Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs.

Prostaglandin synthase 2.

Low dosages of aspirin [1,2] and ingestion of certain fish oils [3-6] have recently been touted as having some value in preventing cardiovascular disease. Aspirin is a nonsteroidal anti-inflammatory drug which exerts its action by inhibiting the synthesis of prostaglandins. The abundant w)3 polyunsaturated fatty acids of fish oils derived from cod and salmon also affect the synthesis of prostaglandins, as well as the synthesis of the leukotrienes and related hydroxy fatty acids; the effects of 3 fatty acids on prostaglandin and leukotriene synthesis result from the ability of O3 fatty acids to replace the more

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The eicosanoids and their biochemical mechanisms of action.

The rate-limiting enzyme in arachidonate metabolism is mediated by enzymes known as cyclooxygenases (COXs), These enzymes catalyze the biosynthesis of prostaglandin H 2 , the precursor of molecules, such as prostaglandins, prostacyclin, and thromboxanes. The COX enzyme family consists of the classical COX-1 enzyme, which is constitutively expressed in many tissues, and a second enzyme, i.e., COX-2, which is induced by various stimuli, such as mitogens and cytokines, and is involved in many inflammatory reactions. Because nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulating evidence indicates that nonsteroidal anti-inflammatory drugs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the polyp number and size in patients with familial adenomatous polyposis. This Part I (of a two-part review) focuses on the discovery of the COXs; their biochemical, molecular, and structural properties ; and on the discovery of isozyme-specific inhibitors of COX activity.

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F.J. Van Der Ouderaa

Papers

Purification and characterisation of prostaglandin endoperoxide synthetase from sheep vesicular glands

On the haemoprotein character of prostaglandin endoperoxide synthetase

Enzymes involved in the conversion of endoperoxides.