Abstract：
:Previous studies with both intact cells and ram seminal vesicles microsomes have shown that the specific PGHS-2 inhibitors NS-398 (N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide) and DuP-697 (5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene) attenuate the inhibition of PGHS-1 caused by aspirin and indomethacin. This effect occurs at concentrations of PGHS-2 inhibitors that do not inhibit the cyclooxygenase activity of PGHS-1. Here we study the effect of NS-398 and ibuprofen, a nonspecific inhibitor, on the indomethacin-induced inhibition of purified PGHS-1 and compare this effect with that observed with microsomal enzyme. Dissociation constants are obtained for the interaction of NS-398 with the purified and microsomal PGHS-1 using curve fitting of experimental data on the interaction of indomethacin with the enzyme. The dissociation constants for ibuprofen and NS-398 for interaction with PGHS-1 are similar. This finding indicates that specific PGHS-2 inhibitors are similar to ibuprofen in their ability to compete with aspirin, an irreversible time-dependent inhibitor of PGHS-1 often used for prevention of spontaneous thrombosis. Importantly, the concentrations at which PGHS-2 inhibitors attenuate the inhibition induced by aspirin and indomethacin are well below those required to cause inhibition of PGHS-1. Our results suggest that arachidonic acid not only competes with PGHS-2 inhibitors for binding to the cyclooxygenase site of PGHS-1 but it also reduces the affinities of PGHS-1 for these inhibitors by an additional, as yet unresolved mechanism.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Burde T,Rimon Gdoi
10.1016/s0014-2999(02)02450-0keywords:
subject
Has Abstractpub_date
2002-10-25 00:00:00pages
167-73issue
2-3eissn
0014-2999issn
1879-0712pii
S0014299902024500journal_volume
453pub_type
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journal_title：European journal of pharmacology
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