Inhibition by salicylic acid of the activation and thus oxidation of long chain fatty acids. Possible role in the development of Reye's syndrome.
Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine.
Deschamps
D
D
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U-24), Hôpital Beaujon, Clichy, France.
Fisch
C
C
Fromenty
B
B
Berson
A
A
Degott
C
C
Pessayre
D
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D005218:Fat Necrosis / Q000175:diagnosis; D005227:Fatty Acids / Q000378:metabolism*; D007657:Ketone Bodies / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D012202:Reye Syndrome / Q000209:etiology* / Q000378:metabolism; D012459:Salicylates / Q000097:blood / Q000494:pharmacology*; D020156:Salicylic Acid; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D007657:Ketone Bodies; D012459:Salicylates; D014280:Triglycerides; D002245:Carbon Dioxide; D000255:Adenosine Triphosphate; D020156:Salicylic Acid