Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases

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Abstract
1 Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo‐oxygenase activity of prostaglandin endoperoxide synthase‐1 (PGHS‐1) and PGHS‐2. 2 Human blood from volunteers was drawn and allowed to clot at 37°C for 1 h in the presence of increasing concentrations of the test compounds (R‐ibuprofen, S‐ibuprofen, R‐ibuprofenoyl‐CoA, S‐ibuprofenoyl‐CoA, NS‐398). Immunoreactive (ir) thromboxane B2 (TXB2) concentrations in serum were determined by a specific EIA assay as an index of the cyclo‐oxygenase activity of platelet PGHS‐1. 3 Heparin‐treated blood from the same donors was incubated at 37°C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 μg ml−1). The contribution of PGHS‐1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS‐2 activity immunoreactive prostaglandin E2 (irPGE2) plasma concentrations were determined by a specific EIA assay. 4 S‐ibuprofen inhibited the activity of PGHS‐1 (IC50 2.1 μM) and PGHS‐2 (IC50 1.6 μM) equally. R‐ibuprofen inhibited PGHS‐1 (IC50 34.9) less potently than S‐ibuprofen and showed no inhibition of PGHS‐2 up to 250 μM. By contrast R‐ibuprofenoyl‐CoA thioester inhibited PGE2 production from LPS‐stimulated monocytes almost two orders of magnitude more potently than the generation of TXB2 (IC50 5.6 vs 219 μM). 5 Western blotting of PGHS‐2 after LPS induction of blood monocytes showed a concentration‐dependent inhibition of PGHS‐2 protein expression by ibuprofenoyl‐CoA thioesters. 6 These data confirm that S‐ibuprofen represents the active entity in the racemate with respect to cyclo‐oxygenase activity. More importantly the data suggest a contribution of the R‐enantiomer to therapeutic effects not only by chiral inversion to S‐ibuprofen but also via inhibition of induction of PGHS‐2 mediated by R‐ibuprofenoyl‐CoA thioester. 7 The data may explain why racemic ibuprofen is ranked as one of the safest non‐steroidal anti‐inflammatory drugs (NSAIDs) so far determined in epidemiological studies. British Journal of Pharmacology (1997) 122, 487–492; doi:10.1038/sj.bjp.0701415