There are two isoenzymes of prostaglandin endoperoxide (PGH) synthase (cyclooxygenase) called PGH synthase-1 and -2 or COX I and II. Both isoenzymes catalyze the conversion of arachidonate to PGH2, the committed step in the formation of prostaglandins and thromboxane. PGH synthase-1 is expressed constitutively in most tissues whereas PGH synthase-2 expression is induced in a variety of cell types by treatment with growth factors, tumour promoters and/or cytokines. Although PGH-synthase-1 has long been thought to be the site of action of non-steroidal anti-inflammatory drugs (NSAIDs), recent evidence suggests that PGH synthase-2 is the actual target of NSAIDs acting in their anti-inflammatory capacity. PGH synthase isoenzymes differ in gene and protein structures and regulation of expression; the isoenzymes utilize similar amino acids in catalysis. Subtle differences in active site structure are apparent from sequence comparisons and measurements of interactions with common NSAIDs including aspirin. The two PGH synthase isoenzymes are pharmacologically distinct implying that it will be feasible to develop isoenzyme-specific antagonists. NS-398 (Taisho) is a developmental new NSAID which appears to cause minimal ulcerogenic effects and which appears to inhibit PGH synthase-2 selectively.
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Smith et al. (1994) studied this question.
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