The effects of ibuprofen enantiomers on hepatocyte intermediary metabolism and mitochondrial respiration.
In vivo and in vitro (-)R-ibuprofen is inverted to the (+)S antipode via stereoselective formation of an R-ibuprofenyl-CoA intermediate. In this study the effects of (-)R- and (+)S-ibuprofen on metabolism and respiration were studied using isolated rat hepatocytes and mitochondria. R-Ibuprofen significantly increased the lactate to pyruvate ratio, perturbed mitochondrial ketogenesis as evidenced by alterations in the beta-hydroxybutyrate to acetoacetate ratio and uncoupled mitochondrial oxidative phosphorylation. In addition, substantial dose- and time-dependent sequestration of reduced CoA (CoASH) occurred in the presence of the R enantiomer. Similarly, S-ibuprofen altered both the cytosolic and mitochondrial redox states although the magnitude of the effect was substantially less than that observed with the R enantiomer. In contrast to R-ibuprofen, S-ibuprofen did not uncouple oxidative phosphorylation or sequester hepatocyte CoASH. It is proposed that the perturbations observed in hepatocyte intermediary metabolism and mitochondrial function are attributable to a combination of the direct effects of R-ibuprofen per se and the sequestration of CoASH as R-ibuprofenyl-CoA during the process of chiral inversion. On the basis of these results, R-ibuprofen should be considered more in terms of metabolism to a reactive acyl-CoA intermediate rather than as a pro-drug for the pharmacologically active S-enantiomer.
Knights
K M
KM
Dept of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park.
Drew
R
R
D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D006885:Hydroxybutyrates / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology*; D007657:Ketone Bodies / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000090:Acetoacetates; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D007773:Lactates; D011773:Pyruvates; D019344:Lactic Acid; C016635:acetoacetic acid; D019289:Pyruvic Acid; D020155:3-Hydroxybutyric Acid; D007052:Ibuprofen