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Cyclo-oxygenase 3 Enzyme
Two cyclooxygenase isozymes, COX-1 and COX-2, are known to convert arachidonic acid prostaglandins and are the targets of nonsteroidal antiinflammatory drugs(NSAID).A third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins) have been discovered.
COX-3 is made from the COX-1 gene, with some modifications. In human, COX-3 is most abundant in cerebral cortex and heart.
The COX-1/COX-2 model did not explain everything about fever and inflammation. Even though in inflammatory models COX-2 inhibitors were as active as traditional NSAIDs,there were still some confusing issues. For example, the widespread use of the newer generation of COX-2-selective compounds demonstrated that COX-2 also had physiological roles, being involved, for instance, in the maintenance of fluid balance by the kidney. The COX-1/COX-2 model was also not accommodating to the characteristics of Acetaminophen: although its antipyretic and analgesic effects might be explained by inhibition of COX-2, it was not antiinflammatory.Dan Simmon's group suggest this is because of the presence of a variant of COX-1, which they have named COX-3, that is especially sensitive to acetaminophen and related compounds. If this enzyme were particularly expressed in the brain, could it explain both the characteristics of acetaminophen, which has been reputed for while to be an antipyretic that is centrally acting. COX-2-selective inhibitors, react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1. These as good at reducing fever similarly as older NSAIDs. The fever response has also been clearly associated with a rapid induction of COX-2 expression and an associated increase in PGE2 production, with no role for COX-1 or a COX-1 gene product (e.g., COX-3). Finally, the sites of COX-3 expression do not appear to fit in well with those sites associated with fever, and we might expect to see the protein present within the hypothalamus rather than the cerebral cortex. All these considerations appear to argue against the COX-3 of Chandrasekharan et al. being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results from Chandrasekharan et al. could be read as showing that acetaminophen acts at a different site to the other NSAIDs and that more than one COX isoform contributes to the fever response.
Acetaminophen has been found to be a selective COX-3 inhibitor in rodent studies.
Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol (acetaminophen), arguably the most widely used analgesic drug in the world. (Chandrasekharan et al, 2002). The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
The relevance of this research has been called into question as the putative COX-3 gene encodes proteins with completely different amino acid sequences than COX-1 or COX-2. The expressed proteins do not show COX activity and it is unlikely that they play a role in prostaglandin mediated physiological responses.
The clinical ramifications and knowledge of COX isozymes are rapidly expanding and may offer significant hope for future treatments of pain, inflammation, and fever.
Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
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|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "COX-3". A list of authors is available in Wikipedia.|