The primary effect of the nonsteroidal antiinflammatory drugs (NSAIDs) is to inhibit cyclooxygenase (COX or prostaglandin synthase [PGHS]), thereby impairing the ultimate transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes (picture 1) . The extent of enzyme inhibition varies among the different NSAIDs, although there are no studies relating the degree of cyclooxygenase inhibition with antiinflammatory efficacy in individual patients [2,3]. (See "NSAIDs: Mechanism of action".)
Two related isoforms of the COX enzyme have been described [4,5]: COX-1 (PGHS-1) and COX-2 (PGHS-2). They possess 60 percent homology in those amino acid sequences apparently conserved for catalysis of arachidonic acid [6-10]. The most important differences between the two isoforms are the regulation and expression of the enzymes in various tissues:
●COX-1 is expressed in most tissues, but variably. It is described as a "housekeeping" enzyme, regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function), and it is stimulated by hormones or growth factors.
●COX-2 is constitutively expressed in the brain, in the kidney, in bone, and probably in the female reproductive system . Its expression at other sites is increased during states of inflammation or, experimentally, in response to mitogenic stimuli. As an example, growth factors, phorbol esters, and interleukin-1 stimulate the expression of COX-2 in fibroblasts, while endotoxin serves the same function in monocytes/macrophages [5,12].
●Both COX isoforms are regulated by physiologic stimuli, including shear stress in the vasculature  and ovulation and implantation in the female reproductive tract of rodents . In the human kidney, in non-physiologic states, such as diabetic nephropathy, hypertension, bone fracture, and heart failure, increased expression of COX-2 mRNA and protein has been noted . The clinical relevance of this is not yet clear.