Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
Microvesicular steatosis of the liver has been reported in two subjects receiving amineptine (a tricyclic antidepressant metabolized by beta-oxidation of its acyl chain). A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation, or in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of amineptine on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation was inhibited by 27, 33, 46 and 57% respectively, in the presence of 0.25, 0.5, 1 and 2 mM of amineptine. Inhibition was reversible. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetyl coenzyme A by mouse liver mitochondria, was inhibited by 22, 23, 47, 54, 60 and 62%, respectively, in the presence of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mM of amineptine. In vivo, administration of amineptine, 0.5 and 0.75 mmol.kg-1, inhibited by 70 and 84%, respectively, the exhalation of [14C] CO2 during the first 3 hr after the administration of a tracer dose of [U-14C]palmitic acid. Administration of amineptine, 0.0625, 0.25, 0.5 or 1 mmol.kg-1, 6 hr before the measurement, increased hepatic triglycerides by 73, 139, 295 and 320%, respectively. After 1 mmol.kg-1, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 5-fold the control value; liver histology at that time showed microvesicular steatosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Le Dinh
T
T
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U24), Clichy, France.
Freneaux
E
E
Labbe
G
G
Letteron
P
P
Degott
C
C
Geneve
J
J
Berson
A
A
Larrey
D
D
Pessayre
D
D
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic; D001944:Breath Tests; D056486:Chemical and Drug Induced Liver Injury; D003986:Dibenzocycloheptenes; D005218:Fat Necrosis / Q000139:chemically induced* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D007657:Ketone Bodies / Q000097:blood; D051379:Mice; D008833:Microcirculation; D008930:Mitochondria, Liver / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced*; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D003986:Dibenzocycloheptenes; D005227:Fatty Acids; D007657:Ketone Bodies; D010169:Palmitic Acids; C011597:amineptin; D019308:Palmitic Acid; D000105:Acetyl Coenzyme A