Publication: Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H<inf>2</inf>synthases by ibuprofen, naproxen, and indomethacin
Issued Date
2001-12-15
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00062952
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2-s2.0-0035894284
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Mahidol University
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SCOPUS
Bibliographic Citation
Biochemical Pharmacology. Vol.62, No.12 (2001), 1587-1595
Suggested Citation
Maisa S. Jaradat, Buanus Wongsud, Srichan Phornchirasilp, Shamina M. Rangwala, Gamal Shams, Melissa Sutton, Karl J. Romstedt, Daniel J. Noonan, Dennis R. Feller Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H<inf>2</inf>synthases by ibuprofen, naproxen, and indomethacin. Biochemical Pharmacology. Vol.62, No.12 (2001), 1587-1595. doi:10.1016/S0006-2952(01)00822-X Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/26425
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Title
Activation of peroxisome proliferator-activated receptor isoforms and inhibition of prostaglandin H<inf>2</inf>synthases by ibuprofen, naproxen, and indomethacin
Abstract
A series of nonsteroidal anti-inflammatory drugs (NSAIDs) [S(+)-naproxen, ibuprofen isomers, and indomethacin] were evaluated for their activation of peroxisome proliferator-activated receptor (PPAR) α and γ isoforms in CV-1 cells co-transfected with rat PPAR α and γ, and peroxisome proliferator response element (PPRE)-luciferase reporter gene plasmids, for stimulation of peroxisomal fatty acyl CoA β-oxidase activity in H4IIEC3 cells, and for comparative inhibition of ovine prostaglandin endoperoxide H synthase (PGHS)-1 and PGHS-2 and arachidonic acid-induced human platelet activation. Each drug produced a concentration-dependent activation of the PPAR isoforms and fatty acid β-oxidase activity, inhibition of human arachidonic acid-induced platelet aggregation and serotonin secretion, and inhibition of PGHS-1 and PGHS-2 activities. For PPARα activation in CV-1 and H4IIEC3 cells, and the stimulation of fatty acyl oxidase activity in H4IIEC3 cells, the rank order of stereoselectivity was S(+)- ibuprofen > R(-)-ibuprofen; S(+)-ibuprofen was more potent than indomethacin and naproxen on these parameters. On PPARγ, the rank order was S(+)-naproxen > indomethacin > S(+)-ibuprofen > R(-)-ibuprofen. Each drug inhibited PGHS-1 activity and platelet aggregation with the same rank order of indomethacin > S(+)-ibuprofen > S(+)-naproxen > R(-)-ibuprofen. Notably, the S(+)-isomer of ibuprofen was 32-, 41-, and 96-fold more potent than the R(-)-isomer for the inhibition of PGHS-1 activity, human platelet aggregation, and serotonin secretion, respectively. On PGHS-2, the ibuprofen isomers showed no selectivity, and indomethacin, S(+)-ibuprofen, and S(+)-naproxen were 6-, 27-, and 5-fold more potent as inhibitors of PGHS-1 than PGHS-2 activity. These results demonstrate that the mechanisms of action of NSAIDs on these cell systems are different, and we propose that the pharmacological effects of NSAIDs may be related to both their profile of inhibition of PGHS enzymes and the activation of PPARα and/or PPARγ isoforms. © 2001 Elsevier Science Inc. All rights reserved.
