attempt to better understand the mechanisms for pseudoalcoholic liver lesions in human beings, we determined the effects of perhexiline on mitochondrial functions in mice and rats. A first series of studies suggested that protonated perhexiline entered mouse mitochondria along the mitochondrial membrane potential. Release of a proton in the mitochondrial matrix led to uncoupling of oxidative phosphorylation, and accumulation of perhexiline inhibited complexes I and II of the respiratory chain, decreased ATP formation in vitro and decreased the mitochondrial beta-oxidation of long-, medium- and short-chain fatty acids in vitro and in vivo in mice. In cultured rat hepatocytes, exposure for 24 hr to 25 mumol/L perhexiline markedly decreased hepatocellular ATP and cell viability. Exposure to 5 mumol/L perhexiline did not modify ATP and viability but decreased the beta-oxidation of palmitic acid uniformly labeled with carbon 14 by 38%, increased hepatocyte triglyceride levels by 98% and produced microvesicular steatosis after 72 hr of culture. We conclude that perhexiline is concentrated inside mitochondria, where it inhibits both oxidative phosphorylation and the mitochondrial beta-oxidation of fatty acids. These effects may contribute to the development of necrosis, steatosis and possibly certain other pseudoalcoholic liver lesions in human beings.
authors.affiliation: Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France.
authors.forename: D
authors.initials: D
authors.lastname: Deschamps
authors.forename: V
authors.initials: V
authors.lastname: DeBeco
authors.forename: C
authors.initials: C
authors.lastname: Fisch
authors.forename: B
authors.initials: B
authors.lastname: Fromenty
authors.forename: A
authors.initials: A
authors.lastname: Guillouzo
authors.forename: D
authors.initials: D
authors.lastname: Pessayre
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D010480:Perhexiline / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013775:Tetraphenylborate / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D009840:Oligomycins; D010169:Palmitic Acids; D014280:Triglycerides; D019308:Palmitic Acid; D013775:Tetraphenylborate; D000255:Adenosine Triphosphate; D010480:Perhexiline