Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug.
Administration of pirprofen may produce microvesicular steatosis of the liver in humans. The effects of pirprofen on the mitochondrial beta-oxidation of fatty acids have been investigated in mice. In vitro, addition of 2 mM pirprofen decreased by 50% the formation of [14C]acid-soluble beta-oxidation products, and decreased by 70% the formation of [14C]CO2 upon incubation of hepatic mitochondria with [14C]palmitic acid, ATP, carnitine and coenzyme A. In vivo, administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before that of [U-14C]palmitic acid, decreased by 70% the exhalation of [14C]CO2 during the next 6 hr. Administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before the measurement, decreased plasma beta-hydroxybutyrate by 60%, plasma acetoacetate by 30% and blood glucose by 40%. Administration of pirprofen (2 mmol . kg-1 i.p.) 6 hr before sacrifice, doubled hepatic triglycerides content and produced microvesicular steatosis of the liver. We conclude that pirprofen inhibits the mitochondrial beta-oxidation of fatty acids in mice, thus explaining the microvesicular steatosis observed in mice and in some human subjects.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002245:Carbon Dioxide / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D010666:Phenylpropionates / Q000633:toxicity*; D014280:Triglycerides / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005227:Fatty Acids; D010169:Palmitic Acids; D010666:Phenylpropionates; D014280:Triglycerides; D002245:Carbon Dioxide; D019308:Palmitic Acid; C008924:pirprofen