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Inhibition ofCyclooxygenases

COX-1 and COX-2 There are two genes encoding for proteins with cyclooxygenase activity: COX-1, which is constitutively expressed and present ubiquitously in the organism and COX-2, which is also constitutively expressed in some tissues, including vascular endothelium, kidney, and CNS, but becomes markedly upregulated by inflammatory and mitogenic stimuli. Immunocompetent white cells, such as monocytes/macrophages, are rich sources for COX-2 [90] upon stimulation by inflammatory cytokines or tumor promoters. COX-1 is the dominating isoform in blood platelets, and its constant constitutive expression in platelets is an important prerequisite for the irreversibility of the antiplatelet action of aspirin. The gene for COX-2 belongs to the group of "early response genes" and encodes for a protein with high turnover rate and short half-life that synthesizes prostaglandins "on demand." COX-2-derived prostaglandins are, therefore, involved not only in pathologic situations, such as inflammation, pain, and immune reactions, but also in physiological functions, such as renal perfusion and sodium excretion, pregnancy (from fertility to labor), and neuronal signal transmission in the CNS. A significant proportion of endothelial prostacyclin and PGE2 is also generated via COX-2. Prostacyclin contributes to the antithrombotic effects of endothelium, PGE2 to the regulation of vessel tone. Both functions become relevant in advanced atherosclerosis, an inflammatory disease, where COX-2 is (constitutively) upregulated (Section 2.3.1).

The three-dimensional structures of COX enzymes are well known. They are integral membrane enzymes that catalyze the first step in the conversion of arachidonic acid to prostaglandins and thromboxanes. The entrance to the catalytic site lies at the apex of a long, narrow hydrophobic channel that runs from the membrane surface into the protein interior, providing an access for arachi-donic acid to diffuse directly from the membrane inferior to the enzyme active site without traversing the aqueous department [91, 92]; Loll, personal communication, 2006). The generation of eicosa-noids from arachidonic acid through the prosta-

Arachidonic acid

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