Biosynthesis of the Prostanoids

Prostanoids, the prostaglandins, and thromboxane are end products of fatty acid metabolism with important physiological functions and pathological effects in areas relevant to pain. 

In 1971, Vane and Piper found that NSAIDs inhibit the biosynthesis of prostaglandins from arachidonic acid by preventing the substrate from binding to the COX enzyme active site. As it was 

Prostaglandin endoperoxide H synthase (PGHS-l PGHS-2) (Cycloc ygenase [COX-1, COX-2]) 

NSAIDs can be classified on the basis of their COX inhibitory and selectivity properties. In general, most NSAIDs inhibit both COX-1 and COX-2 to some extent, but most are mainly COX-1-selective (e.g., aspirin, sulindac, indomethacin, ketoprofen, piroxicam) some are somewhat selective for COX-1 (e.g., ibuprofen, diclofenac, naproxen) others are slightly selective for COX-2 (etodolac, meloxicam) while NSAIDs like luntiracoxib, rofecoxib, and cele-coxib are clear selective inhibitors of COX-2 (Fig. 9.3). Clearly, knowing the relative inhibitory potencies of different NSAIDs for COX-1 and COX-2 would be useful in attempting to 

Group Inhibitory potencies of NSAIDs for COX-1 and COX-2 Examples of NSAID 

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Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

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