Psychiatry/Research, Emory University
The inhibition of cyclooxygenases by nonspecific nonsteroidal anti-inflammatory drugs: Probing the differential effect of aspirin on COX-2
Utilizing in vitro methods, I am assessing the observed differential effect of classic, “nonselective” NSAIDs on cyclooxygenase (COX) isozyme activity. In short, aspirin is a covalent inhibitor of COX activity that acetylates an active site serine. In COX-1, the acetylation confers complete inhibition. In COX-2, however, there is persistent activity despite acetylation and there is a concomitant alteration in the product profile from generation of predominantly prostaglandin H2 (PGH2) to 15R-hydroxyeicosatetraenoic acid (15R-HETE). 15R-HETE is a precursor in the production of 15-epi-lipoxins in vivo, which are pro-resolving lipid mediators. The alteration in regio- and stereoselectivity induced by acetylation of COX-2 is a matter of debate and the molecular basis is yet to be elucidated. Using recombinant technologies, functional assays, chromatographic techniques, and x-ray crystallography, I hope to shed light onto the matter.