Biology:Cyclooxygenase-3
Cyclooxygenase-3 (COX-3) is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.[1][2]
The other two cyclooxygenase isozymes are known to convert dihomo-γ-linolenic acid and arachidonic acid into prostaglandins, and are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs).
Transcription
COX-3 is transcribed from the PTGS1 (COX1) 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 a frame-shift mechanism. This mechanism is due to the fact that the spliced intron has 93 bases in dogs, resulting in the loss of 93:3 = 31 amino acids in the COX-3 sequence, which apparently does not impair its functionality. In humans, the intron is 94 bases long, leading to a protein with a completely different amino acid sequence from those of COX-1 or COX-2. The expressed protein does not show COX activity, and it is unlikely to play a role in prostaglandin-mediated physiological responses.[citation needed]
Discovery
The original COX-1/COX-2 model did not fully explain the immune responses of fever and inflammation. Even though COX-2 inhibitors are as active as traditional NSAIDs in inflammatory models, there were still some unexplained issues. For example, the widespread use of the newer generation of COX-2-selective compounds demonstrated that COX-2 also has other physiological roles, e.g. in the maintenance of fluid balance by the kidneys. In addition, the COX-1/COX-2 model did not explain the properties of paracetamol (acetaminophen): although its antipyretic (fever reducing) and analgesic (pain relieving) effects might be explained by inhibition of COX-2, it is not anti-inflammatory. Daniel L. Simmons' group suggested this was because of the presence of a variant of COX-1, which they named COX-3, that would be especially sensitive to paracetamol and related compounds. If this enzyme were particularly expressed in the brain, it could explain both the characteristics of paracetamol, which has been reputed for some time of being a centrally-acting antipyretic.[1][2]
COX-3 was actually discovered in 2002, and been found to be selectively inhibited by paracetamol, phenacetin, antipyrine, dipyrone, and some NSAIDs in rodent studies.[1][2] Acetaminophen is thought of as a mild analgesic and antipyretic suitable, at best, for mild to moderate pain. Its site of action has recently been identified as a COX-3 isoenzyme, a variant of the COX-1 enzyme (Chandrasekharan et al., 2002; Schwab et al., 2003; Ayoub et al., 2004). This discovery raises the possibility of developing more potent and selective drugs targeting the site.
A number of arguments counted against the COX-3 hypothesis: COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the site is identical to that in COX-1, but they 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 prostaglandin E2 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 the protein should be present within the hypothalamus rather than the cerebral cortex. All these considerations appeared to argue against COX-3 being the site of the antipyretic actions of NSAIDs and COX-2-selective agents. However, the results could be read as showing that paracetamol acts at a different site than the other NSAIDs and that more than one COX isoform contribute to the fever response.
Finally, the discovery of the frame-shift mechanism has made it highly unlikely that COX-3 plays a role in inflammation and fever in humans.
References
- ↑ 1.0 1.1 1.2 Botting R (June 2003). "COX-1 and COX-3 inhibitors". Thromb. Res. 110 (5–6): 269–72. doi:10.1016/S0049-3848(03)00411-0. PMID 14592546.
- ↑ 2.0 2.1 2.2 "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. October 2002. doi:10.1073/pnas.162468699. PMID 12242329.
Further reading
- "Antipyretics: mechanisms of action and clinical use in fever suppression". Am. J. Med. 111 (4): 304–15. September 2001. doi:10.1016/S0002-9343(01)00834-8. PMID 11566461..
- Botting R (December 2000). "Paracetamol-inhibitable COX-2". J. Physiol. Pharmacol. 51 (4 Pt 1): 609–18. PMID 11192935.
- "Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases". Proc. Natl. Acad. Sci. U.S.A. 99 (10): 7130–5. May 2002. doi:10.1073/pnas.102588199. PMID 12011469. Bibcode: 2002PNAS...99.7130B.
- "Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty". Am J Ther 9 (1): 43–51. 2002. doi:10.1097/00045391-200201000-00009. PMID 11782819.
- "Endothelial cells of the rat brain vasculature express cyclooxygenase-2 mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever". Brain Res. 733 (2): 263–72. September 1996. doi:10.1016/0006-8993(96)00575-6. PMID 8891309.
- "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. October 2002. doi:10.1073/pnas.162468699. PMID 12242329.–13931.
- "Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized, placebo-controlled clinical trial". Clin Ther 24 (4): 490–503. April 2002. doi:10.1016/S0149-2918(02)85126-8. PMID 12017395.
- "Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug". Arthritis Rheum. 44 (1): 180–5. January 2001. doi:10.1002/1529-0131(200101)44:1<180::AID-ANR24>3.0.CO;2-K. PMID 11212158.
- FitzGerald GA (March 2002). "Cardiovascular pharmacology of nonselective nonsteroidal anti-inflammatory drugs and coxibs: clinical considerations". Am. J. Cardiol. 89 (6A): 26D–32D. doi:10.1016/S0002-9149(02)02234-8. PMID 11909558.
- "Structure of the mitogen-inducible TIS10 gene and demonstration that the TIS10-encoded protein is a functional prostaglandin G/H synthase". J. Biol. Chem. 267 (7): 4338–44. March 1992. doi:10.1016/S0021-9258(18)42840-2. PMID 1339449.
- "Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol)". Nature 240 (5381): 410–1. December 1972. doi:10.1038/240410a0. PMID 4564318. Bibcode: 1972Natur.240..410F.
- "Peripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue injury model". Clin. Pharmacol. Ther. 72 (2): 175–83. August 2002. doi:10.1067/mcp.2002.126501. PMID 12189364.
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- "Pharmacology of cyclooxygenase-2 inhibition in the kidney". Kidney Int. 61 (4): 1210–9. April 2002. doi:10.1046/j.1523-1755.2002.00263.x. PMID 11918727.
- "TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue". J. Biol. Chem. 266 (20): 12866–72. July 1991. doi:10.1016/S0021-9258(18)98774-0. PMID 1712772.
- "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents". Nature 384 (6610): 644–8. 1996. doi:10.1038/384644a0. PMID 8967954. Bibcode: 1996Natur.384..644K.
- "The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice". Brain Res. 825 (1–2): 86–94. April 1999. doi:10.1016/S0006-8993(99)01225-1. PMID 10216176.
- "Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2". Nat. Struct. Biol. 3 (11): 927–33. November 1996. doi:10.1038/nsb1196-927. PMID 8901870.
- "Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase". Proc. Natl. Acad. Sci. U.S.A. 90 (24): 11693–7. December 1993. doi:10.1073/pnas.90.24.11693. PMID 8265610. Bibcode: 1993PNAS...9011693M.
- "Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy". Br. J. Pharmacol. 128 (6): 1121–32. November 1999. doi:10.1038/sj.bjp.0702897. PMID 10578123.
- "cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4888–92. June 1992. doi:10.1073/pnas.89.11.4888. PMID 1594589. Bibcode: 1992PNAS...89.4888O.
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- Prescott LF (March 2000). "Paracetamol: past, present, and future". Am J Ther 7 (2): 143–7. doi:10.1097/00045391-200007020-00011. PMID 11319582.
- "Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor". Br. J. Pharmacol. 121 (1): 105–17. May 1997. doi:10.1038/sj.bjp.0701076. PMID 9146894.
- "Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2". J. Pharmacol. Exp. Ther. 296 (2): 558–66. February 2001. PMID 11160644.
- "Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity". Nature 410 (6827): 471–5. March 2001. doi:10.1038/35068566. PMID 11260714. Bibcode: 2001Natur.410..471S.
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- "Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 3275–80. March 1999. doi:10.1073/pnas.96.6.3275. PMID 10077674. Bibcode: 1999PNAS...96.3275S.
- "The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing". Annu. Rev. Pharmacol. Toxicol. 42: 553–83. 2002. doi:10.1146/annurev.pharmtox.42.092401.143905. PMID 11807183.
- "Up-regulation of COX-2 by inhibition of COX-1 in the rat: a key to NSAID-induced gastric injury". Aliment. Pharmacol. Ther. 16 Suppl 2: 90–101. April 2002. doi:10.1046/j.1365-2036.16.s2.22.x. PMID 11966529.
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- "Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7563–8. June 1999. doi:10.1073/pnas.96.13.7563. PMID 10377455. Bibcode: 1999PNAS...96.7563W.
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- "Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing". Proc. Natl. Acad. Sci. U.S.A. 88 (7): 2692–6. April 1991. doi:10.1073/pnas.88.7.2692. PMID 1849272. Bibcode: 1991PNAS...88.2692X.
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