Cyclooxygenase isoforms

TABLE 36.2 Adverse Effects of NSAIDs - Relationship to Prostaglandin Synthesis inhibition and Cyclooxygenase Isoforms... 

The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic in function, while COX-2 is induced during inflammation and tends to facilitate the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and marketed on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy. 

Ouellet M, Percival MD (1995) Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J 306 247-251... 

No historical perspective of natural product derived drugs would be complete without a discussion of aspirin (acetylsalicylic acid)—probably the most widely utilised drug of all time when the numbers of tablets consumed worldwide on an annual basis are considered. Even today, where presumably the major pharmacological effect is modulation of the cyclooxygenase isoforms, its full activity is still not fully defined. 

The prostaglandin pathway Renal prostanoid receptors Cyclooxygenase isoforms 420 421 422... 

Venturini C M, Isakson P, Needleman P 1998 Non-steroidal anti-inflammatory drug-induced renal failure a brief review of the role of cyclooxygenase isoforms. Current Opinion in Nephrology and Hypertension 7 79-82... 

Garavito RM, DeWitt DL. The cyclooxygenase isoforms Structural insights into the conversion of arachidonic acid to prostaglandins. Biochim Biophys Acta 1999 1441 278-287. 

Aspirin and the older nonselective NSAlDs inhibit both cyclooxygenase isoforms and thereby decrease prostaglandin and thromboxane synthesis throughout the body. Prostaglandins necessary for normal cell function are depleted, as well as prostaglandins involved in inflammation. Theoretically, the COX-2-selective inhibitors should have less effect upon the prostaglandins involved in normal cell function, particularly those in the gastrointestinal tract. 

There is a structural basis for COX-2 selectivity. Although the active sites within both cyclooxygenase isoforms are similar, a single amino acid difference in position 523 accoimts for the COX-2 selectivity of celecoxib. The substitution of the smaller valine molecule in COX-2 as opposed to the larger isoleucine molecule in COX-1 provides access to a side-pocket that is the binding site for the phenylsulfonamide moiety of celecoxib (Figure 56.2) [3]. 

Indomethacin (INDO) is a potent and non-selective inhibitor of both cyclooxygenase isoforms (COX-1 and COX-2) that exhibits slow, tight-binding and functionally irreversible inhibition/binding kinetics. 

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