Perspectives in Pharmacology Cyclooxygenase-2—10 Years Later

The enzyme cyclooxygenase (COX) catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a “housekeeping” enzyme in most tissues. By contrast, COX-2 can be up-regulated by various proinflammatory agents, including lipopolysaccharide, cytokines, and growth factors. Whereas many of the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) are caused by a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic, and antipyretic effects of NSAIDs. During the past few years specific inhibitors of the COX-2 enzyme have emerged as important pharmacological tools for treatment of pain and arthritis. However, although COX-2 was initially regarded as a source of pathological prostanoids only, recent studies have indicated that this isoenzyme mediates a variety of physiological responses within the organism. The present review assesses recent advances in COX-2 research, with particular emphasis on new insights into pathophysiological and physiological functions of this isoenzyme. In 1971, Vane showed that the anti-inflammatory action of nonsteroidal anti-inflammatory drugs (NSAIDs) rests in their ability to inhibit the activity of the cyclooxygenase (COX) enzyme, which in turn results in a diminished synthesis of proinflammatory prostaglandins (Vane, 1971). This action is considered to be not the sole but a major factor of the mode of action of NSAIDs. The pathway leading to the generation of prostaglandins has been elucidated in detail. Within this process, the COX enzyme (also referred to as prostaglandin H synthase) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for specific prostaglandin synthases. The enzyme is bifunctional, with fatty acid COX activity (catalyzing the conversion of arachidonic acid to prostaglandin G2) and prostaglandin hydroperoxidase activity (catalyzing the conversion of prostaglandin G2 to prostaglandin H2) (Fig. 1). In the early 1990s, COX was demonstrated to exist as two distinct isoforms (Fu et al., 1990; Xie et al., 1991). COX-1 is constitutively expressed as a housekeeping enzyme in nearly all tissues, and mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation). On the other hand, COX-2 expressed by cells that are involved in inflammation (e.g., macrophages, monocytes, synoviocytes) has emerged as the isoform that is primarily responsible for the synthesis of the prostanoids involved in pathological processes, such as acute and chronic inflammatory states. Accordingly, many of the side effects of NSAIDs (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) can be ascribed to a suppression of COX-1-derived prostanoids, whereas inhibition of COX-2-dependent prostaglandin synthesis accounts for the anti-inflammatory, analgesic, and antipyretic effects of NSAIDs (Fig. 1). Consequently, the hypothesis that specific inhibition of COX-2 might have therapeutic actions similar to those of NSAIDs, but without causing the unwanted side effects, was the rationale for the development of specific inhibitors of the COX-2 enzyme as a new class of anti-inflammatory and analgesic agents with improved gastrointestinal tolerability. Regulation of COX-2 Expression The genes for COX-1 and COX-2 are located on human chromosomes 9 and 1, respectively (Kraemer et al., 1992). Whereas COX-1 represents a housekeeping gene which lacks a TATA box (Kraemer et al., 1992), the promotor of the immediate-early gene COX-2 contains a TATA box and binding sites for several transcription factors including nuclear ABBREVIATIONS: NSAIDs, non-steroidal anti-inflammatory drugs; COX, cyclooxygenase; NFB, nuclear factorB; POAG, primary open angle glaucoma; CLASS, Celecoxib Long-Term Arthritis Safety Study; VIGOR, Vioxx Gastrointestinal Outcomes Research. 0022-3565/02/3002-367–375$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 300, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 900061/961097 JPET 300:367–375, 2002 Printed in U.S.A. 367 at A PE T Jornals on A uust 5, 2017 jpet.asjournals.org D ow nladed from