Pharmacological Analysis of Cyclooxygenase-1 in Inflammation
Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13313–13318, October 1998 Pharmacology Pharmacological analysis of cyclooxygenase-1 in inflammation CHRISTOPHER J. SMITH,YAN ZHANG,CAROL M. KOBOLDT,JERRY MUHAMMAD,BEN S. ZWEIFEL,ALEX SHAFFER, JOHN J. TALLEY,JAIME L. MASFERRER,KAREN SEIBERT, AND PETER C. ISAKSON* Searle Research and Development, 700 Chesterfield Parkway North, St. Louis, MO 63198 Communicated by Philip Needleman, Monsanto Company, St. Louis, MO, August 25, 1998 (received for review May 11, 1998) ABSTRACT The enzymes cyclooxygenase-1 and cycloox- and is expressed constitutively in most tissues and cells (17), ygenase-2 (COX-1 and COX-2) catalyze the conversion of although it can be induced in some cell lines under certain arachidonic acid to prostaglandin (PG) H2, the precursor of conditions (18). A second, inducible, form of COX was PGs and thromboxane. These lipid mediators play important hypothesized to exist on the basis of the finding of a glucocor- roles in inflammation and pain and in normal physiological ticoid-regulated increase in COX activity observed in vitro and functions. While there are abundant data indicating that the in vivo in response to inflammatory stimuli (19, 20). The inducible isoform, COX-2, is important in inflammation and isolation of a distinct gene and enzyme for COX-2 confirmed pain, the constitutively expressed isoform, COX-1, has also this hypothesis and led to the supposition that selective inhi- been suggested to play a role in inflammatory processes. To bition of inducible COX-2 would be anti-inflammatory, while address the latter question pharmacologically, we used a preserving the physiological functions of COX-1 derived PGs.
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