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The Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah (D.L.S.); The William Harvey Research Institute, St. Bartholomew's and William and Mary Medical College, London, England (R.M.B.); and Center for Vascular Biology, Department of Physiology, University of Connecticut School of Medicine, Farmington, Connecticut (T.H.)
Abstract
Abstract I. Cyclooxygenase Isozymes A. Prostaglandins and Cyclooxygenase B. Early Evidence for Multiple Cyclooxygenases C. Studies of Cell Division and the Discovery of Cyclooxygenase-2 D. Structure of Cyclooxygenase-1 and Cyclooxygenase-2 E. Post-Translational Modification of Cyclooxygenases F. Variants of Cyclooxygenase Isoenzymes G. Cyclooxygenase Activation by Endogenous Compounds H. Enzyme Autoinactivation I. Synthetic Cyclooxygenase Inhibitors—Nonsteroidal Anti-Inflammatory Drugs J. Modulation of Cyclooxygenase and Peroxidase Activity II. Pharmacological Actions of Cyclooxygenase Isozyme-Generated Prostanoids A. Prostaglandin Receptors B. Inflammation C. Pain D. Fever E. Immune System F. Gastrointestinal Tract G. Cardiovascular System H. Kidney I. Lungs J. Reproduction K. Brain and Spinal Cord III. Regulation of Expression of Cyclooxygenase-1 and -2 IV. Cyclooxygenase Isozymes in Human Disease A. Treatment of Inflammatory Diseases B. Neoplastic Disease C. Alzheimer's Disease V. Cyclooxygenase Isozymes and the Future
Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.
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