Yes, but do they still get headaches?

Much of our present understanding of the action of prostaglandins derives from observing the effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The anti-inflammatory, antipyretic, and analgesic effects resulting from inhibition of prostaglandin synthesis by aspirin, ibuprofen, and other NSAlDs indicate that these lipid-signaling molecules are critical regulators of immune responses, fever, and pain; we now know that prostaglandins are also ubiquitous autocrinelparacrine modulators of cellular responses and likely play roles in mitogenesis and apoptosis. (For a general review, see Smith and Dewitt, 1995). It therefore seems fitting that our latest advance in the understanding of the physiological roles of prostaglandins should again result from inhibition of prostaglandin synthesis, this time as a result of the genetic ablation of the enzymes required for their synthesis. In this issue of Cell, Langenbach et al. (1995) and Morham et al. (1995) describe the construction and phenotypic characterization of transgenic mice deficient in two isozymes central to prostaglandin synthesis, cyclooxygenases 1 and 2 (COX-1 and COX-2), also known as prostaglandin H synthase 1 and 2 (PGHS-1 and PGHSQ). The uniquely different phenotypes of the two knockout strains confirm that the closely related COX-1 and COX-2 isozymes are not redundant, and the genetic pathologies of these mice, or lack thereof, allow us more precisely to assign specific signaling roles to the two prostaglandin biosynthetic pathways defined by these enzymes. In a related article, Tsujii and DuBois (1995 [this issue of Cc//J) describe an unexpected function for the COX-2 pathway and, at the same time, provide a potential solution to a vitally important mystery: how does aspirin reduce the incidence of colon cancer? Separate Prostoglandin Biosynthetic Pathways COX catalyzes the first committed step in the formation of prostaglandins and thromboxanes (Figure 1). Arachidonic acid (AA) released from membrane phospholipids by phospholipase A2 is converted to prostaglandin HP (PGH*) through the action of COX; PGH2 is then converted to PGDz, PGE,, PGF*, PGlz, or thromboxane AZ by cellspecific synthases. Prostaglandins act, at least in part, through specific G protein-linked receptors to modulate the levels of the second messengers CAMP and Ca*+. There are two COX enzymes, referred to as COX-1 and COX-2. The relatively recent and unexpected discovery of the second of these isozymes has stimulated a great deal of research in the field, much of which has been directed at determining the biological rationale for this apparent redundancy. COX-1 and COX-2 are encoded by separate genes, but the enzymes are structurally homologous, and both catalyze the formation of PGH2 from AA with similar kinetic properties. Minireview