Biomaterial Database

Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. 1994

W L Smith, and E A Meade, and D L DeWitt

Department of Biochemistry, Michigan State University, East Lansing 48824.

There are two isozymes of prostaglandin endoperoxide (PGH) synthase (cyclooxygenase) called PGH synthase-1 and -2 or COX I and II. Both isozymes catalyze the same two reactions: oxygenation of arachidonate to yield PGG2 and reduction of PGG2 to PGH2. PGH synthase-1 is expressed constitutively and is found in most tissues. PGH synthase-2 is undetectable in most cells but can be induced in fibroblasts, endothelial cells, ovarian follicles, and macrophages by various mitogens, cytokines, and tumor promoters. PGH synthase-1 (PGHS-1) has been presumed to be the site of action of nonsteroidal antiinflammatory drugs (NSAIDs). However, the discovery of the second isozyme, PGH synthase-2 (PGHS-2), and its association with inflammation has suggested that this latter enzyme may be the therapeutic target of NSAIDs functioning in their antiinflammatory capacities. We have cloned cDNAs for murine PGHS-1 and PGHS-2, expressed these enzymes in cos-1 cells, and compared the relative sensitivities of the two isozymes to some common NSAIDs. Indomethacin, piroxicam, and sulindac sulfide were found to preferentially inhibit PGHS-1. Ibuprofen and meclofenamate inhibit both enzymes with comparable potencies. 6-Methoxy-2-naphthylacetic acid, the active metabolite of Relafen, inhibits murine PGHS-2 preferentially. Aspirin irreversibly inhibits PGHS-1, preventing this isozyme from forming PGH2 or any other oxygenated product; in contrast, aspirin treatment of PGHS-2 causes this enzyme to form 15-hydroxy-5c,8c,11c,13t-eicosatetraenoic acid (15-HETE) instead of PGH2. Our results indicate mouse PGHS-1 and PGHS-2 are pharmacologically distinct. Thus, it should be possible to develop agents highly selective for each PGHS isozyme. PGHS-2 is not expressed in stomach but is increased by inflammatory cytokines in cells such as macrophages. Thus, a selective inhibitor of PGHS-2 could be an antiinflammatory agent but without being ulcerogenic.

UI	MeSH Term	Description	Entries
D007527	Isoenzymes	Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.	Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D011451	Prostaglandin-Endoperoxide Synthases	Enzyme complexes that catalyze the formation of PROSTAGLANDINS from the appropriate unsaturated FATTY ACIDS, molecular OXYGEN, and a reduced acceptor.	Fatty Acid Cyclo-Oxygenase,PGH Synthase,Prostaglandin H Synthase,Prostaglandin Synthase,Prostaglandin-Endoperoxide Synthase,Arachidonic Acid Cyclooxygenase,Cyclo-Oxygenase,Cyclooxygenase,Cyclooxygenases,Hydroperoxide Cyclase,PGH2 Synthetase,Prostaglandin Cyclo-Oxygenase,Prostaglandin Cyclooxygenase,Prostaglandin Endoperoxide Synthetase,Prostaglandin G-H Synthase,Prostaglandin H2 Synthetase,Prostaglandin Synthetase,Cyclase, Hydroperoxide,Cyclo Oxygenase,Cyclo-Oxygenase, Fatty Acid,Cyclo-Oxygenase, Prostaglandin,Cyclooxygenase, Arachidonic Acid,Cyclooxygenase, Prostaglandin,Endoperoxide Synthetase, Prostaglandin,Fatty Acid Cyclo Oxygenase,G-H Synthase, Prostaglandin,Prostaglandin Cyclo Oxygenase,Prostaglandin Endoperoxide Synthases,Prostaglandin G H Synthase,Synthase, PGH,Synthase, Prostaglandin,Synthase, Prostaglandin G-H,Synthase, Prostaglandin H,Synthase, Prostaglandin-Endoperoxide,Synthases, Prostaglandin-Endoperoxide,Synthetase, PGH2,Synthetase, Prostaglandin,Synthetase, Prostaglandin Endoperoxide,Synthetase, Prostaglandin H2
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000894	Anti-Inflammatory Agents, Non-Steroidal	Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects.	Analgesics, Anti-Inflammatory,Aspirin-Like Agent,Aspirin-Like Agents,NSAID,Non-Steroidal Anti-Inflammatory Agent,Non-Steroidal Anti-Inflammatory Agents,Nonsteroidal Anti-Inflammatory Agent,Anti Inflammatory Agents, Nonsteroidal,Antiinflammatory Agents, Non Steroidal,Antiinflammatory Agents, Nonsteroidal,NSAIDs,Nonsteroidal Anti-Inflammatory Agents,Agent, Aspirin-Like,Agent, Non-Steroidal Anti-Inflammatory,Agent, Nonsteroidal Anti-Inflammatory,Anti-Inflammatory Agent, Non-Steroidal,Anti-Inflammatory Agent, Nonsteroidal,Anti-Inflammatory Analgesics,Aspirin Like Agent,Aspirin Like Agents,Non Steroidal Anti Inflammatory Agent,Non Steroidal Anti Inflammatory Agents,Nonsteroidal Anti Inflammatory Agent,Nonsteroidal Anti Inflammatory Agents,Nonsteroidal Antiinflammatory Agents
D016861	Cyclooxygenase Inhibitors	Compounds or agents that combine with cyclooxygenase (PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES) and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of eicosanoids, prostaglandins, and thromboxanes.	Cyclo-Oxygenase Inhibitor,Cyclooxygenase Inhibitor,Prostaglandin Endoperoxide Synthase Inhibitor,Prostaglandin Endoperoxide Synthase Inhibitors,Prostaglandin Synthase Inhibitor,Prostaglandin Synthase Inhibitors,Prostaglandin Synthesis Antagonist,Prostaglandin Synthesis Antagonists,Cyclo-Oxygenase Inhibitors,Inhibitors, Cyclo-Oxygenase,Inhibitors, Cyclooxygenase,Inhibitors, Prostaglandin Synthase,Inhibitors, Prostaglandin-Endoperoxide Synthase,Antagonist, Prostaglandin Synthesis,Antagonists, Prostaglandin Synthesis,Cyclo Oxygenase Inhibitor,Cyclo Oxygenase Inhibitors,Inhibitor, Cyclo-Oxygenase,Inhibitor, Cyclooxygenase,Inhibitor, Prostaglandin Synthase,Inhibitors, Cyclo Oxygenase,Inhibitors, Prostaglandin Endoperoxide Synthase,Synthase Inhibitor, Prostaglandin,Synthesis Antagonist, Prostaglandin
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus