Characterization of Prostaglandin H Synthase 2 Deficient Mice and Implications for Mechanisms of NSAID Action

Abstract

The prostaglandins (PGs) are a diverse group of autocrine and paracrine hormones that mediate many cellular and physiologic processes. Prostaglandin H₂ (PGH₂) is an obligate intermediate in the formation of all prostaglandins (Vane and Robertson, 1974). Prostaglandin synthase, an enzyme with two known isoforms, catalyzes formation of PGH₂ from arachidonic acid (AA). The two prostaglandin H synthase isoforms are cyclooxy-genase-1 (COX-1) and cyclooxygenase-2 (COX-2); the respective genes in the mouse are Ptgs1 and Ptgs2. These prostaglandin H synthases are thought to be the primary enzymatic targets for NSAIDs (Flower and Vane, 1972; Flower et al., 1972; DeWitt et al., 1993), and since PGH₂ is the major precursor for further PG synthesis, inhibition of cyclooxygenase by NSAIDs leads to a corresponding reduction in the production of PGs. In addition to their shared enzymatic function, COX-1 and COX-2 have similar amino acid sequences (O’Banion et al., 1992; Ryseck et al., 1992; Fletcher et al., 1992; Hsi et al., 1994). However, their physiologic functions are thought to be quite different (Smith et al., 1994).