Distinct functions of COX-1 and COX-2
Introduction
Prostaglandins are known to be involved in many physiological and pathological processes including inflammation [1], bone resorption [2], ovulation [3], and angiogenesis [4]. Since the discovery of prostaglandin H synthase-2, which is referred to as cyclooxygenase-2 (COX-2) in this review, numerous studies have focused on delineating the distinct roles of COX-1 and COX-2. These studies have been of four general types: (a) expression of either COX-1 or COX-2 mRNA and protein in tissues and organs; (b) pharmacological inhibition of COX-1 and/or COX-2; (c) COX-1 and COX-2 gene disruptions in mice; and (d) overexpression of COX-1 and COX-2 in various cells. These studies led to the conclusion that these two closely related enzymes have distinct functions in the tissues and organs and have raised the possibility that selective inhibition of either COX isozyme may have useful therapeutic outcomes. In this chapter, I focus on the distinct functions of COX-1 and COX-2 and discuss the reason why two COX isozymes are necessary in the mammals.
Section snippets
Expression of COX-1 in various tissues and cells
It is recognized that COX-1 mRNA and protein are present at relatively stable levels in many tissues and cells. Because few cis-acting response elements and no TATA box have been identified in the 5′-flanking region of the COX-1 gene [5], COX-1 gene has been considered to be a “housekeeping” gene. Many but not all tissues and cells express COX-1 [6]. Moreover, COX-1 is inducible in some systems [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. As shown in Table 1, in some
Properties of COX-1 and COX-2 enzymes
Small differences in the structure of COX-1 and COX-2 lead to their important pharmacological and biological differences (Table 3). The active site of COX-1 is smaller than that of COX-2. Several substitutions including replacement of Ile434 in COX-1 with Val434 in COX-2 increase the relative volume of the active site of COX-1 [28]. In part, the discovery that the active sites of COX-1 and COX-2 are of different sizes led to the development of the COX-2 specific inhibitors [29]. Moreover, the
Phenotypic changes in COX-1 and COX-2 deficient mice
Using gene disruption experiments, the biological roles of proteins can be tested. In the case of COX-1 and COX-2 the phenotypes of deficient mice have supported the data obtained from pharmacological and epidemiological experiments. Overall, for the maintenance of normal physiology, it appears that a deficiency of COX-2 has more profound effects than a deficiency of COX-1.
COX-1(−/−) mice have reduced platelet aggregation and decreased arachidonic acid-induced inflammation but phorbol-induced
Conclusion
In intact cells, COX-2 utilizes a low concentration of arachidonic acid about equivalent to the concentration of arachidonic acid released endogenously. This means the production of prostaglandins via COX-2 is regulated by the activation of phospholipases and the expression of the COX-2 gene. Many cytokines and growth factors affect the phospholipases and COX-2, and glucocorticoids inhibit both phospholipase activity and the induction of COX-2. In contrast, COX-1 functions only at relatively
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