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  • The enzyme cyclooxygenase COX or prostaglandin endoperoxide


    The enzyme cyclooxygenase (COX) or prostaglandin endoperoxide H synthase (PGHS) is the key enzyme in the conversion of arachidonic Ivachtin sale (AA) into prostaglandins (PGs) [1]. In 1991, researchers found that there were two isoforms of this enzyme called COX-1 and COX-2 with independent genes and different gene expression patterns in mammals [[2], [3]]. Cyclooxygenases are integral, glycosylated, homodimeric proteins consisting of 70-kDa subunits. Each subunit has a heme molecule and a catalytic site and passes through the hydrophobic sides of amphipathic helices to get inside a layer of phospholipid membranes [4]. Both the COX-1 and the COX-2 isoforms are present on the luminal membrane surfaces of endoplasmic reticulum and the inner and outer membranes of the nuclear envelope [5]. The COX isoforms are almost similar to each other in amino acid sequences, structural form, and enzymatic activity [[6], [7]]. In the COX enzymatic route, the two known isotherms of this enzyme (COX-1 and COX-2) are involved in the first step of synthesis of PGs, thromboxanes (TXs) and other eicosanoids. Production of these eicosanoids is dependent on the presence of AA. Secretion of AA from membrane phospholipids is mediated by the secretory or cytoplasmic phospholipase A2 (PLA2). The COX isoforms catalyze the formation of PGH2 from AA that may be converted into PGE2, PGF2, PGD2, PGI2 and thromboxane A2 (TXA2) [8]. In the process of inflammation and carcinogenesis, both the COX-1 and the COX-2 isoforms are involved, and COX-2 plays a dual role in initiating and eliminating inflammation [[5], [9]]. When both COX-1 and COX-2 isoforms are identically present in cells, their activities are determined by the concentration of the substrate (AA) and the extent of the expression of these enzymes. For example, at low concentrations of AA, COX-1 is inactive but COX-2 is active. Moreover, in cells where both isoenzymes are present, COX-2 activates prostaglandin synthases that cause the production of PGE2 and PGI2 [10]. The COX-1 and COX-2 genes are located at chromosome regions 9q32-q33.3 and 1q25.2-q25.3 respectively [11]. The COX-1 gene has 22 kb and 11 exons but lacks TATAbox. There is little information concerning with what mechanism the expression of the COX-1 gene is regulated. The COX-2 gene is 8 kb with 10 exons. The COX-2 gene has a TATAbox and inducible enhancers such as CRE and NF-кb [[11], [12]]. Studies have shown that the COX enzyme has a short half-life and, therefore, its regulation takes place mainly at the level of transcription [4]. The expression of these two isozymes is regulated differently after the transcription and translation stages because of the difference in the 3′-untranslated region (3′-UTR). The important biological difference between the two isozymes COX-1 and COX-2 are that COX-1 is normally present in most cells and is always active, and the quantity of the COX-1 protein remains constant under pathological and physiological conditions. On the contrary, the COX-2 protein is not normally found in most cells (except for the brain and the kidneys) and is expressed in large quantities within 2–4 h under pathological (often inflammatory) conditions [[4], [7]]. The non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, naproxen, and ibuprofen attach to the hydrophobic channel of COX isozymes and suppress it [[13], [14], [15]]. Aspirin is the only COX suppressor that forms a covalent bond with it (by acetylation). The acetylation of the amino acid serine 530 prevents attachment of AA to the active site, which causes an irreversible suppression of the enzyme [16]. Other NSAIDs compete with AA for attachment to the active site and cause irreversible suppression of the two isozymes. The mentioned drugs suppress the two mentioned isozymes identically so that the sufficient doses for reducing inflammation, the risk of stomach irritation, and damage to digestive tract mucosa are reduced [17]. Therefore, to date, the research is centralized in the production of drugs that are selective COX-2 inhibitors [18]. COXIBs are selective COX-2 inhibitors and their attachment to COX-1 is weak and reversible [19]. The preferential inhibition of COX-2 results in extra space in the hydrophobic channel of COX-2 [19]. Drugs such as Dup-697, Ns-398, meloxicam, and nimesulide are selective COX-2 inhibitors [[20], [21], [22], [23]].