Aspirin and other cyclooxygenase inhibitors: new therapeutic insights.
Aspirin acetylates serine-530 of cyclooxygenase-1 (COX-1), thereby blocking thromboxane A (2) synthesis in platelets and reducing platelet aggregation. This mechanism of action accounts for the effect of aspirin on prevention of coronary artery and cerebrovascular thrombosis. Aspirin is less effective in inhibiting COX-2 activity, whereas celecoxib and rofecoxib selectively inhibit COX-2 activity as they contain a side chain to anchor to the side pocket of COX-2 substrate channel. Aspirin and salicylate at therapeutic concentrations inhibit COX-2 protein expression through interference with binding of CCAAT/enhancer binding protein beta (C/EBPbeta) to its cognate site on COX-2 promoter/enhancer. Expression of other genes, such as inducible nitric oxide synthase and interleukin-4, may be inhibited by aspirin and salicylate by a C/EBP-dependent mechanism. Aspirin at suprapharmacological concentrations inhibits NF-kappaB-mediated gene transcription and protects tissue from injury. These recent studies provide new insight into the pharmacological actions of aspirin and salicylate preparations and implicate C/EBPbeta as a potential target for therapy of inflammation and tissue injury.
Wu
Kenneth K
KK
Vascular Biology Research Center and Division of Hematology, The University of Texas-Houston Health Science Center, Houston, TX 77030-1503, USA. kenneth.k.wu@uth.tmc.edu
D000818:Animals; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D016328:NF-kappa B / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology / Q000627:therapeutic use; D015533:Transcriptional Activation / Q000187:drug effects
D022782:CCAAT-Enhancer-Binding Protein-beta; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D010975:Platelet Aggregation Inhibitors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D012980:Sodium Salicylate