PGHS-2 inhibitors, NS-398 and DuP-697, attenuate the inhibition of PGHS-1 by aspirin and indomethacin without altering its activity.
Since the discovery of the inducible form of prostaglandin (PG) H synthase (PGHS), PGHS-2, considerable effort has been made to design selective inhibitors of this isozyme. N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) and 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl) thiophene (DuP-697) have been shown to interact reversibly with PGHS-1, while irreversibly inhibiting PGHS-2 in a time-dependent manner. In the present study we have tested the effects of DuP-697 and NS-398 on the activity of PGHS-1 and further explored the interactions between these agents and the inhibition of PGHS-1 by aspirin, indomethacin and ibuprofen. Three independent experimental systems, namely bovine aortic endothelial cells (BAEC), human fibroblasts and ram seminal vesicle microsomes were used to investigate the effects of DuP-697 and NS-398 on PGHS-1. The results show that DuP-697 and NS-398, at concentrations ranges which do not inhibit PGHS-1 activity, significantly attenuated the inhibition of PGHS-1 that was caused by aspirin and indomethacin. The same concentrations of DuP-697 and NS-398 did not affect the inhibition of PGHS-1 that was induced by the competitive reversible inhibitors ibuprofen and naproxen. Similar effects of DuP-697 and NS-393 were obtained with ram seminal vesicle microsomes. These results suggest that PGHS-2 inhibitors DuP-697 and NS-398 possibly interact with PGHS-1 at a site different from the enzyme's catalytic site, thus causing attenuation of PGHS-1 inhibition by aspirin and indomethacin without altering PGHS-1 basal activity or the ibuprofen-induced inhibition.
Rosenstock
M
M
Department of Clinical Pharmacology, The Corob Center for Health Sciences, Ben-Gurion University and Soroka Medical Center, P.O. Box 653, Beer-Sheva, Israel.
Danon
A
A
Rimon
G
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D012669:Seminal Vesicles / Q000187:drug effects / Q000201:enzymology; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D013876:Thiophenes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C064874:DuP 697; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D007213:Indomethacin