同: cyclooxygenase 2

WordNet

the 3rd letter of the Roman alphabet (同)c
(music) the keynote of the scale of C major
a general-purpose programing language closely associated with the UNIX operating system
act as the coxswain, in a boat race

PrepTutorEJDIC

carbonの化学記号
=coxswain
Colorado

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/02/13 06:27:01」(JST)

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History[edit]

COX-2 was discovered in 1991 by the Daniel Simmons laboratory^[2] at Brigham Young University.

Structure[edit]

COX-2 exists as a homodimer, each monomer with a molecular mass of about 70 kDa. The tertiary and quaternary structures of COX-1 and COX-2 enzymes are almost identical. Each subunit has three different structural domains: a short N-terminal epidermal growth factor (EGF) domain; an α-helical membrane-binding moiety; and a C-terminal catalytic domain. COX enzymes are monotopic membrane proteins; the membrane-binding domain consists of a series of amphipathic α helices with several hydrophobic amino acids exposed to a membrane monolayer. COX-1 and COX-2 are bifunctional enzymes that carry out two consecutive chemical reactions in spatially distinct but mechanistically coupled active sites. Both the cyclooxygenase and the peroxidase active sites are located in the catalytic domain, which accounts for approximately 80% of the protein. The catalytic domain is homologous to mammalian peroxidases such as myeloperoxidase.^[3]^[4]

Figure 1. As shown, different ligands bind either the allosteric or the catalytic subunit. Allosteric subunit binds a non-substrate, activating FA (e.g., palmitic acid). The allosteric subunit with bound fatty acid activates the catalytic subunit by decreasing the Km for AA.^[5]

It has been found that human COX-2 functions as a conformational heterodimer having a catalytic monomer (E-cat) and an allosteric monomer (E-allo). Heme binds only to the peroxidase site of E-cat while substrates, as well as certain inhibitors (e.g. celecoxib), bind the COX site of E-cat. E-cat is regulated by E-allo in a way dependent on what ligand is bound to E-allo. Substrate and non-substrate fatty acid (FAs) and some COX inhibitors (e.g. naproxen) preferentially bind to the COX site of E-allo. Arachidonic acid can bind to E-cat and E-allo, but the affinity of AA for E-allo is 25 times that for Ecat. Palmitic acid, an efficacious stimulator of huPGHS-2, binds only E-allo in palmitic acid/murine PGHS-2 co-crystals. Non-substrate FAs can potentiate or attenuate COX inhibitors depending on the fatty acid and whether the inhibitor binds E-cat or E-allo. Studies suggest that the concentration and composition of the free fatty acid pool in the environment in which PGHS-2 functions in cells, also referred to as the FA tone, is a key factor regulating the activity of PGHS-2 and its response to COX inhibitors.(Figure 1)^[5]

Function[edit]

Figure 2. COX enzymes produce PGH2 from AA in two consecutive chemical reactions. PGH2 is converted to other prostanoids (at the bottom) by tissue-specific enzymes called isomerases. In the first step of the reaction, two moles of oxygen are added to arachidonic acid to yield PGG2. This is referred to as the COX reaction. The latter is followed by the peroxidase reaction, which reduces PGG2 to give PGH2. The COX reaction and the peroxidase reaction occur at two different locations in COX enzymes. In addition to prostaglandins, COX enzymes also produce small amounts of mono-oxygenated metabolites of AA called HETEs.

Prostaglandin endoperoxide H synthase, COX 2, converts arachidonic acid (AA) to prostaglandin endoperoxide H2. PGHSs are targets for NSAIDs and COX-2 specific inhibitors called coxibs. PGHS-2 is a sequence homodimer. Each monomer of the enzyme has a peroxidase and a COX active site. The COX enzymes catalyze the conversion of arachidonic acid to prostaglandins in a two steps. First, hydrogen is abstracted from carbon 13 of arachidonic acid, and then two molecules of oxygen are added by the COX-2, giving PGG2. Second, PGG2 is reduced to PGH2 in the peroxidase active site. The synthesized PGH2 is converted to prostaglandins (PGD2, PGE2, PGF_2α), prostacyclin (PGI2), or thromboxane A2 by tissue-specific isomerases.(Figure 2)^[6]

Both the peroxidase and the cyclooxygenase activities are inactivated during catalysis by mechanism-based, first-order processes, which means that PGHS-2 peroxidase or cyclooxygenase activities fall to zero within 1–2 minutes, even in the presence of sufficient substrates.^[7]^[8]^[9]

Arachidonic acid bound to the COX-2 enzyme. polar interactions between Archidonic Acid (cyan) and Ser-530 and Tyr-385 residues are shown with yellow dashed lines. The substrate is stabilized by hydrophobic interactions.^[10]

Mechanism[edit]

The conversion of arachidonic acid to PGG2 can be shown as a series of radical reactions analogous to polyunsaturated fatty acid autoxidation (Figure 3).^[11] The 13-pro(S) -hydrogen is abstracted and dioxygen traps the pentadienyl radical at carbon 11. The 11-peroxyl radical cyclizes at carbon 9 and the carbon-centered radical generated at C-8 cyclizes at carbon 12, generating the endoperoxide. The allylic radical generated is trapped by dioxygen at carbon 15 to form the 15-(S) -peroxyl radical; this radical is then reduced to PGG2 . This is supported by the following evidence: 1) a significant kinetic isotope effect is observed for the abstraction of the 13-pro (S )-hydrogen; 2) carbon-centered radicals are trapped during catalysis;^[12] 3) small amounts of oxidation products are formed due to the oxygen trapping of an allylic radical intermediate at positions 13 and 15.^[13]^[14]

Another mechanism shown in Figure 4 in which the 13-pro (S )-hydrogen is deprotonated and the carbanion is oxidized to a radical is theoretically possible. However, oxygenation of 10,10-difluoroarachidonic acid to 11-(S )-hydroxyeicosa-5,8,12,14-tetraenoic acid is not consistent with the generation of a carbanion intermediate because it would eliminate fluoride to form a conjugated diene.^[15] The absence of endoperoxide-containing products derived from 10,10-difluoroarachidonic acid has been thought to indicate the importance of a C-10 carbocation in PGG2 synthesis.^[16] However, the cationic mechanism requires that endoperoxide formation comes before the removal of the 13-pro (S )-hydrogen. This is not consistent with the results of the isotope experiments of arachidonic acid oxygenation.^[17]

Figure 3. Mechanism of COX activation and catalysis. A hydroperoxide oxidizes the heme to a ferryl-oxo derivative that either is reduced in the first step of the peroxidase cycle or oxidizes Tyrosine 385 to a tyrosyl radical. The tyrosyl radical can then oxidize the 13-pro(S) hydrogen of arachidonic acid to initiate the COX cycle.

Clinical significance[edit]

Cyclooxygenase-2 (COX-2, prostaglandin H synthase-2, PGHS-2) is unexpressed under normal conditions in most cells, but elevated levels are found during inflammation. COX-1 (prostaglandin H2 synthase 1) is constitutively expressed in many tissues and is the predominant form in gastric mucosa and in the kidneys. Inhibition of COX-1 reduces the basal production of cytoprotective PGE2 and PGI2 in the stomach, which may contribute to gastric ulceration. Since COX-2 is generally expressed only in cells where prostaglandins are upregulated (e.g., during inflammation), drug-candidates that selectively inhibit COX-2 were suspected to show fewer side-effects ^[4] but proved to substantially increase risk for cardiovascular events such as heart attack and stroke.The penn Group found that this was due to the for several reasons for instance low-dose aspirin protects against heart attacks and strokes by blocking COX-1 from forming a prostaglandin called thromboxane A2 which sticks platelets together and promotes clotting therefore inhibiting this helps prevent heart disease. On the other hand, COX-2 is a more important source of prostaglandins, particularly ones called prostacyclin, which is found in blood vessel lining and this relaxes or unsticks platelets so in drugs like Celebrex(celecoxib) and other coxibs (Rofecoxib) because they selectively block this mechanism you get an increase risk in cardiovascular events.More than 10 years later, it is now clear what the COX inhibitors do in the body. Eight placebo-controlled, randomized trials, performed to find new uses of these drugs, showed that they posed a cardiovascular hazard, similar in magnitude to that resulting from being a smoker or a diabetic, notes FitzGerald. "Despite this, controversy has continued about how all this came about, until now."

Arguments against the proposed mechanism were threefold. First, it was proposed that COX-2 didn't exist under normal circumstances in the blood-vessel lining and that PGI-M (prostacyclin in humans, as reflected by its major metabolite in urine), came from some other source. The kidneys were suggested as the source by some researchers. Second, even if blood-vessel prostacyclin was blocked, other protective mechanisms, especially formation of nitric oxide (NO) would take over. And third, although NSAIDs elevate blood pressure, it was proposed that this observation was unrelated to COX-2 and treating high blood pressure would deal with the problem.

FitzGerald's group has now "closed the loop" with its earlier clinical studies and answered these questions in a paper just published in Science Translational Medicine. In it, they confirm that COX-2 is expressed in cells lining blood vessels and that selectively removing it predisposes mice to blood clotting and high blood pressure. These mice, just like humans taking COX-2 inhibitors, also see a fall in PGI-M. What's more, the Penn group discovered that COX-2 in lining cells controls the expression of eNOS, the enzyme that makes NO in the body. "So, rather than replacing the missing prostacyclin, as others have proposed, NO is lost and amplifies the effects of COX-2 inhibition on the cardiovascular system," says FitzGerald.

Indeed, the lost NO may not be the only step that magnifies the effects of losing prostacyclin. In a second paper, published in April 2012, in the Proceedings of the National Academy of Sciences, FitzGerald's group shows that arachidonic acid, the fat broken down by COX-2 to make prostacyclin, can be shunted down another pathway to make a new series of dangerous fats called leukotrienes when COX-2 is disrupted.

Clinical studies have shown that those most at risk from COX-2 inhibitors are patients who already have heart disease. However, the Penn group now suggests broader implications. Here, the group resolves one aspect of the controversy, showing that COX-2 disruption causes hardening of the arteries in mice. This result is provocative because randomized trials of Vioxx and Celebrex in patients at low risk of heart disease detected an increase in heart attacks after patients had been taking the drugs for more than a year. These current Penn studies raise the disturbing prospect that heart-healthy patients taking NSAIDs for prolonged periods might be gradually increasing their risk of heart attacks and strokes by progressively hardening their arteries.

"However, it's not all bad news," says FitzGerald. This risk of hardening of the arteries was diminished in mice by reducing leukotriene formation, via blocking a critical protein called the 5-lipoxygenase activating protein, or FLAP. Inhibitors of FLAP are already in trials in humans to see if they work in asthma. Perhaps, FitzGerald concludes, they can now find an additional use—protecting the heart from NSAIDs.^[18] ^[19] Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin production by cyclooxygenases (COX) 1 and 2. NSAIDs selective for inhibition of COX-2 are less likely than traditional drugs to cause gastrointestinal adverse effects, but could cause cardiovascular events, such as heart failure, myocardial infarction, and stroke. Studies with human pharmacology and genetics, genetically manipulated rodents, and other animal models and randomized trials indicate that this is due to suppression of COX-2-dependent cardioprotective prostaglandins, prostacyclin in particular.^[20]

NSAID (non-specific inhibitor of COX-2) Flurbiprofen (green) bound to COX-2. Flurbiprofen is stabilized via hydrophobic interactions and polar interactions (Tyr-355 and Arg-120).^[21]

The expression of COX-2 is upregulated in many cancers. The overexpression of COX-2 along with increased angiogenesis and GLUT-1 expression is significantly associated with gallbladder carcinomas.^[22] Furthermore the product of COX-2, PGH₂ is converted by prostaglandin E2 synthase into PGE₂, which in turn can stimulate cancer progression. Consequently inhibiting COX-2 may have benefit in the prevention and treatment of these types of cancer.^[23]^[24]

The mutant allele PTGS2 5939C carriers among the Han Chinese population have been shown to have a higher risk of gastric cancer. In addition, a connection was found between Helicobacter pylori infection and the presence of the 5939C allele.^[25]

Interactions[edit]

PTGS2 has been shown to interact with Caveolin 1.^[26]

References[edit]

^ Hla T, Neilson K (August 1992). "Human cyclooxygenase-2 cDNA". Proc. Natl. Acad. Sci. U.S.A. 89 (16): 7384–8. doi:10.1073/pnas.89.16.7384. PMC 49714. PMID 1380156.
^ 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. doi:10.1073/pnas.88.7.2692. PMC 51304. PMID 1849272. ^{[better source needed]}
^ Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489.
^ ^a ^b Kurumbail RG, Kiefer JR, Marnett LJ (December 2001). "Cyclooxygenase enzymes: catalysis and inhibition". Curr. Opin. Struct. Biol. 11 (6): 752–60. doi:10.1016/S0959-440X(01)00277-9. PMID 11751058.
^ ^a ^b Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL (May 2011). "Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer". J. Biol. Chem. 286 (21): 19035–46. doi:10.1074/jbc.M111.231969. PMC 3099718. PMID 21467029.
^ O'Banion MK (1999). "Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology". Crit Rev Neurobiol 13 (1): 45–82. PMID 10223523.
^ Smith WL, Garavito RM, DeWitt DL (December 1996). "Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2". J. Biol. Chem. 271 (52): 33157–60. doi:10.1074/jbc.271.52.33157. PMID 8969167.
^ Wu G, Wei C, Kulmacz RJ, Osawa Y, Tsai AL (April 1999). "A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1". J. Biol. Chem. 274 (14): 9231–7. doi:10.1074/jbc.274.14.9231. PMID 10092596.
^ Callan OH, So OY, Swinney DC (February 1996). "The kinetic factors that determine the affinity and selectivity for slow binding inhibition of human prostaglandin H synthase 1 and 2 by indomethacin and flurbiprofen". J. Biol. Chem. 271 (7): 3548–54. doi:10.1074/jbc.271.7.3548. PMID 8631960.
^ PDB 3OLT
^ Porter NA (1986). "Mechanisms for the autoxidation of polyunsaturated lipids". Accounts of Chemical Research 19 (9): 262–8. doi:10.1021/ar00129a001.
^ Mason RP, Kalyanaraman B, Tainer BE, Eling TE (June 1980). "A carbon-centered free radical intermediate in the prostaglandin synthetase oxidation of arachidonic acid. Spin trapping and oxygen uptake studies". J. Biol. Chem. 255 (11): 5019–22. PMID 6246094.
^ Hecker M, Ullrich V, Fischer C, Meese CO (November 1987). "Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase". Eur. J. Biochem. 169 (1): 113–23. doi:10.1111/j.1432-1033.1987.tb13587.x. PMID 3119336.
^ Xiao G, Tsai AL, Palmer G, Boyar WC, Marshall PJ, Kulmacz RJ (February 1997). "Analysis of hydroperoxide-induced tyrosyl radicals and lipoxygenase activity in aspirin-treated human prostaglandin H synthase-2". Biochemistry 36 (7): 1836–45. doi:10.1021/bi962476u. PMID 9048568.
^ Kwok PY, Muellner FW, Fried J (June 1987). "Enzymatic conversions of 10,10-difluoroarachidonic acid with PGH synthase and soybean lipoxygenase". Journal of the American Chemical Society 109 (12): 3692–3698. doi:10.1021/ja00246a028.
^ Dean AM, Dean FM (May 1999). "Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH synthase? A radical departure!". Protein Sci. 8 (5): 1087–98. doi:10.1110/ps.8.5.1087. PMC 2144324. PMID 10338019.
^ Hamberg M, Samuelsson B (November 1967). "On the mechanism of the biosynthesis of prostaglandins E-1 and F-1-alpha". J. Biol. Chem. 242 (22): 5336–43. PMID 6070851.
^ Wolfe MM (December 2004). "Rofecoxib, Merck, and the FDA". N. Engl. J. Med. 351 (27): 2875–8; author reply 2875–8. doi:10.1056/NEJM200412303512719. PMID 15625749.
^ http://www.uphs.upenn.edu/news/News_Releases/2012/05/risk/
^ Wang D, Patel VV, Ricciotti E, Zhou R, Levin MD, Gao E, Yu Z, Ferrari VA, Lu MM, Xu J, Zhang H, Hui Y, Cheng Y, Petrenko N, Yu Y, FitzGerald GA (May 2009). "Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function". Proc. Natl. Acad. Sci. U.S.A. 106 (18): 7548–52. doi:10.1073/pnas.0805806106. PMC 2670242. PMID 19376970.
^ PDB 3PGH
^ Legan M (August 2010). "Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas". Bosn J Basic Med Sci 10 (3): 192–6. PMID 20846124.
^ EntrezGene 5743
^ Menter DG, Schilsky RL, DuBois RN (March 2010). "Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward". Clin. Cancer Res. 16 (5): 1384–90. doi:10.1158/1078-0432.CCR-09-0788. PMID 20179228.
^ Li Y, He W, Liu T, Zhang Q (December 2010). "A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma". Mol Diagn Ther 14 (6): 351–5. doi:10.2165/11586400-000000000-00000. PMID 21275453.
^ Liou JY, Deng WG, Gilroy DW, Shyue SK, Wu KK (September 2001). "Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts". J. Biol. Chem. 276 (37): 34975–82. doi:10.1074/jbc.M105946200. PMID 11432874.

External links[edit]

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UpToDate Contents

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1. COX-2選択的阻害剤の概要 overview of selective cox 2 inhibitors
2. COX-2選択的阻害剤：有害な心血管系への影響 cox 2 selective inhibitors adverse cardiovascular effects
3. COX-2阻害剤および胃十二指腸障害-大規模臨床試験から cox 2 inhibitors and gastroduodenal toxicity major clinical trials
4. 非ステロイド性抗炎症剤（NSAIDs）：作用機序 nsaids mechanism of action
5. Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus

English Journal

The aromatic volatile organic compounds toluene, benzene and styrene induce COX-2 and prostaglandins in human lung epithelial cells via oxidative stress and p38 MAPK activation.

Mogel I, Baumann S, Bohme A, Kohajda T, von Bergen M, Simon JC, Lehmann I.SourceUFZ - Helmholtz Centre for Environmental Research, Department of Environmental Immunology, Leipzig, Germany.
Toxicology.Toxicology.2011 Oct 28;289(1):28-37. Epub 2011 Jul 27.
Toluene, benzene and styrene are volatile organic compounds (VOCs) widely distributed in the environment. Tobacco smoke, traffic exposure and solvents used for paints, rubber and adhesives are known sources for these compounds. The aim of the present study was to investigate whether toluene, benzene
PMID 21801798

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease.

Rosillo MA, Sanchez-Hidalgo M, Cardeno A, Alarcon de la Lastra C.SourceDepartment of Pharmacology, Faculty of Pharmacy, University of Seville, Profesor Garcia Gonzalez Street 2, 41012 Seville, Spain.
Biochemical pharmacology.Biochem Pharmacol.2011 Oct 1;82(7):737-45. Epub 2011 Jul 7.
Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, pre
PMID 21763290

Japanese Journal

Prediction of outcome of patients with oral squamous cell carcinoma using vascular invasion and the strongly positive expression of vascular endothelial growth factors.

Seki Sachiko,Fujiwara Mutsunori,Matsuura Masaaki,Fujita Shuichi,Ikeda Hisazumi,Asahina Izumi,Ikeda Tohru
Oral Oncology 47(7), 588-593, 2011-07
… Ninety specimens of patients from 1991 to 2002 with previously untreated OSCC, who underwent either biopsy or surgery, were histopathologically and immunohistochemically analyzed using antibodies for vascular endothelial growth factor (VEGF)-A, VEGF-C, cyclooxygenase (COX)-2 and Midkine. … Neither COX-2 nor Midkine contributed to predict the prognosis of the patients. …
NAID 120003238494

Activation of epidermal growth factor receptor signaling by the prostaglandin E2 receptor EP4 pathway during gastric tumorigenesis

Oshima Hiroko,Popivanova Boryana K.,Oguma Keisuke,Kong Dan,Ishikawa Tomoo,Oshima Masanobu
Cancer Science 102(4), 713-719, 2011-04
… Cyclooxygenase-2 (COX-2) plays an important role in tumorigenesis through prostaglandin E2 (PGE2) biosynthesis. … It has been shown by in vitro studies that PGE2 signaling transactivates epidermal growth factor receptor (EGFR) through an intracellular mechanism. … However, the mechanisms underlying PGE2-induced EGFR activation in in vivo tumors are still not fully understood. …
NAID 120002986036

Related Pictures

★リンクテーブル★

リンク元	「糖質コルチコイド」「シクロオキシゲナーゼ2」
拡張検索	「COX-2 inhibitor」
関連記事	「C」「CO」「COX」

「糖質コルチコイド」

Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
	; PDB rendering based on 6COX
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1V0X
Identifiers
Symbols	PTGS2; COX-2; COX2; GRIPGHS; PGG/HS; PGHS-2; PHS-2; hCox-2
External IDs	OMIM: 600262 MGI: 97798 HomoloGene: 31000 ChEMBL: 230 GeneCards: PTGS2 Gene
EC number	1.14.99.1
Gene Ontology
Molecular function	• peroxidase activity; • prostaglandin-endoperoxide synthase activity; • lipid binding; • enzyme binding; • heme binding; • protein homodimerization activity; • metal ion binding; • arachidonate 15-lipoxygenase activity;
Cellular component	• nucleus; • cytoplasm; • endoplasmic reticulum membrane; • neuron projection; • protein complex;
Biological process	• prostaglandin biosynthetic process; • angiogenesis; • prostaglandin metabolic process; • cellular component movement; • inflammatory response; • response to oxidative stress; • embryo implantation; • learning; • memory; • regulation of blood pressure; • negative regulation of cell proliferation; • response to fructose stimulus; • response to manganese ion; • response to lithium ion; • positive regulation vascular endothelial growth factor production; • sensory perception of pain; • arachidonic acid metabolic process; • cyclooxygenase pathway; • lipoxygenase pathway; • bone mineralization; • ovulation; • positive regulation of prostaglandin biosynthetic process; • positive regulation of fever generation; • positive regulation of synaptic plasticity; • negative regulation of synaptic transmission, dopaminergic; • response to estradiol stimulus; • response to lipopolysaccharide; • response to vitamin D; • response to tumor necrosis factor; • cellular response to UV; • maintenance of blood-brain barrier; • positive regulation of NF-kappaB import into nucleus; • response to drug; • anagen; • positive regulation of apoptotic process; • small molecule metabolic process; • positive regulation of nitric oxide biosynthetic process; • negative regulation of cell cycle; • positive regulation of vasoconstriction; • negative regulation of smooth muscle contraction; • positive regulation of smooth muscle contraction; • decidualization; • positive regulation of smooth muscle cell proliferation; • regulation of inflammatory response; • brown fat cell differentiation; • response to glucocorticoid stimulus; • negative regulation of calcium ion transport; • positive regulation of synaptic transmission, glutamatergic; • response to fatty acid; • cellular response to mechanical stimulus; • cellular response to ATP; • cellular response to hypoxia; • positive regulation of transforming growth factor beta production; • positive regulation of cell migration involved in sprouting angiogenesis; • positive regulation of fibroblast growth factor production; • positive regulation of brown fat cell differentiation; • positive regulation of platelet-derived growth factor production;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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　　[★]

英: glucocorticoid (Z), glucocorticoids
関: グルココルチコイド
関: 副腎皮質、副腎皮質ホルモン

以下、内的に合成される糖質コルチコイドについて述べる

種類

ステロイドホルモン

分類

副腎皮質ホルモン

性状

ステロイド

産生組織

副腎皮質索状層

標的組織

生理作用

1. エネルギー代謝

糖新生においてグルコースの前駆体となるアミノ酸を肝臓に供給すべく動員する作用 (SP.894)

a. 糖代謝作用

糖新生の亢進

血糖上昇

肝細胞以外のグルコースの取り込みを抑制 (SP.894) ←　末梢でインスリンの作用に拮抗

グルコース-6-ホスファターゼの活性亢進 (SP.894)

グリコーゲンの合成亢進

血糖値の上昇に伴い、肝臓などでグルコースからグリコーゲンが作られる (SP.894)

b. タンパク質代謝作用

肝臓での糖新生の基質を末梢から供給する作用

肝細胞以外でのアミノ酸取り込み阻害 (SP.894)

特定のアミノ酸合成を阻害 (SP.894)

生理的範囲：(肝臓)同化作用が起こる、(肝臓以外)異化作用が起こる

ステロイド大量投与時：ほとんど異化作用が起こる→副作用につながる

c. 脂質代謝作用

脂肪細胞に対して、インスリンの拮抗作用を持つが、一方で糖質コルチコイドにより血糖値が上昇する

脂肪分解↑→血糖値↑　…(1)

脂肪細胞に対してグルコースの取り込みを抑制し、中性脂肪の生合成を抑制し、さらに大量の遊離脂肪酸とグリセロールを放出させる。肝臓でグリセロールからグルコースが合成される。 (SP.894)

血糖値↑→脂肪合成↑　…(2)

血糖値の上昇によりインスリンが分泌され、脂肪細胞で脂肪の合成が促進される (SP.894)

(1)、(2)のいずれの反応が起こるかは体の部位によって異なり、脂肪分布の変化が生じる。

中心性肥満、満月様顔貌、バッファローハンプ

2. 電解質代謝作用

糖質コルチコイドの電解質コルチコイド様作用。

Na+再吸収↑、K+排泄↑

コルチゾールの電解質作用はアルドステロンの約１／４００

コルチゾールの量　　　　はアルドステロンの約　２００倍

ゆえに、電解質コルチコイドの１／２の作用力を持つ

3. 水代謝作用

GFR↑、ADHに拮抗、細胞内への水移動の抑制→水利尿作用を有する。　　尿崩症 + 副腎不全　→　多尿がいくらか改善されると考えて良いと思われる。仮面尿崩症

4. 骨・軟骨に対する作用

a. ビタミンDと拮抗して腸管からのCa吸収阻害 (SP.894)
b. 腎尿細管におけるCa再吸収阻害 (SP.894)
c. 骨芽細胞の分化・増殖を抑制 (SP.894)

糖質コルチコイドの大量投与→軟骨↓骨成長↓(活性型ビタミンD₃に拮抗・尿細管Ca再吸収↓→PTH↑、骨芽細胞の分化抑制、タンパク質の異化作用↑)→骨粗鬆症、骨壊死 or 骨端線閉鎖を促進(←？要調査)

b.の機序で尿に排泄されるカルシウムが増加　　→　　高カルシウム尿症　→　尿路結石

5. 抗炎症作用

胸腺やリンパ組織を萎縮させる　→　炎症反応や免疫反応を抑制

リンパ球数の減少、白血球の遊走抑制、抗体産生低下、ヒスタミン放出抑制(局所の毛細血管拡張抑制) (SP.894)

末梢好中球数は増加する(YN.F-78)　→　白血球増多症

SPC.330

a) 核内受容体を介してlipocortinを発現させ、これがphospholipase A2を阻害する。これにより、アラキドン酸の産生が抑制され、炎症を促進するロイコトリエンの産生も抑制される。
b) 末梢血Tリンパ球、単球、好酸球、好塩基球：骨髄からの放出減少と再分配(?)のため末梢血中では減少する。
c) 末梢血好中球：炎症部位への集合が抑制され(血管外への遊走が抑制される(GOO.1600))、末梢血中では増加する。
d) Bリンパ球はヘルパーT細胞が抑制されるために抗体産生能が減少する。
e) リンパ球などの細胞表面の立体構造を換えて抗体や補体の結合を抑制する。
f) 毛細血管(毛細管)の収縮により、血管の透過性は低下する。

6. 循環器

カテコールアミン・アンジオテンシンIIによる血管収縮作用の許容作用　→　糖質コルチコイドなしではその作用を十分に及ぼし得ない

欠乏症では血管のカテコールアミン・アンジオテンシンIIに対する感受性低下

7. 中枢神経系

認知機能や情動を修飾 (SP.895)

8. 成長発達

胎児期の消化酵素・リン脂質(肺胞表面の張力に関与)の合成に関与 (SP.895)
小児期で骨や熱強訴域に直接作用して身長の伸びを抑制する (SP.895)

作用機序

免疫抑制(GOO. 657,674,1600)

COX-2の抑制
phospholipase A₂の抑制

糖質コルチコイドはリポコルチンを産生→リポコルチンはホスホリパーゼA₂の活性を修飾→アラキドン酸産生↓

分泌調節

1. 概日リズム
2. フィードバック制御
- 糖質コルチコイドがACTHやCRHを抑制
3. ストレス反応

臨床関連

クッシング症候群(糖質コルチコイド過剰) (SP.894)

合成ステロイドホルモン

用量

低用量から中等量：40mg未満

Low-to-moderate doses — Doses of 1 mg/kg per day of prednisone in children or 40 mg per day in adults may be considered an approximate threshold at which significant toxicities begin to appear with extended use in most individuals.

副作用

副腎皮質ホルモン剤

副腎機能の低下、骨粗鬆症(無菌性大腿骨頭壊死)、高脂血症、高血圧、筋力低下、筋肉痛、白内障、緑内障
ニューモシスチス肺 PCP

Patients receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer who also have another cause of immunocompromise (eg, certain hematologic malignancies or a second immunosuppressive drug)

https://www.uptodate.com/contents/treatment-and-prevention-of-pneumocystis-pneumonia-in-hiv-uninfected-patients?

0.5mg/kg以上のプレドニゾロン(PSL)を3週間以上投与され、かつST予防投与されていない間質性肺炎74例中7例(9.5％)でPCPを発症(榎本達治，他．ステロイド療法中の間質性肺炎患者に発症したニューモシスチス肺炎の臨床的検討．日呼吸会誌 2005: 43: 725-30)

Table 59–2 Relative Potencies and Equivalent Doses of Representative Corticosteroids
COMPOUND	ANTIINFLAMMATORY POTENCY	Na+-RETAINING POTENCY	DURATION OF ACTION*	EQUIVALENT DOSE, MG
cortisol	1	1	S	20
cortisone	0.8	0.8	S	25
fludrocortisone	10	125	I	‡
prednisone	4	0.8	I	5
prednisolone	4	0.8	I	5
6α-methylprednisolone	5	0.5	I	4
triamcinolone	5	0	I	4
betamethasone	25	0	L	0.75
dexamethasone	25	0	L	0.75

「シクロオキシゲナーゼ2」

　　[★]

英: cyclooxygenase-2 cyclooxygenase 2 COX-2 COX2
関: シクロオキシゲナーゼ、シクロオキシゲナーゼ1、アスピリン、NSAID、糖質コルチコイド

炎症に伴うサイトカインと炎症メディエーターはCOX-2の産生を誘導する。(GOO.674)　←　つまり、このシクロオキシゲナーゼが炎症部位におけるプロスタグランジンの産生に関わっている。よって、COX-2を抑制することで消炎作用が得られる。
アスピリンとNSAIDはCOX enzyme and prostaglandin産生を抑制する。一方、アラキドン酸代謝において、リポキシゲナーゼの代謝経路は抑制しない。このためロイコトリエンの形成は抑制されない。(GOO.674)
糖質コルチコイドはCOX-2の発現誘導を抑制する。また、phospholipase A2の活性も抑制する(アラキドン酸の産生に関与)。

「COX-2 inhibitor」

　　[★]

シクロオキシゲナーゼ-2阻害薬、シクロオキシゲナーゼ-2阻害剤

関: coxib、cyclooxygenase-2 inhibitor

「C」

　　[★]

炭素 carbon
シトシン cytosine
システイン cysteine
シチジン
セルシウス度摂氏 degrees Celsius degree C
産婦人科領域で「子宮外頚子宮外頚部 exocervix」を表現するための略語

「CO」

　　[★]

「COX」

　　[★] シクロオキシゲナーゼ COX

[pmid1380156-1] Hla T, Neilson K (August 1992). "Human cyclooxygenase-2 cDNA". Proc. Natl. Acad. Sci. U.S.A. 89 (16): 7384–8. doi:10.1073/pnas.89.16.7384. PMC 49714. PMID 1380156.

[pmid1849272-2] 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. doi:10.1073/pnas.88.7.2692. PMC 51304. PMID 1849272. ^{[better source needed]}

[pmid8121489-3] Picot D, Loll PJ, Garavito RM (January 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489.

[pmid11751058-4] Kurumbail RG, Kiefer JR, Marnett LJ (December 2001). "Cyclooxygenase enzymes: catalysis and inhibition". Curr. Opin. Struct. Biol. 11 (6): 752–60. doi:10.1016/S0959-440X(01)00277-9. PMID 11751058.

[Dong_2011-5] Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL (May 2011). "Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer". J. Biol. Chem. 286 (21): 19035–46. doi:10.1074/jbc.M111.231969. PMC 3099718. PMID 21467029.

[pmid10223523-6] O'Banion MK (1999). "Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology". Crit Rev Neurobiol 13 (1): 45–82. PMID 10223523.

[pmid8969167-7] Smith WL, Garavito RM, DeWitt DL (December 1996). "Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2". J. Biol. Chem. 271 (52): 33157–60. doi:10.1074/jbc.271.52.33157. PMID 8969167.

[pmid10092596-8] Wu G, Wei C, Kulmacz RJ, Osawa Y, Tsai AL (April 1999). "A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1". J. Biol. Chem. 274 (14): 9231–7. doi:10.1074/jbc.274.14.9231. PMID 10092596.

[pmid8631960-9] Callan OH, So OY, Swinney DC (February 1996). "The kinetic factors that determine the affinity and selectivity for slow binding inhibition of human prostaglandin H synthase 1 and 2 by indomethacin and flurbiprofen". J. Biol. Chem. 271 (7): 3548–54. doi:10.1074/jbc.271.7.3548. PMID 8631960.

[10] PDB 3OLT

[Porter_1986-11] Porter NA (1986). "Mechanisms for the autoxidation of polyunsaturated lipids". Accounts of Chemical Research 19 (9): 262–8. doi:10.1021/ar00129a001.

[pmid6246094-12] Mason RP, Kalyanaraman B, Tainer BE, Eling TE (June 1980). "A carbon-centered free radical intermediate in the prostaglandin synthetase oxidation of arachidonic acid. Spin trapping and oxygen uptake studies". J. Biol. Chem. 255 (11): 5019–22. PMID 6246094.

[pmid3119336-13] Hecker M, Ullrich V, Fischer C, Meese CO (November 1987). "Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase". Eur. J. Biochem. 169 (1): 113–23. doi:10.1111/j.1432-1033.1987.tb13587.x. PMID 3119336.

[pmid9048568-14] Xiao G, Tsai AL, Palmer G, Boyar WC, Marshall PJ, Kulmacz RJ (February 1997). "Analysis of hydroperoxide-induced tyrosyl radicals and lipoxygenase activity in aspirin-treated human prostaglandin H synthase-2". Biochemistry 36 (7): 1836–45. doi:10.1021/bi962476u. PMID 9048568.

[Kwok_1987-15] Kwok PY, Muellner FW, Fried J (June 1987). "Enzymatic conversions of 10,10-difluoroarachidonic acid with PGH synthase and soybean lipoxygenase". Journal of the American Chemical Society 109 (12): 3692–3698. doi:10.1021/ja00246a028.

[pmid10338019-16] Dean AM, Dean FM (May 1999). "Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH synthase? A radical departure!". Protein Sci. 8 (5): 1087–98. doi:10.1110/ps.8.5.1087. PMC 2144324. PMID 10338019.

[pmid6070851-17] Hamberg M, Samuelsson B (November 1967). "On the mechanism of the biosynthesis of prostaglandins E-1 and F-1-alpha". J. Biol. Chem. 242 (22): 5336–43. PMID 6070851.

[pmid15625749-18] Wolfe MM (December 2004). "Rofecoxib, Merck, and the FDA". N. Engl. J. Med. 351 (27): 2875–8; author reply 2875–8. doi:10.1056/NEJM200412303512719. PMID 15625749.

[19] ttp://www.uphs.upenn.edu/news/News_Releases/2012/05/risk/

[card-20] Wang D, Patel VV, Ricciotti E, Zhou R, Levin MD, Gao E, Yu Z, Ferrari VA, Lu MM, Xu J, Zhang H, Hui Y, Cheng Y, Petrenko N, Yu Y, FitzGerald GA (May 2009). "Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function". Proc. Natl. Acad. Sci. U.S.A. 106 (18): 7548–52. doi:10.1073/pnas.0805806106. PMC 2670242. PMID 19376970.

[21] PDB 3PGH

[pmid20846124-22] Legan M (August 2010). "Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas". Bosn J Basic Med Sci 10 (3): 192–6. PMID 20846124.

[entrez-23] EntrezGene 5743

[pmid20179228-24] Menter DG, Schilsky RL, DuBois RN (March 2010). "Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward". Clin. Cancer Res. 16 (5): 1384–90. doi:10.1158/1078-0432.CCR-09-0788. PMID 20179228.

[pmid21275453-25] Li Y, He W, Liu T, Zhang Q (December 2010). "A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma". Mol Diagn Ther 14 (6): 351–5. doi:10.2165/11586400-000000000-00000. PMID 21275453.

[pmid11432874-26] Liou JY, Deng WG, Gilroy DW, Shyue SK, Wu KK (September 2001). "Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts". J. Biol. Chem. 276 (37): 34975–82. doi:10.1074/jbc.M105946200. PMID 11432874.

匿名

検索

案内

COX-2