Original ArticlesStereoselective and substrate-dependent inhibition of hepatic mitochondrial β-oxidation and oxidative phosphorylation by the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen, and ketorolac
Section snippets
Chemicals and reagents
S(+)- and R(−)-ibuprofen (99% optically pure) and S(+)- and R(−)-flurbiprofen (95.7% optically pure) were supplied by The Boots Company P/L. S(−)-ketorolac (96.4% optically pure) and R(+)-ketorolac (>99% optically pure) were supplied by Syntex Laboratories Inc. Reagents and chemicals were obtained from the following sources: methoxyflurane (Penthrane), Abbott Australasia; ATP, CoA lithium salt, l-carnitine.HCl, BSA, Tris hydrochloride and base, and ADP potassium salt, Sigma Chemical Co.;
Effects of NSAID enantiomers on mitochondrial β-oxidation
There was a significant relationship between the concentrations of both R- and S-ibuprofen and inhibition of the β-oxidation of palmitate by rat hepatic mitochondria when assessed as inhibition of formation of acid-soluble products (Fig. 1a; P = 0.0001). R-ibuprofen was much more potent than its S-antipode when assessed by the general linear models procedure (P = 0.015). The effects of R- and S-flurbiprofen (Fig. 1b) on the oxidation of palmitate were similar (P = 0.002, P = 0.004,
Discussion
The stereoselective inhibition of β-oxidation displayed by R-ibuprofen was consistent with previous data 1, 2, supporting the conclusion that a CoA-dependent mechanism was involved, although the degree of inhibition was rather greater in the present study. However, S-ibuprofen also inhibited β-oxidation, albeit less potently, while both enantiomers of flurbiprofen were inhibitory. This suggested that a non-CoA-dependent process was also involved, because previous data have indicated that S
Acknowledgements
This study was supported by an NHMRC grant to K.W. and R.D., and by the Boots Company, PLC (U.K.). The authors also wish to thank Dr. Kathleen Knights (Flinders University, Adelaide), Dr. Mark Hicks (St Vincents, Sydney), and Dr. Eric Brass (Harbor-UCLA Medical School, CA) for advice, and Dr. Gerd Geisslinger (Erlangen, Germany) for the purity assessment of the ketorolac enantiomers.
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