Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids.
The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.
Freneaux
E
E
Unité de Recherches de Physiolopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France.
Fromenty
B
B
Berson
A
A
Labbe
G
G
Degott
C
C
Letteron
P
P
Larrey
D
D
Pessayre
D
D
D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D005227:Fatty Acids / Q000378:metabolism*; D007052:Ibuprofen / Q000494:pharmacology*; D066298:In Vitro Techniques; D007657:Ketone Bodies / Q000097:blood; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D002250:Carbon Radioisotopes; D005227:Fatty Acids; D007657:Ketone Bodies; D002245:Carbon Dioxide; D007052:Ibuprofen