COX-3

Cyclo-oxygenase 3 Enzyme

Two cyclooxygenase isozymes, COX-1 and COX-2, are known to convert arachidonic acid into prostaglandins and are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs). A third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins), has been discovered.but how the mecanism is still confused.

Genetics

COX-3 is transcribed from the COX-1 gene, but the resulting mRNA is spliced differently. In dogs the resulting protein resembles the other two COX enzymes, but in mice and humans it does not, owing to frame-shift. In human, COX-3 mRNA is most abundant in cerebral cortex and heart.

Discovery

The COX-1/COX-2 model did not explain everything about fever and inflammation. Even though COX-2 inhibitors were as active as traditional NSAIDs in inflammatory models, 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 other physiological roles, being involved, for instance, in the maintenance of fluid balance by the kidney. In addition, the COX-1/COX-2 model did not explain the properties of acetaminophen (paracetamol): although its antipyretic and analgesic effects might be explained by inhibition of COX-2, it was not anti-inflammatory. Dan Simmon's group suggests 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, it could explain both the characteristics of acetaminophen, which has been reputed for some time of being a centrally-acting antipyretic. COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1. These are as good at reducing fever 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 than the other NSAIDs and that more than one COX isoform contributes to the fever response.

Inhibitors

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 human COX-3 mRNA (with introns removed) encodes proteins with completely different amino acid sequences from those of 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.

Future

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 anti-inflammatory 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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