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, aminopyrine, dipyrone, and strongly inhibited by diclofenac, indomethacin, ibuprofen and aspirin 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.[2][3][4] 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.[5]
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.[citation needed]
References
- ^ a b c 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.
- ^ a b c d 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. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329.
- ^ Schwab, Jan M.; Schluesener, Hermann J.; Meyermann, Richard; Serhan, Charles N. (2003). "COX-3 the enzyme and the concept: steps towards highly specialized pathways and precision therapeutics?". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 69 (5): 339–343. doi:10.1016/j.plefa.2003.07.003. ISSN 0952-3278. PMID 14580368.
- ^ Ayoub, Samir S.; Botting, Regina M.; Goorha, Sarita; Colville-Nash, Paul R.; Willoughby, Derek A.; Ballou, Leslie R. (2004-07-27). "Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein". Proceedings of the National Academy of Sciences of the United States of America. 101 (30): 11165–11169. doi:10.1073/pnas.0404185101. ISSN 0027-8424. PMC 503757. PMID 15263079.
- ^ Berenbaum, Francis (2004). "COX-3: Fact or fancy?". Joint Bone Spine. 71 (6): 451–453. doi:10.1016/j.jbspin.2004.02.003.
Further reading
- Aronoff DM, Neilson EG (September 2001). "Antipyretics: mechanisms of action and clinical use in fever suppression". Am. J. Med. 111 (4): 304–15. 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.
- Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA (May 2002). "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. Bibcode:2002PNAS...99.7130B. doi:10.1073/pnas.102588199. PMC 124540. PMID 12011469.
- Camu F, Beecher T, Recker DP, Verburg KM (2002). "Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty". Am J Ther. 9 (1): 43–51. doi:10.1097/00045391-200201000-00009. PMID 11782819. S2CID 10726593.
- Cao C, Matsumura K, Yamagata K, Watanabe Y (September 1996). "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. doi:10.1016/0006-8993(96)00575-6. PMID 8891309. S2CID 7960474.
- 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. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329.–13931.
- Chang DJ, Desjardins PJ, Chen E, Polis AB, McAvoy M, Mockoviak SH, Geba GP (April 2002). "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. doi:10.1016/S0149-2918(02)85126-8. PMID 12017395.
- Dougados M, Béhier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, Zeidler H, Herman H (January 2001). "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. 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.
- Fletcher BS, Kujubu DA, Perrin DM, Herschman HR (March 1992). "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. doi:10.1016/S0021-9258(18)42840-2. PMID 1339449.
- Flower RJ, Vane JR (December 1972). "Inhibition of prostaglandin synthetase in brain explains the anti-pyretic activity of paracetamol (4-acetamidophenol)". Nature. 240 (5381): 410–1. Bibcode:1972Natur.240..410F. doi:10.1038/240410a0. PMID 4564318. S2CID 4174100.
- Gordon SM, Brahim JS, Rowan J, Kent A, Dionne RA (August 2002). "Peripheral prostanoid levels and nonsteroidal anti-inflammatory drug analgesia: replicate clinical trials in a tissue injury model". Clin. Pharmacol. Ther. 72 (2): 175–83. doi:10.1067/mcp.2002.126501. PMID 12189364. S2CID 32072662.
- Grèen K, Drvota V, Vesterqvist O (March 1989). "Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol)". Prostaglandins. 37 (3): 311–5. doi:10.1016/0090-6980(89)90001-4. PMID 2664901.
- Henry D, Lim LL, Garcia Rodriguez LA, Perez Gutthann S, Carson JL, Griffin M, Savage R, Logan R, Moride Y, Hawkey C, Hill S, Fries JT (June 1996). "Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis". BMJ. 312 (7046): 1563–6. doi:10.1136/bmj.312.7046.1563. PMC 2351326. PMID 8664664.
- Khan KN, Paulson SK, Verburg KM, Lefkowith JB, Maziasz TJ (April 2002). "Pharmacology of cyclooxygenase-2 inhibition in the kidney". Kidney Int. 61 (4): 1210–9. doi:10.1046/j.1523-1755.2002.00263.x. PMID 11918727.
- Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (July 1991). "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. doi:10.1016/S0021-9258(18)98774-0. PMID 1712772.
- Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996). "Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents". Nature. 384 (6610): 644–8. Bibcode:1996Natur.384..644K. doi:10.1038/384644a0. PMID 8967954. S2CID 4326310.
- Li S, Wang Y, Matsumura K, Ballou LR, Morham SG, Blatteis CM (April 1999). "The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2(-/-), but not in cyclooxygenase-1(-/-) mice". Brain Res. 825 (1–2): 86–94. doi:10.1016/S0006-8993(99)01225-1. PMID 10216176. S2CID 38071906.
- Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF (November 1996). "Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2". Nat. Struct. Biol. 3 (11): 927–33. doi:10.1038/nsb1196-927. PMID 8901870. S2CID 24829484.
- Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR (December 1993). "Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase". Proc. Natl. Acad. Sci. U.S.A. 90 (24): 11693–7. Bibcode:1993PNAS...9011693M. doi:10.1073/pnas.90.24.11693. PMC 48050. PMID 8265610.
- Mitchell JA, Warner TD (November 1999). "Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy". Br. J. Pharmacol. 128 (6): 1121–32. doi:10.1038/sj.bjp.0702897. PMC 1571744. PMID 10578123.
- O'Banion MK, Winn VD, Young DA (June 1992). "cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4888–92. Bibcode:1992PNAS...89.4888O. doi:10.1073/pnas.89.11.4888. PMC 49193. PMID 1594589.
- Patrono C (January 2001). "Aspirin: new cardiovascular uses for an old drug". Am. J. Med. 110 (1A): 62S–65S. doi:10.1016/S0002-9343(00)00645-8. PMID 11166001.
- Prescott LF (March 2000). "Paracetamol: past, present, and future". Am J Ther. 7 (2): 143–7. doi:10.1097/00045391-200007020-00011. PMID 11319582. S2CID 7754908.
- Riendeau D, Percival MD, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Falgueyret JP, Ford-Hutchinson AW, Gordon R, Greig G, Gresser M, Guay J, Kargman S, Léger S, Mancini JA, O'Neill G, Ouellet M, Rodger IW, Thérien M, Wang Z, Webb JK, Wong E, Chan CC (May 1997). "Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor". Br. J. Pharmacol. 121 (1): 105–17. doi:10.1038/sj.bjp.0701076. PMC 1564640. PMID 9146894.
- Riendeau D, Percival MD, Brideau C, Charleson S, Dubé D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G, Guay J, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D, Girard Y, Prasit P, Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson AW, Young RN, Chan CC (February 2001). "Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2". J. Pharmacol. Exp. Ther. 296 (2): 558–66. PMID 11160644.
- Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (March 2001). "Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity". Nature. 410 (6827): 471–5. Bibcode:2001Natur.410..471S. doi:10.1038/35068566. PMID 11260714. S2CID 4428033.
- Samuelsson B (September 1983). "From studies of biochemical mechanism to novel biological mediators: prostaglandin endoperoxides, thromboxanes, and leukotrienes. Nobel Lecture, 8 December 1982". Biosci. Rep. 3 (9): 791–813. doi:10.1007/BF01133779. PMID 6315101. S2CID 86802611.
- Simmons DL, Botting RM, Robertson PM, Madsen ML, Vane JR (March 1999). "Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 3275–80. Bibcode:1999PNAS...96.3275S. doi:10.1073/pnas.96.6.3275. PMC 15932. PMID 10077674.
- Svensson CI, Yaksh TL (2002). "The spinal phospholipase-cyclooxygenase-prostanoid cascade in nociceptive processing". Annu. Rev. Pharmacol. Toxicol. 42: 553–83. doi:10.1146/annurev.pharmtox.42.092401.143905. PMID 11807183.
- Tanaka A, Araki H, Hase S, Komoike Y, Takeuchi K (April 2002). "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. doi:10.1046/j.1365-2036.16.s2.22.x. PMID 11966529.
- Turini ME, DuBois RN (2002). "Cyclooxygenase-2: a therapeutic target". Annu. Rev. Med. 53: 35–57. doi:10.1146/annurev.med.53.082901.103952. PMID 11818462.
- Vane JR (December 2000). "The fight against rheumatism: from willow bark to COX-1 sparing drugs". J. Physiol. Pharmacol. 51 (4 Pt 1): 573–86. PMID 11192932.
- Vane JR (June 1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs". Nature New Biology. 231 (25): 232–5. doi:10.1038/newbio231232a0. PMID 5284360.
- Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR (June 1999). "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. Bibcode:1999PNAS...96.7563W. doi:10.1073/pnas.96.13.7563. PMC 22126. PMID 10377455.
- Wolfe MM, Lichtenstein DR, Singh G (June 1999). "Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs". N. Engl. J. Med. 340 (24): 1888–99. doi:10.1056/NEJM199906173402407. PMID 10369853.
- Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL (April 1991). "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. Bibcode:1991PNAS...88.2692X. doi:10.1073/pnas.88.7.2692. PMC 51304. PMID 1849272.