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cyclooxygenase 1
Symbol(s): PTGS1 COX-1
Locus: 9 q32 -q33.3
EC number
EntrezGene 5742
OMIM 176805
RefSeq NM_080591
UniProt P23219
cyclooxygenase 2
Symbol(s): PTGS2 COX-2
Locus: 1 q25.2 -25.3
EC number
EntrezGene 5743
OMIM 600262
RefSeq NM_000963
UniProt P35354

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (EC that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, exert their effects through inhibition of COX. The names "prostaglandin synthase (PHS)" and "prostaglandin endoperoxide synthetase (PES)" are still used to refer to COX.

Function Edit

See also: Prostaglandin and Eicosanoid

COX converts arachidonic acid (AA, an ω-6 PUFA) to prostaglandin H2 (PGH2), the precursor of the series-2 prostanoids. The enzyme contains two active sites: a heme with peroxidase activity, responsible for the reduction of PGG2 to PGH2, and a cyclooxygenase site, where arachidonic acid is converted into the hydroperoxy endoperoxide prostaglandin G2 (PGG2). The reaction proceeds through H atom abstraction from arachidonic acid by a tyrosine radical generated by the peroxidase active site. Two O2 molecules then react with the arachidonic acid radical, yielding PGG2.

At present, three COX isoenzymes are known: COX-1, COX-2, and COX-3. COX-3 is a splice variant of COX-1, which retains intron one and has a frameshift mutation; thus some prefer the name COX-1b or COX-1 variant (COX-1v).[1]

Different tissues express varying levels of COX-1 and COX-2. Although both enzymes act basically in the same fashion, selective inhibition can make a difference in side-effects. COX-1 is considered a constitutive enzyme, being found in most mammalian cells. COX-2, on the other hand, is undetectable in most normal tissues. It is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation. More recently, it has been shown to be upregulated in various carcinomas and to have a central role in tumorigenesis.

Both COX-1 and -2 (also known as PGHS-1 and -2) also oxygenate two other essential fatty acids – DGLA (ω-6) and EPA (ω-3) – to give the series-1 and series-3 prostanoids, which are less inflammatory than those of series-2. DGLA and EPA are competitive inhibitors with AA for the COX pathways. This inhibition is a major mode of action in the way that dietary sources of DGLA and EPA (e.g., borage, fish oil) reduce inflammation.[2]


Pharmacology Edit

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight, approximately 70 and 72 kDa, respectively, and having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The smaller Val523 residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2.

Classical NSAIDs Edit

The main COX inhibitors are the non-steroidal anti-inflammatory drugs (NSAIDs).

The classical COX inhibitors are not selective and inhibit all types of COX. The resulting inhibition of prostaglandin and thromboxane synthesis has the effect of reduced inflammation, as well as antipyretic, antithrombotic and analgesic effects. The most frequent adverse effect of NSAIDs is irritation of the gastric mucosa as prostaglandins normally have a protective role in the gastrointestinal tract. Some NSAIDs are also acidic which may cause additional damage to the gastrointestinal tract.

Newer NSAIDs Edit

Selectivity for COX-2 is the main feature of celecoxib, rofecoxib, and other members of this drug class. Because COX-2 is usually specific to inflamed tissue, there is much less gastric irritation associated with COX-2 inhibitors, with a decreased risk of peptic ulceration. The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of renal failure, and there is evidence that indicates an increase in the risk for heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition). [citation needed] Rofecoxib (brand name Vioxx) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as celecoxib, and etoricoxib, are still on the market.

Natural COX inhibition Edit

Culinary mushrooms, like Maitake, may be able to partially inhibit COX-1 and COX-2.[3][4]

A variety of flavonoids have been found to inhibit COX-2.[5]

Fish oils contain a natural inhibitor of COX.[6]

Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.[7]

Calcitriol(Vitamin D) significantly inhibits the expression of the COX-2 gene.[8]

Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa. COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.[9]

Cardiovascular side-effects of COX inhibitors Edit

COX-2 inhibitors have been found to increase the risk of atherothrombosis even with short-term use. A 2006 analysis of 138 randomised trials and almost 150 000 participants[10] showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of myocardial infarction, and also that high-dose regimens of some traditional NSAIDs such as diclofenac and ibuprofen are associated with a similar increase in risk of vascular events.

Fish oils have been proposed as a reasonable alternative for the treatment of rheumatoid arthritis e.g. cod liver oil and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs.[6]

See also Edit

References Edit

  1. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL (October 2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13926–31.
  2. Simopoulos AP (December 2002). Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21 (6): 495–505.
  3. Zhang Y, Mills GL, Nair MG (December 2002). Cyclooxygenase inhibitory and antioxidant compounds from the mycelia of the edible mushroom Grifola frondosa. J. Agric. Food Chem. 50 (26): 7581–5.
  4. Zhang Y, Mills GL, Nair MG (2003). Cyclooxygenase inhibitory and antioxidant compounds from the fruiting body of an edible mushroom, Agrocybe aegerita. Phytomedicine 10 (5): 386–90.
  5. O'Leary KA, de Pascual-Tereasa S, Needs PW, Bao YP, O'Brien NM, Williamson G (July 2004). Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat. Res. 551 (1–2): 245–54.
  6. 6.0 6.1 Fish oil: what the prescriber needs to know by Leslie G Cleland, Michael J James, and Susanna M Proudman
  7. Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. (December 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 15;64(12):1767-75. PMID: 12445866
  8. Moreno J, Krishnan AV, Peehl DM, Feldman D. (July–August 2006). Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway.. Anticancer Res. 26 (4A): 2525–2530.
  9. Wallace JL (October 2008). Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?. Physiol. Rev. 88 (4): 1547–65.
  10. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332 (7553): 1302–8.

External linksEdit

  1. REDIRECT Template:Dioxygenases

Template:Metabolism of complex lipids

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