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AUTHOR AND EDITOR INFORMATION

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Author: George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine

George T Griffing is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Coauthor(s): Anu Bhalla Davis, MD, Assistant Professor, Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Texas Health Science Center at Houston; John R Witherow, MD, Staff Physician, Department of Diagnostic Radiology, Yale University School of Medicine

Editors: Dimitris A Papanicolaou, MD, Assistant Professor, Department of Medicine/Endocrinology, Emory University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC; George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine

Author and Editor Disclosure

Synonyms and related keywords: cyclooxygenase deficiency, COX deficiency, prostaglandin-endoperoxide synthase deficiency, PTGS deficiency, fatty acid cyclooxygenase deficiency, prostaglandin H synthase deficiency, PGH synthase deficiency, EC 1.14.99.1 deficiency, eicosanoid, seminal fluid, COX inhibition, COX-1, PTGS-1,COX-2, PTGS-2, thromboxane A2, TXA2

COX DEFICIENCY

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Cyclooxygenase (COX), also known as prostaglandin-endoperoxide synthase (PTGS), fatty acid COX, PGH synthase, and EC 1.14.99.1, is a key regulatory enzyme in the synthetic pathway of eicosanoid production.1 Eicosanoids are responsible for multiple inflammatory, mitogenic, and angiogenic activities in various tissue and organ systems. Therefore, COX is implicated in the production of fever, inflammation, and pain.

Regardless of the etiology, a deficiency of COX results in beneficial and detrimental physiological conditions relative to imbalances of the eicosanoids. Thus, tracing research of the COX pathway is essential to an understanding of COX deficiency, and examining the variable effects of COX inhibition are advantageous.

In 1930, American gynecologists Kurzok and Lieb first described the stimulatory effects of seminal fluid on human uterine muscle tissue. A few years later, von Euler of Sweden independently discovered similar effects of human seminal fluid on smooth muscle tissue. He localized the biologic activity to a fraction of lipid soluble acids that he termed "prostaglandin," hypothesizing that these substances originate in the prostate gland. Two decades later, the prostaglandins were deduced to be a family of related compounds that contain 20-carbon polyunsaturated fatty acids with a cyclopentane ring (see Image 1).

By 1964, after recognition of this basic structure, Bergstrom and colleagues successfully synthesized series 2 prostaglandins from arachidonic acid using sheep seminal fluid. However, the physiologic significance of prostaglandin production did not unfold until 1971, when Vane, Smith, and Willis discovered that aspirin and indomethacin inhibited prostaglandin biosynthesis. Further investigations by Smith concluded that aspirin and indomethacin inhibited synthesis by specifically blocking oxygenation of arachidonic acid. Collectively, these landmark discoveries have provided initial insight into the COX pathway of arachidonate metabolism.

Advances in genomic analysis have led to a clearer understanding of the COX pathway. Initial investigations by Miyamoto, in 1976, and Simmons, in 1989, demonstrated that 2 isoforms exist: COX-1 (PTGS-1) and COX-2 (PTGS-2) respectively. The transcription of COX-1 yields a 2.7-kilobase (kb) mRNA that encodes a 576-residue, 65-kd protein. Conversely, the transcription of COX-2 yields a 4.5-kb mRNA that encodes a 70-kd protein with roughly 70-75% homology to the COX-1 protein.

By 1991, Funk and co-investigators had localized COX-1 to 9q32-q33.3 via somatic hybrid DNA analysis. Three years later, Tay and colleagues localized COX-2 to 1q25.2-q25.3 via fluorescein in situ hybridization. Furthermore, using sequence analysis of human genomic DNA, researchers concluded that the amino acids important for catalysis by COX-1 are conserved and are equally important for catalysis by COX-2.

Evidence suggests that COX-1 and COX-2 are similar in structure and function but that they exist as 2 distinct enzymatic entities. They have been defined as monotropic integral membrane proteins located primarily in the endoplasmic reticulum (COX-1) and the perinuclear envelope (COX-2). Their distinct biosynthetic activity includes an endoperoxidase synthase reaction that oxygenates and cyclizes polyunsaturated fatty acid precursors (eg, arachidonic acid) to form prostaglandin G2 (PGG2), and a peroxidase reaction that converts PGG2 to prostaglandin H2 ([PGH2] (see Image 2). In turn, PGH2 is converted to biologically active products (ie, prostaglandin E2 [PGE2]) by individual synthase and reductase reactions.

Studies have demonstrated that the eicosanoids produced by cytosolic COX-1 participate in autocrine and paracrine activities, while those produced by perinuclear COX-2 result in intracrine activity. This subcellular localization of the COX enzyme (through the use of new microscopy techniques) has helped to explain why 2 isoforms exist. Furthermore, researchers have proposed that COX-1 and COX-2 acquire arachidonic acid from different phospholipases, suggesting participation through separate pathways.

COX-1 is expressed constitutively and is isolated throughout most cell lines in almost all mammalian tissues. It is described as a housekeeping enzyme, being responsible for cell-to-cell signaling, tissue homeostasis, and cytoprotection. In view of this, researchers hypothesize that COX-1 is a rapid responder to various physiologic conditions.

Conversely, COX-2 is described as an inducible isoform influenced by a plethora of proinflammatory mediators. Without appropriate stimulation, isolation of the COX-2 protein is negligible in most tissues. However, newer literature reveals that COX-2 is expressed constitutively in some cell lines of the brain, kidney, and trachea. Although vaguely described, COX-2 is considered to be a principle mediator of inflammation, mitogenesis, and angiogenesis.

COX deficiency typically denotes an acquired cause-and-effect relationship between the protein's enzymatic activity and nonsteroidal anti-inflammatory drugs (NSAIDs). However, Nyman and co-investigators, while studying bleeder families on the Aland Islands, reported an autosomal dominant pattern of inheritance for COX deficiency.2, 3

In addition, Horellou and colleagues described 3 family members of 2 successive generations with bleeding tendencies and concluded that their platelets were compatible with a COX deficiency.4 This study also described an autosomal dominant pattern of inheritance but deduced that COX was not imperative to aggregation and adenosine triphosphate (ATP) release in the face of high collagen concentrations. Sporadically documented familial and constitutional bleeding disorders have been associated with platelet COX-1 deficiency.

Two types of platelet COX-1 deficiency have been recognized. The type 1 defect is characterized by a complete absence of COX-1 protein in platelets. In the type 2 deficiency, on the other hand, a normal level of protein exists, but COX-1 enzymatic activity is impaired. The physiologic consequences of COX deficiency, however, are best described as acquired, rather than inherited, disorders.

The effect of COX-1 deficiency varies from tissue to tissue and largely is determined by the fate of the end products. Several studies have concluded that direct inhibition of COX-1 coincides with a loss of cytoprotection. In turn, COX-1 deficiency has been deemed as a significant participant in gastric and renal pathology.5

However, Langenbach and colleagues reported that mice deficient in COX-1 live uneventful lives despite a 99% reduction in overall prostaglandin production.6 He also emphasized that a lack of gastric and renal pathology existed in spite of observed prostaglandin deficiency. Confirming earlier literature, Langenbach reported that female mice deficient in COX-1 had difficulties with parturition, while male mice deficient in COX-1 were unimpaired. Langenbach also has demonstrated that, contrary to popular belief, COX-1 deficiency correlates with reduced edema in the face of inflammatory mediators that increase arachidonate, illuminating its significance in the inflammatory cascade.

Without significant controversy, the consensus has been that the inhibition of COX-2 is responsible, in part, for the antipyretic, analgesic, and anti-inflammatory properties of NSAIDs. However, novel investigations using genetically altered COX knockout mice have uncovered new ramifications associated with COX-2. First, Lim and colleagues observed that COX-2–deficient female mice incurred reproductive failures via abnormalities of ovulation, fertilization, implantation, and decidualization, although follicular development was normal.7

Independently, Dinchuck and co-authors described reduced neonatal viability in mice deficient in COX-2, as a consequence of renal dysplasia, cardiac fibrosis, infertility, and endotoxin-induced, hepatocellular cytotoxicity.8 He concluded that COX-2 deficiency does not affect viability in utero and that heterozygous and wild type mice do not have disease. Cheng and colleagues subsequently cited the importance of COX-2 as a "mediator of increased renin production in response to inhibition of angiotensin II production."9 As a result, they proposed that a component of the renin-angiotensin feedback system may be modulated by COX-2 expression.

Through the evolving study of COX, new theories have been integrated into previously well-described pathways. Nevertheless, the influence that COX has on each cell, tissue, organ, and system results from precursor, product, and receptor variability. Inevitably, additional ramifications of COX deficiency will unfold as knockout mice are investigated further.

Related Medscape topic:
Resource Center Pharmacologic Management of Pain


PRECURSORS

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The eicosanoids, which include prostaglandins, leukotrienes, thromboxanes, and lipoxins, are derived from the oxygenation of 20-carbon polyunsaturated essential fatty acids via the COX and lipoxygenase pathways.1, 10 However, only a fraction of these 20-carbon polyenoic acid precursors are the substrates that actually yield eicosanoids. The most significant of the precursors include the following:

  • 8,11,14-eicosatetraenoic acid (dihomo-g-linolenic acid)
  • 5,8,11,14-eicosatetraenoic acid (arachidonic acid)
  • 5,8,1,14,17-eicosapentaenoic acid

Omega-6 fatty acids, the essential substrates of dihomo-g-linolenic acid and arachidonic acid, are derivatives of linoleic acid. Omega-3 fatty acids, the essential substrates of eicosapentaenoic acid, are derivatives of a-linolenic acid. As a result, linoleic and linolenic fatty acid pathways of desaturation and elongation provide the essential precursors for COX and lipoxygenase that ultimately result in the production of eicosanoids.10


PRODUCTS

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As previously noted, COX metabolizes arachidonic acid (5,8,11,14-eicosatetraenoic acid) into PGH2 intermediates. Subsequently, PGH2 is converted into biologically active products via cell-specific enzymatic reactions. The products include not only classic prostaglandins (ie, prostaglandin D2 [PGD2], PGE2, prostaglandin F2-alpha [PGF2-alpha]) but also prostacyclin (PGI2) and thromboxane A2 (TXA2).

Besides these bienoic products, COX metabolizes analogous fatty acids into monoenoic and trienoic prostaglandins and thromboxanes as a consequence of the number of precursor double bonds. Collectively, their diverse properties are implicated in several physiologic processes as receptor-dependent mediators and as intracellular secondary messengers. However, the potencies of different monoenoic, bienoic, and trienoic prostaglandins and thromboxanes vary with respect to each family. Studies emphasize that the products are particularly influential in local biologic environments because of their rapid conversion to inactive metabolites. Hence, precursor availability and enzyme kinetics play a key role in the regulation of individual responses.

TXA2, the predominate product of COX in platelets and macrophages, is converted from PGH2 by thromboxane synthase. The structural characteristics include a 6-membered ring containing an ether (see Image 3). The functional characteristics include platelet aggregation, vascular smooth muscle constriction, and bronchial smooth muscle constriction with a corresponding 30-second tissue half-life. Furthermore, TXA2 has a different affinity for each eicosanoid-specific receptor because of distinct receptor ligands. As a result, the physiologic responses via TXA2 are tailored to the situation and are less haphazard when stimulated.

PGI2, the predominate product of COX in microvascular endothelium, is converted from PGH2 by PGI2 synthase. The structural characteristics include not only a 5-member ring similar to all prostaglandins but also an enzyme-specific arrangement of respective hydroxyl and carbonyl groups (see Image 4). The functional characteristics include inhibition of platelet aggregation, inhibition of platelet and neutrophil adhesion, dilation of bronchial and vascular smooth muscle, and modulation of cholesterol efflux from arterial walls with a corresponding 3-minute tissue half-life. Furthermore, the biosynthesis of PGI2 is enhanced in the face of thrombogenesis and vasoconstriction to balance the physiologic milieu, not unlike several well-known stimulation/inhibition processes.

PGD2, the predominate product of COX in mast cells, is converted from PGH2 by endoperoxide-D isomerase. Again, the structural characteristics are similar to those of all other prostaglandins. The functional characteristics include symptoms associated with histamine release (eg, hypotension) and poorly defined roles associated with immunologic processes. However, the formation of 9-alpha,11-beta-prostaglandin F (PGF) metabolites by preferential conversion of PGD2 results in the inhibition of platelet aggregation and the contraction of vascular smooth muscle tissue. This might explain the occasional hypertensive patient observed with systemic mastocytosis.

PGE2 is a significant product of COX in the gastric mucosa, renal medulla, and microvascular endothelium, as well as in some tumors.11 This biologically active product is converted from PGH2 by endoperoxide-E isomerase. Although the products are structurally related (see Image 5), each functional temperament is curiously diverse.

In the gastric mucosa, PGE2 preserves integrity by influencing mucus and bicarbonate secretion.12 It also maintains mucosal blood flow and participates in cellular repair. In the renal medulla, PGE2 enhances vasodilatation and inhibits tubular sodium absorption.5 Hence, a deficiency of PGE2, as observed in essential hypertension, results in unopposed vasoconstriction. Further attributes include stimulation of local osteoclasts, relaxation of bronchial smooth muscle tissue, contraction of uterine smooth muscle tissue, and modulation of presynaptic adrenergic neuron receptors. Despite vague interpretation, PGE2 is hypothesized to also be a key participant in local inflammatory responses.


COX EXPRESSION AND PLATELET FUNCTION

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Platelets have 3 distinct roles in coagulation: (1) initial adhesion, (2) phospholipid externalization, and (3) platelet aggregation.

Research suggests that TXA2, the final product of platelet arachidonic acid metabolism, is necessary for normal platelet function. Aggregation occurs as TXA2 diffuses from the platelet and binds to glycoprotein IIb-IIIa (GPIIb-IIIa) platelet membrane receptors to enhance alpha-granule and dense-granule secretion. The alpha granules store platelet activation markers, whereas the dense granules store calcium, serotonin, and ATP. Thus, inhibition of COX diminishes platelet secretion and inevitably disrupts normal platelet function.

Platelets also are unique in that they do not regenerate COX. This becomes apparent in the face of irreversible inhibitors, including, notoriously, aspirin.13 Therefore, COX inhibition by aspirin results in diminished TXA2 production and inevitably in the loss of platelet aggregatory properties for the life of the platelet (ie, 7-10 d).14, 15

However, studies have demonstrated that high concentrations of strong promoters (eg, thrombin, collagen) are not dependent on TXA2. In fact, it has been reported that total inhibition of platelet COX does not alter a complete platelet response, suggesting that multiple pathways of platelet activation exist. Perhaps this observation accounts for the normal hemostasis observed in persons who are taking aspirin.


COX EXPRESSION AND COLON CARCINOMA

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COX expression has been implicated in colon carcinoma since epidemiologic studies first described reduced mortality rates in subjects taking aspirin. Initially, Tsujii and DuBois studied the effects of COX-2 overexpression by transfecting rat intestinal epithelium.16 They demonstrated that overexpression increased adhesion and inhibited apoptosis, perhaps enhancing the tumorigenic potential.11

In 1996, however, Oshima and colleagues bred mice with APC mutations similar to those of humans, and COX was uncovered as a significant factor in colon carcinoma.17, 18 They reported that mice carrying an APC mutation and who were wild type for COX-2 expression developed an average of 652 polyps at 10 weeks, whereas heterozygous mice developed 224 polyps, and null mice, 93 polyps. They also found that drugs that inhibited COX-2 (but not COX-1) greatly reduced polyp formation. Further research by Langenbach and co-authors, that used multiple intestinal neoplasia mice (which led to 100% incidence of carcinoma), showed that COX-1 and COX-2 deficiency decreased polyps by 70-80%.6 Although a correlation exists between COX expression and colon carcinoma, the mechanism of action remains unknown.19

These studies may represent only 1 of many antitumorigenic pathways that, irrespective of COX dependence, are affected by NSAIDs.

Related Medscape topic:
Resource Center Colorectal Cancer


INFLUENCE OF NSAIDS

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Since Reverend Stone of England professed "the success of the bark of the willow in the cure of agues" (fever) in the mid-eighteenth century, the anti-inflammatory properties of related compounds have been exploited for medicinal purposes. Once Vane and colleagues deduced that aspirin and indomethacin inhibited the COX pathway of arachidonate metabolism, numerous investigations were performed to better understand the mechanism by which NSAIDs interacted with COX. Smith and Dewitt explained fundamental differences among the NSAIDs based on their interaction with COX active sites.20 Consequently, they described the following 3 distinct classes of inhibitors, which are currently recognized:

  • Class I NSAIDs - Defined as simple, competitive COX inhibitors, these NSAIDs include ibuprofen, piroxicam, naproxen, mefenamic acid, sulindac sulfide, and flufenamic acid. They interact rapidly and reversibly with COX active sites to form an enzyme-inhibitor (EI) complex. Smith and Dewitt determined the IC50 of several class I NSAIDs and observed that an overall higher affinity for the COX-1 isoform exists.21 However, they emphasized that the relative potency of individual class I NSAIDs may vary between in vitro and in vivo models.
  • Class II NSAIDs - These agents, which include indomethacin, flurbiprofen, meclofenamate, and diclofenac, are defined as competitive, time-dependent COX inhibitors. Their interaction with COX active sites is laggard relative to class I inhibitors. After initial formation of the EI complex, the inhibitor causes a slow but reversible conformational change in the protein to form an EI* complex. This non–covalently bound, semistable complex is less susceptible to proteases and dissociates from COX active sites at a slower rate than do EI complexes. Several studies have indicated that different class II inhibitors possess different k2 and k-2 values for COX-1 and COX-2 active sites based on in vivo selectivity. Although the biochemical mechanism of EI* complex formation is unknown, researchers attribute the kinetic properties of class II inhibitors to structural differences.
  • Class III NSAIDs - These NSAIDs, which include aspirin, salicylic acid, and valeryl salicylate, are defined as irreversible, competitive, time-dependent COX inhibitors. Although these agents are categorized together, only aspirin covalently modifies COX-1 and COX-2. This modification results after aspirin binds to the COX active site and transfers its acetyl group to a definitive serine residue. The acetylation of COX-1 specifically interferes with the endoperoxidase reaction that normally oxygenates and cyclizes arachidonic acid to form PGG2. Conversely, acetylation of COX-2 results in isoform modification that yields 15R-hydroxyeicosatetraenoic acid (15R-HETE) instead of PGG2.

 


MULTIMEDIA

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Media file 1:  Twenty-carbon polyunsaturated fatty acid with cyclopentane ring.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Image

Media file 2:  Cyclooxygenase conversion of arachidonic acid into prostaglandin H2 (PGH2).
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Image

Media file 3:  Thromboxane A2 (TXA2).
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Image

Media file 4:  Prostacyclin (PGI2).
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Image

Media file 5:  Prostaglandin E2 (PGE2).
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Image


REFERENCES

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  1. Khanapure SP, Garvey DS, Janero DR, et al. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. 2007;7(3):311-40. [Medline].
  2. Nyman D, Eriksson AW, Blombäck M, et al. Recent investigations of the first bleeder family in Aland (Finland) described by von Willebrand. Thromb Haemost. Feb 23 1981;45(1):73-6. [Medline].
  3. Nyman D, Eriksson AW, Lehmann W, et al. Inherited defective platelet aggregation with arachidonate as the main expression of a defective metabolism of arachidonic acid. Thromb Res. 1979;14(4-5):739-46. [Medline].
  4. Horellou MH, Lecompte T, Lecrubier C, et al. Familial and constitutional bleeding disorder due to platelet cyclo-oxygenase deficiency. Am J Hematol. Feb 1983;14(1):1-9. [Medline].
  5. Nasrallah R, Clark J, Hébert RL. Prostaglandins in the kidney: developments since Y2K. Clin Sci (Lond). Oct 2007;113(7):297-311. [Medline].
  6. Langenbach R, Loftin C, Lee C, et al. Cyclooxygenase knockout mice: models for elucidating isoform-specific functions. Biochem Pharmacol. Oct 15 1999;58(8):1237-46. [Medline].
  7. Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. Oct 17 1997;91(2):197-208. [Medline].
  8. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. Nov 23 1995;378(6555):406-9. [Medline].
  9. Cheng HF, Wang JL, Zhang MZ, et al. Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest. Apr 1999;103(7):953-61. [Medline]. [Full Text].
  10. Pidgeon GP, Lysaght J, Krishnamoorthy S, et al. Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Rev. Dec 2007;26(3-4):503-24. [Medline].
  11. Wang MT, Honn KV, Nie D. Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev. Dec 2007;26(3-4):525-34. [Medline].
  12. Fortun PJ, Hawkey CJ. Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol. Mar 2007;23(2):134-41. [Medline].
  13. Schafer AI. Effects of nonsteroidal anti-inflammatory therapy on platelets. Am J Med. May 31 1999;106(5B):25S-36S. [Medline].
  14. Goodman T, Sharma P, Ferro A. The genetics of aspirin resistance. Int J Clin Pract. May 2007;61(5):826-34. [Medline].
  15. Patrono C, Rocca B. Drug insight: aspirin resistance--fact or fashion?. Nat Clin Pract Cardiovasc Med. Jan 2007;4(1):42-50. [Medline].
  16. Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. Nov 3 1995;83(3):493-501. [Medline].
  17. Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. Nov 29 1996;87(5):803-9. [Medline].
  18. Oshima M, Oshima H, Tsutsumi M, et al. Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in Apc delta 716 knockout mice. Mol Carcinog. Jan 1996;15(1):11-7. [Medline].
  19. Sanborn R, Blanke CD. Cyclooxygenase-2 inhibition in colorectal cancer: boom or bust?. Semin Oncol. Feb 2005;32(1):69-75. [Medline].
  20. Smith WL, DeWitt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin Nephrol. May 1995;15(3):179-94. [Medline].
  21. Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol. 1996;62:167-215. [Medline].
  22. Arakawa T, Higuchi K, Fukuda T, et al. Prostaglandins in the stomach: an update. J Clin Gastroenterol. 1998;27 Suppl 1:S1-11. [Medline].
  23. Baylis C, Slangen B, Hussain S, et al. Relationship between basal NO release and cyclooxygenase products in the normal rat kidney. Am J Physiol. Nov 1996;271(5 Pt 2):R1327-34. [Medline].
  24. Bjordal JM, Ljunggren AE, Klovning A, et al. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. Dec 4 2004;329(7478):1317. [Medline]. [Full Text].
  25. Botting R, Ayoub SS. COX-3 and the mechanism of action of paracetamol/acetaminophen. Prostaglandins Leukot Essent Fatty Acids. Feb 2005;72(2):85-7. [Medline].
  26. Botting RM. Inhibitors of cyclooxygenases: mechanisms, selectivity and uses. J Physiol Pharmacol. Nov 2006;57 Suppl 5:113-24. [Medline]. [Full Text].
  27. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol. Apr 20 2005;23(12):2840-55. [Medline].
  28. Brune K. Safety of anti-inflammatory treatment--new ways of thinking. Rheumatology (Oxford). Feb 2004;43 Suppl 1:i16-20. [Medline]. [Full Text].
  29. Chinery R, Coffey RJ, Graves-Deal R, et al. Prostaglandin J2 and 15-deoxy-delta12,14-prostaglandin J2 induce proliferation of cyclooxygenase-depleted colorectal cancer cells. Cancer Res. Jun 1 1999;59(11):2739-46. [Medline]. [Full Text].
  30. Coceani F, Barogi S, Brizzi F, et al. Cyclooxygenase isoenzymes and patency of ductus arteriosus. Prostaglandins Leukot Essent Fatty Acids. Feb 2005;72(2):71-7. [Medline].
  31. Davidge ST, Hubel CA, McLaughlin MK. Cyclooxygenase-dependent vasoconstrictor alters vascular function in the vitamin E-deprived rat. Circ Res. Jul 1993;73(1):79-88. [Medline].
  32. Davis BJ, Lennard DE, Lee CA, et al. Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin-1beta. Endocrinology. Jun 1999;140(6):2685-95. [Medline]. [Full Text].
  33. Egan K, FitzGerald GA. Eicosanoids and the vascular endothelium. Handb Exp Pharmacol. 2006;(176 Pt 1):189-211. [Medline].
  34. FitzGerald GA. Prostaglandins and related compounds. In: Wyngaarden J, Smith L, eds. Cecil Textbook of Medicine. 19th ed. Philadelphia, Pa: WB Saunders; 1992:1206-12.
  35. Francois H, Coffman TM. Prostanoids and blood pressure: which way is up?. J Clin Invest. Sep 2004;114(6):757-9. [Medline]. [Full Text].
  36. Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol. Mar 21 2002;89(6A):18D-25D. [Medline].
  37. Fuse I, Hattori A, Nagayama R. Characterization of platelet cytoplasmic Ca2+ mobilization in patients with congenital cyclo-oxygenase deficiency and with defective platelet aggregation to A23187. Nippon Ketsueki Gakkai Zasshi. Dec 1989;52(8):1522-33. [Medline].
  38. Fürstenberger G, Krieg P, Müller-Decker K, et al. What are cyclooxygenases and lipoxygenases doing in the driver's seat of carcinogenesis?. Int J Cancer. Nov 15 2006;119(10):2247-54. [Medline].
  39. George JN, Shattil SJ. Acquired disorders of platelet function. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 2nd ed. New York, NY: Churchill Livingstone; 1995:1926-30.
  40. Gudis K, Sakamoto C. The role of cyclooxygenase in gastric mucosal protection. Dig Dis Sci. Oct 2005;50 Suppl 1:S16-23. [Medline].
  41. Harding P, Sigmon DH, Alfie ME, et al. Cyclooxygenase-2 mediates increased renal renin content induced by low-sodium diet. Hypertension. Jan 1997;29(1 Pt 2):297-302. [Medline]. [Full Text].
  42. Harris RC, McKanna JA, Akai Y, et al. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. Dec 1994;94(6):2504-10. [Medline]. [Full Text].
  43. Hawkey CJ, Langman MJ. Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors. Gut. Apr 2003;52(4):600-8. [Medline]. [Full Text].
  44. Hersh EV, Lally ET, Moore PA. Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray?. Curr Med Res Opin. Aug 2005;21(8):1217-26. [Medline].
  45. Huntjens DR, Danhof M, Della Pasqua OE. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford). Jul 2005;44(7):846-59. [Medline]. [Full Text].
  46. Insel PA. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. In: Goodman LS, Gilman A, Gilman AG, eds. Goodman and Gilman's The Pharmacologic Basis of Therapeutics. 9th ed. New York, NY: Pergamon Press; 1996:617-21.
  47. Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role. Anaesthesia. May 2000;55(5):442-9. [Medline].
  48. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther. Oct 2005;315(1):1-7. [Medline]. [Full Text].
  49. Konstantinopoulos PA, Lehmann DF. The cardiovascular toxicity of selective and nonselective cyclooxygenase inhibitors: comparisons, contrasts, and aspirin confounding. J Clin Pharmacol. Jul 2005;45(7):742-50. [Medline].
  50. Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS10 prostaglandin synthase/cyclooxygenase gene. J Biol Chem. Apr 25 1992;267(12):7991-4. [Medline]. [Full Text].
  51. Li L, Pettit AR, Gregory LS, et al. Regulation of bone biology by prostaglandin endoperoxide H synthases (PGHS): a rose by any other name... Cytokine Growth Factor Rev. Jun 2006;17(3):203-16. [Medline].
  52. Matijevic-Aleksic N, McPhedran P, Wu KK. Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency. Br J Haematol. Jan 1996;92(1):212-7. [Medline].
  53. Meydani M. Modulation of the platelet thromboxane A2 and aortic prostacyclin synthesis by dietary selenium and vitamin E. Biol Trace Elem Res. Apr-Jun 1992;33:79-86. [Medline].
  54. Murphy FJ, Reen DJ. Diminished production of prostaglandin E2 by monocytes of newborns is due to altered fatty acid membrane content and reduced cyclooxygenase activity. J Immunol. Oct 1 1996;157(7):3116-21. [Medline].
  55. O'Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett. Sep 13 1993;330(2):156-60. [Medline].
  56. Smith HS. Arachidonic acid pathways in nociception. J Support Oncol. Jun 2006;4(6):277-87. [Medline].
  57. Sohn HY, Krötz F. Cyclooxygenase inhibition and atherothrombosis. Curr Drug Targets. Oct 2006;7(10):1275-84. [Medline].
  58. Straube S, Derry S, McQuay HJ, et al. Effect of preoperative Cox-II-selective NSAIDs (coxibs) on postoperative outcomes: a systematic review of randomized studies. Acta Anaesthesiol Scand. May 2005;49(5):601-13. [Medline].
  59. Tseng CC, Wolfe MM. Nonsteroidal anti-inflammatory drugs. Med Clin North Am. Sep 2000;84(5):1329-44. [Medline].
  60. Weir MR, Sperling RS, Reicin A, et al. Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program. Am Heart J. Oct 2003;146(4):591-604. [Medline].
  61. Williams CS, DuBois RN. Prostaglandin endoperoxide synthase: why two isoforms?. Am J Physiol. Mar 1996;270(3 Pt 1):G393-400. [Medline].
  62. Wilson DE. Role of prostaglandins in gastroduodenal mucosal protection. J Clin Gastroenterol. 1991;13 Suppl 1:S65-71. [Medline].

Cyclooxygenase Deficiency excerpt

Article Last Updated: May 22, 2008