COX isozymes

Although NSAIDs are effective in the treatment of pain and inflammation, their routine and long-term administration is limited, because of their GI and renal side effects. COX isozymes are the main targets of NSAIDs. While the inhibition of COX-2 is related to anti-inflammatory effects, that of COX-1 is associated with the adverse effects. The idea behind developing COX-2 inhibitors was to have a NSAID devoid of GI toxicity. However, GI toxicity depends on multiple factors, not just COX-2 selectivity. 

The two isozymes are both homodimers, composed of approximately 600 amino acids and possess approximately 60% homology. The three-dimensional structures of COX-1 and COX-2 are very similar. Each one consists of three independent units an epidermal growth factor-like domain, a membrane-binding section and an enzymic domain. The catalytic sites and the residues immediately adjacent are identical but for two small but crucial variations that result in an increase in the volume of the COX-2-active site, enabling it to accept inhibitor-molecules larger than those that could be accommodated in the COX-1 molecule. 

NSAIDs are associated with gastrointestinal, renal, hepatic, and central nervous system toxicity and may increase blood pressure. NSAIDs that are selective for the cyclooxygenase-2 (COX-2) isozyme are less likely to cause gastrointestinal complications but may increase the risk of cardiovascular events. They are no more effective than nonselective NSAIDs. Selective agents should be reserved for patients at high risk of gastrointestinal complications and low risk for cardiovascular events. 

Outlook Cyclooxygenase (COX) has two isozymes COX-1, a constitutive form present in stomach and kidney and COX-2, which is induced in inflammatory cells in response to appropriate stimuli. Presently available NSAIDs inhibit both isozymes. The search for COX-2-selective agents (Celecoxib, Ro-fecoxib) is intensifying because, in theory, these ought to be tolerated better. 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

Mammals have two isozymes of prostaglandin H2 synthase, COX-1 and COX-2. These have different functions but closely similar amino acid sequences (60% to 65% sequence identity) and similar reaction mechanisms at both of their catalytic centers. COX-1 is responsible for the synthesis of the prostaglandins that regulate the secretion of gastric mucin, and COX-2 for the prostaglandins that mediate inflammation, pain, and fever. Aspirin inhibits both isozymes about equally, so a dose sufficient to reduce inflammation also risks stomach irritation. Much research is aimed at developing new NSAIDs that inhibit COX-2 specifically, and several such drugs have become available. 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

COX-1 is expressed in all tissues and regulates the conversion of arachidonic acid to prostaglandin G0 (PGG,), which is the first step in prostanoid synthesis. The COX-2 isozyme is selectively expressed—it appears in renal, bone, brain, and reproductive tissues, as well as in some tumor types. The COX-2 enzyme is inducible by various mediators of inflammation (e.g., interleukins and superoxide radicals), whereas the COX-1 isomer is expressed constitutively. 

The selectivity of drugs is generally assessed with the aid of in vitro or ex-vivo assay systems, and also in human whole blood as appropriate. Occasionally, however, the data show considerable variability. This appears to apply in particular to meloxicam, where, depending on the experimental set-up, almost any selectivity factor may be obtained. [188] COX- inhibitors show in general affinity to both isozymes, cyclooxygenase-1 and -2. In many cases the selectivity factor ranges from 1 to 100 (Fig. 5.90). [189]... 

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