
Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Ciclesonide Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-05-31
Last Updated: 2023-10-25
Ciclesonide is a glucocorticoid used in the relief of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents. It is also used to treat obstructive airway diseases like asthma, bronchoconstriction, and chronic obstructive pulmonary disease (COPD). Ciclesonide is a pro-drug so it is enzymatically hydrolyzed to C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1), the active metabolite. Des-ciclesonide has anti-inflammatory activity with an affinity for the glucocorticoid receptor that is 120 times higher than ciclesonide. As des-ciclesonide is a glucocorticoid, its mechanism of action is that of the glucocorticoid response element (GRE) of influencing COX-2/prostaglandin G/H synthase 2 suppression and lipocortin/annexin induction. By binding to the glucocorticoid receptor, it influences transcription factors AP-1 and NF-kB to block the transcription of COX-2/prostaglandin G/H synthase 2 which reduces the amount of prostanoids being produced from arachidonic acid. Prostanoids such as PGI2 and thromboxane A2 influence the effects of inflammation through vasoconstriction/dilation, pain sensitivity, and platelet aggregation. Des-ciclesonide also affects the promoter of annexin-1, an important inflammatory protein as it affects leukocytes and blocks phospholipase A2 which reduces the amount of arachidonic acid being cleaved from the phospholipid bilayer. Reducing the amount of arachidonic acid formed further decreases the concentrations of prostanoids mentioned calming inflammation. Ciclesonide is administered as an inhaler or as a nasal spray.
References
Ciclesonide Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Mutch E, Nave R, McCracken N, Zech K, Williams FM: The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. Biochem Pharmacol. 2007 May 15;73(10):1657-64. doi: 10.1016/j.bcp.2007.01.031. Epub 2007 Jan 28.
Pubmed: 17331475
Barnes NC: The properties of inhaled corticosteroids: similarities and differences. Prim Care Respir J. 2007 Jun;16(3):149-54. doi: 10.3132/pcrj.2007.00038.
Pubmed: 17530144
Necela BM, Cidlowski JA: Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc. 2004;1(3):239-46. doi: 10.1513/pats.200402-005MS.
Pubmed: 16113441
Oeckinghaus A, Ghosh S: The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000034. doi: 10.1101/cshperspect.a000034.
Pubmed: 20066092
Liu T, Zhang L, Joo D, Sun SC: NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023-. doi: 10.1038/sigtrans.2017.23. Epub 2017 Jul 14.
Pubmed: 29158945
Yokoyama C, Tanabe T: Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem Biophys Res Commun. 1989 Dec 15;165(2):888-94. doi: 10.1016/s0006-291x(89)80049-x.
Pubmed: 2512924
Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA: Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J. 1991 Jun;5(9):2304-12.
Pubmed: 1907252
Takahashi Y, Ueda N, Yoshimoto T, Yamamoto S, Yokoyama C, Miyata A, Tanabe T, Fuse I, Hattori A, Shibata A: Immunoaffinity purification and cDNA cloning of human platelet prostaglandin endoperoxide synthase (cyclooxygenase). Biochem Biophys Res Commun. 1992 Jan 31;182(2):433-8. doi: 10.1016/0006-291x(92)91750-k.
Pubmed: 1734857
Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem. 1994 May 1;221(3):889-97. doi: 10.1111/j.1432-1033.1994.tb18804.x.
Pubmed: 8181472
Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM: Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 1993 Apr 25;268(12):9049-54.
Pubmed: 8473346
Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8. doi: 10.1073/pnas.89.16.7384.
Pubmed: 1380156
Yokoyama C, Miyata A, Ihara H, Ullrich V, Tanabe T: Molecular cloning of human platelet thromboxane A synthase. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1479-84. doi: 10.1016/0006-291x(91)91060-p.
Pubmed: 1714723
Ohashi K, Ruan KH, Kulmacz RJ, Wu KK, Wang LH: Primary structure of human thromboxane synthase determined from the cDNA sequence. J Biol Chem. 1992 Jan 15;267(2):789-93.
Pubmed: 1730669
Miyata A, Yokoyama C, Ihara H, Bandoh S, Takeda O, Takahashi E, Tanabe T: Characterization of the human gene (TBXAS1) encoding thromboxane synthase. Eur J Biochem. 1994 Sep 1;224(2):273-9. doi: 10.1111/j.1432-1033.1994.00273.x.
Pubmed: 7925341
Miyata A, Hara S, Yokoyama C, Inoue H, Ullrich V, Tanabe T: Molecular cloning and expression of human prostacyclin synthase. Biochem Biophys Res Commun. 1994 May 16;200(3):1728-34. doi: 10.1006/bbrc.1994.1652.
Pubmed: 8185632
Chevalier D, Cauffiez C, Bernard C, Lo-Guidice JM, Allorge D, Fazio F, Ferrari N, Libersa C, Lhermitte M, D'Halluin JC, Broly F: Characterization of new mutations in the coding sequence and 5'-untranslated region of the human prostacylcin synthase gene (CYP8A1). Hum Genet. 2001 Feb;108(2):148-55. doi: 10.1007/s004390000444.
Pubmed: 11281454
Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. doi: 10.1038/414865a.
Pubmed: 11780052
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B: A model for p53-induced apoptosis. Nature. 1997 Sep 18;389(6648):300-5. doi: 10.1038/38525.
Pubmed: 9305847
Jakobsson PJ, Thoren S, Morgenstern R, Samuelsson B: Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7220-5. doi: 10.1073/pnas.96.13.7220.
Pubmed: 10377395
Forsberg L, Leeb L, Thoren S, Morgenstern R, Jakobsson P: Human glutathione dependent prostaglandin E synthase: gene structure and regulation. FEBS Lett. 2000 Apr 7;471(1):78-82. doi: 10.1016/s0014-5793(00)01367-3.
Pubmed: 10760517
Nagata A, Suzuki Y, Igarashi M, Eguchi N, Toh H, Urade Y, Hayaishi O: Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins. Proc Natl Acad Sci U S A. 1991 May 1;88(9):4020-4. doi: 10.1073/pnas.88.9.4020.
Pubmed: 1902577
White DM, Mikol DD, Espinosa R, Weimer B, Le Beau MM, Stefansson K: Structure and chromosomal localization of the human gene for a brain form of prostaglandin D2 synthase. J Biol Chem. 1992 Nov 15;267(32):23202-8.
Pubmed: 1385416
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Penning TM, Burczynski ME, Jez JM, Lin HK, Ma H, Moore M, Ratnam K, Palackal N: Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3). Mol Cell Endocrinol. 2001 Jan 22;171(1-2):137-49. doi: 10.1016/s0303-7207(00)00426-3.
Pubmed: 11165022
Lovering AL, Ride JP, Bunce CM, Desmond JC, Cummings SM, White SA: Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004 Mar 1;64(5):1802-10.
Pubmed: 14996743
Qin KN, New MI, Cheng KC: Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1993 Dec;46(6):673-9.
Pubmed: 8274401
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings