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| leukotriene C4 |
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| CHEBI:16978 |
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| leukotriene C4 |
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| A leukotriene that is (5S,7E,9E,11Z,14Z)-5-hydroxyicosa-7,9,11,14-tetraenoic acid in which a glutathionyl group is attached at position 6 via a sulfide linkage. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:6422, CHEBI:14504, CHEBI:25025
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| ZINC000004095814 |
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Molfile
XML
SDF
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more structures >>
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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__562118514540372__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__562118514540372__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:6422","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__562118514540372__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"562118514540372","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 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language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__562118514540372__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol LTX - Ideal conformer Mrv1927 06062213473D starting HoverWatcher_5 Time for openFile(LTX - Ideal conformer Mrv1927 06062213473D 90 89 0 0 0 0 999 V2000 -4.3240 7.9290 -2.8620 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.6160 7.3820 -1.8610 C 0 0 0 0 0 0 0 0 0 0 0 0 -3.4710 7.9850 -0.8240 O 0 0 0 0 0 0 0 0 0 0 0 0 -3.0030 6.0160 -2.0300 C 0 0 1 0 0 0 0 0 0 0 0 0 -2.2570 5.6290 -0.7520 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.6340 4.2420 -0.9240 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.8880 3.8560 0.3550 C 0 0 2 0 0 0 0 0 0 0 0 0 0.1860 4.7730 0.5750 O 0 0 0 0 0 0 0 0 0 0 0 0 -0.3280 2.4400 0.2110 C 0 0 1 0 0 0 0 0 0 0 0 0 0.4220 2.0660 1.4630 C 0 0 0 0 0 0 0 0 0 0 0 0 1.7170 1.7570 1.3980 C 0 0 0 0 0 0 0 0 0 0 0 0 2.4460 1.3930 2.6150 C 0 0 0 0 0 0 0 0 0 0 0 0 3.7560 1.0810 2.5490 C 0 0 0 0 0 0 0 0 0 0 0 0 4.4850 0.7170 3.7660 C 0 0 0 0 0 0 0 0 0 0 0 0 5.7560 0.3230 3.6890 C 0 0 0 0 0 0 0 0 0 0 0 0 6.4850 0.3830 2.3720 C 0 0 1 0 0 0 0 0 0 0 0 0 7.7560 1.1770 2.5370 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9020 0.6650 2.1630 C 0 0 0 0 0 0 0 0 0 0 0 0 8.9350 -0.6470 1.4220 C 0 0 1 0 0 0 0 0 0 0 0 0 9.7360 -0.4830 0.1290 C 0 0 1 0 0 0 0 0 0 0 0 0 9.7690 -1.8150 -0.6230 C 0 0 1 0 0 0 0 0 0 0 0 0 10.5700 -1.6510 -1.9160 C 0 0 1 0 0 0 0 0 0 0 0 0 10.6030 -2.9840 -2.6680 C 0 0 0 0 0 0 0 0 0 0 0 0 1.5260 -2.7460 -3.9400 O 0 0 0 0 0 0 0 0 0 0 0 0 1.4260 -3.8220 -3.4000 C 0 0 0 0 0 0 0 0 0 0 0 0 2.1760 -4.8550 -3.8190 O 0 0 0 0 0 0 0 0 0 0 0 0 0.4610 -4.0060 -2.2580 C 0 0 1 0 0 0 0 0 0 0 0 0 -0.2310 -2.7420 -1.9950 N 0 0 0 0 0 0 0 0 0 0 0 0 -1.1480 -2.6680 -1.0100 C 0 0 0 0 0 0 0 0 0 0 0 0 -1.4000 -3.6480 -0.3410 O 0 0 0 0 0 0 0 0 0 0 0 0 -1.8600 -1.3680 -0.7400 C 0 0 2 0 0 0 0 0 0 0 0 0 -0.8360 -0.2920 -0.3730 C 0 0 1 0 0 0 0 0 0 0 0 0 -1.6930 1.2730 -0.0480 S 0 0 0 0 0 0 0 0 0 0 0 0 -2.7990 -1.5460 0.3700 N 0 0 0 0 0 0 0 0 0 0 0 0 -4.0360 -2.0260 0.1360 C 0 0 0 0 0 0 0 0 0 0 0 0 -4.3730 -2.3100 -0.9940 O 0 0 0 0 0 0 0 0 0 0 0 0 -5.0020 -2.2100 1.2780 C 0 0 1 0 0 0 0 0 0 0 0 0 -6.3250 -2.7630 0.7430 C 0 0 1 0 0 0 0 0 0 0 0 0 -7.3050 -2.9500 1.9030 C 0 0 2 0 0 0 0 0 0 0 0 0 -6.7930 -3.9810 2.8160 N 0 0 1 0 0 0 0 0 0 0 0 0 -8.6460 -3.3780 1.3630 C 0 0 0 0 0 0 0 0 0 0 0 0 -8.9670 -4.5420 1.3960 O 0 0 0 0 0 0 0 0 0 0 0 0 -9.4830 -2.4650 0.8460 O 0 0 0 0 0 0 0 0 0 0 0 0 -4.6970 8.8070 -2.7060 H 0 0 0 0 0 0 0 0 0 0 0 0 -3.7890 5.2860 -2.2260 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.3060 6.0310 -2.8670 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.4700 6.3590 -0.5560 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.9540 5.6140 0.0860 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4210 3.5130 -1.1190 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.9370 4.2580 -1.7610 H 0 0 0 0 0 0 0 0 0 0 0 0 -1.5740 3.8910 1.2010 H 0 0 0 0 0 0 0 0 0 0 0 0 0.8370 4.7950 -0.1400 H 0 0 0 0 0 0 0 0 0 0 0 0 0.3490 2.4020 -0.6430 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0900 2.0480 2.4140 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2290 1.7740 0.4470 H 0 0 0 0 0 0 0 0 0 0 0 0 1.9340 1.3760 3.5660 H 0 0 0 0 0 0 0 0 0 0 0 0 4.2680 1.0980 1.5980 H 0 0 0 0 0 0 0 0 0 0 0 0 3.9930 0.7690 4.7260 H 0 0 0 0 0 0 0 0 0 0 0 0 6.2630 -0.0400 4.5710 H 0 0 0 0 0 0 0 0 0 0 0 0 6.7290 -0.6280 2.0450 H 0 0 0 0 0 0 0 0 0 0 0 0 5.8510 0.8630 1.6270 H 0 0 0 0 0 0 0 0 0 0 0 0 7.7210 2.1680 2.9640 H 0 0 0 0 0 0 0 0 0 0 0 0 9.8230 1.1830 2.3850 H 0 0 0 0 0 0 0 0 0 0 0 0 9.4060 -1.4060 2.0470 H 0 0 0 0 0 0 0 0 0 0 0 0 7.9170 -0.9550 1.1820 H 0 0 0 0 0 0 0 0 0 0 0 0 9.2650 0.2750 -0.4960 H 0 0 0 0 0 0 0 0 0 0 0 0 10.7530 -0.1760 0.3690 H 0 0 0 0 0 0 0 0 0 0 0 0 10.2400 -2.5740 0.0020 H 0 0 0 0 0 0 0 0 0 0 0 0 8.7510 -2.1230 -0.8630 H 0 0 0 0 0 0 0 0 0 0 0 0 10.0990 -0.8930 -2.5410 H 0 0 0 0 0 0 0 0 0 0 0 0 11.5880 -1.3440 -1.6760 H 0 0 0 0 0 0 0 0 0 0 0 0 9.5850 -3.2910 -2.9080 H 0 0 0 0 0 0 0 0 0 0 0 0 11.1740 -2.8670 -3.5890 H 0 0 0 0 0 0 0 0 0 0 0 0 11.0740 -3.7420 -2.0420 H 0 0 0 0 0 0 0 0 0 0 0 0 2.7810 -4.6880 -4.5540 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.2690 -4.7730 -2.5190 H 0 0 0 0 0 0 0 0 0 0 0 0 1.0070 -4.3140 -1.3660 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.0300 -1.9590 -2.5300 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.4060 -1.0600 -1.6320 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.2890 -0.5990 0.5180 H 0 0 0 0 0 0 0 0 0 0 0 0 -0.1370 -0.1590 -1.1990 H 0 0 0 0 0 0 0 0 0 0 0 0 -2.5300 -1.3200 1.2740 H 0 0 0 0 0 0 0 0 0 0 0 0 -4.5820 -2.9090 2.0000 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.1800 -1.2500 1.7620 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.7460 -2.0640 0.0210 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.1480 -3.7240 0.2590 H 0 0 0 0 0 0 0 0 0 0 0 0 -7.4140 -2.0090 2.4420 H 0 0 0 0 0 0 0 0 0 0 0 0 -6.6840 -4.8640 2.3390 H 0 0 0 0 0 0 0 0 0 0 0 0 -5.9260 -3.6890 3.2410 H 0 0 0 0 0 0 0 0 0 0 0 0 -10.3320 -2.7870 0.5120 H 0 0 0 0 0 0 0 0 0 0 0 0 24 25 2 0 0 0 0 23 22 1 0 0 0 0 22 21 1 0 0 0 0 25 26 1 0 0 0 0 25 27 1 0 0 0 0 27 28 1 0 0 0 0 21 20 1 0 0 0 0 20 19 1 0 0 0 0 14 15 2 0 0 0 0 14 13 1 0 0 0 0 3 2 2 0 0 0 0 8 7 1 0 0 0 0 28 29 1 0 0 0 0 15 16 1 0 0 0 0 12 13 2 0 0 0 0 12 11 1 0 0 0 0 19 18 1 0 0 0 0 30 29 2 0 0 0 0 10 11 2 0 0 0 0 10 9 1 0 0 0 0 29 31 1 0 0 0 0 2 4 1 0 0 0 0 2 1 1 0 0 0 0 7 6 1 0 0 0 0 7 9 1 0 0 0 0 5 6 1 0 0 0 0 5 4 1 0 0 0 0 16 17 1 0 0 0 0 18 17 2 0 0 0 0 33 9 1 0 0 0 0 33 32 1 0 0 0 0 31 32 1 0 0 0 0 31 34 1 0 0 0 0 34 35 1 0 0 0 0 35 37 1 0 0 0 0 35 36 2 0 0 0 0 42 41 2 0 0 0 0 37 38 1 0 0 0 0 40 39 1 0 0 0 0 41 43 1 0 0 0 0 41 39 1 0 0 0 0 38 39 1 0 0 0 0 1 44 1 0 0 0 0 4 45 1 0 0 0 0 4 46 1 0 0 0 0 5 47 1 0 0 0 0 5 48 1 0 0 0 0 6 49 1 0 0 0 0 6 50 1 0 0 0 0 7 51 1 1 0 0 0 8 52 1 0 0 0 0 9 53 1 6 0 0 0 10 54 1 0 0 0 0 11 55 1 0 0 0 0 12 56 1 0 0 0 0 13 57 1 0 0 0 0 14 58 1 0 0 0 0 15 59 1 0 0 0 0 16 60 1 0 0 0 0 16 61 1 0 0 0 0 17 62 1 0 0 0 0 18 63 1 0 0 0 0 19 64 1 0 0 0 0 19 65 1 0 0 0 0 20 66 1 0 0 0 0 20 67 1 0 0 0 0 21 68 1 0 0 0 0 21 69 1 0 0 0 0 22 70 1 0 0 0 0 22 71 1 0 0 0 0 23 72 1 0 0 0 0 23 73 1 0 0 0 0 23 74 1 0 0 0 0 26 75 1 0 0 0 0 27 76 1 0 0 0 0 27 77 1 0 0 0 0 28 78 1 0 0 0 0 31 79 1 6 0 0 0 32 80 1 0 0 0 0 32 81 1 0 0 0 0 34 82 1 0 0 0 0 37 83 1 0 0 0 0 37 84 1 0 0 0 0 38 85 1 0 0 0 0 38 86 1 0 0 0 0 39 87 1 1 0 0 0 40 88 1 0 0 0 0 40 89 1 0 0 0 0 43 90 1 0 0 0 0 M END): 21 ms reading 90 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 90 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with co-localization of cytosolic phospholipase A2 (cPLA2), arachidonate 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and LTC4 synthase (LTC4S), which couples glutathione to an LTA4 intermediate. The MRP1 transporter then secretes cytosolic LTC4 and cell surface proteases further metabolize it by sequential cleavage of the γ-glutamyl and glycine residues off its glutathione segment, generating the more stable products LTD4 and LTE4. All three leukotrienes then bind at different affinities to two G-protein coupled receptors: CYSLTR1 and CYSLTR2, triggering pulmonary vasoconstriction and bronchoconstriction.
In cells of non-haematopoietic lineage, endoplasmic reticulum (ER) stress and chemotherapy induce LTC4 biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2). ER stress and chemotherapy also trigger nuclear translocation of the two LTC4 receptors. Acting in an intracrine manner, LTC4 then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage. Besides being a potent lipid mediator in asthma and inflammation, LTC4 was reported to be involved in several other diseases, such as allergic airway diseases, dermatological diseases, cardiovascular diseases, liver injury, atherosclerosis and colon cancer. |
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Read full article at Wikipedia
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InChI=1S/C30H47N3O9S/c1- 2-3-4-5-6-7-8-9-10-11-12-13-16-25(24(34)15-14-17-27(36)37)43-21-23(29(40)32-20-28(38)39)33-26(35)19-18-22(31)30(41)42/h6-7,9-13,16,22-25,34H,2-5,8,14-15,17-21,31H2,1H3,(H,32,40)(H,33,35)(H,36,37)(H,38,39)(H,41,42)/b7-6-,10-9-,12-11+,16-13+/t22-,23-,24-,25+/m0/s1 |
| GWNVDXQDILPJIG-NXOLIXFESA-N |
| CCCCC\C=C/C\C=C/C=C/C=C/[C@@H](SC[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)NCC(O)=O)[C@@H](O)CCCC(O)=O |
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Mus musculus
(NCBI:txid10090)
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Found in
bronchoalveolar lavage
(BTO:0000155).
From MetaboLights
See:
MetaboLights Study
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Mus musculus
(NCBI:txid10090)
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From MetaboLights
See:
MetaboLights Study
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Mus musculus
(NCBI:txid10090)
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From MetaboLights
See:
MetaboLights Study
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
blood
(UBERON:0000178).
See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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Found in
cerebrospinal fluid
(UBERON:0001359).
See:
PubMed
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mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
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bronchoconstrictor agent
A drug which causes a narrowing of the lumen of a bronchus or bronchiole.
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View more via ChEBI Ontology
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L-γ-glutamyl-S-[(1R,2E,4E,6Z,9Z)-1-[(1S)-4-carboxy-1-hydroxybutyl]pentadeca-2,4,6,9-tetraen-1-yl]-L-cysteinylglycine
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(R-(R*,S*-(E,E,Z,Z)))-N-(S-(1-(4-Carboxy-1-hydroxybutyl)-2,4,6,9-pentadecatetraenyl)-N-L-gamma-glutamyl-L-cysteinyl)glycine
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ChemIDplus
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5S,6R-Ltc(sub 4)
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ChemIDplus
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5S-hydroxy,6R-(S-glutathionyl),7E,9E,11Z,14Z-eicosatetraenoic acid
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LIPID MAPS
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Leukotriene C4
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KEGG COMPOUND
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LTC (sub 4)
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ChemIDplus
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LTC4
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LIPID MAPS
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LTC4
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KEGG COMPOUND
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LTC4
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ChEBI
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4732117
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Reaxys Registry Number
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Reaxys
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72025-60-6
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CAS Registry Number
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KEGG COMPOUND
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72025-60-6
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CAS Registry Number
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ChemIDplus
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Voisin T, Perner C, Messou MA, Shiers S, Ualiyeva S, Kanaoka Y, Price TJ, Sokol CL, Bankova LG, Austen KF, Chiu IM (2021)
The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.
Proceedings of the National Academy of Sciences of the United States of America 118, e2022087118 [PubMed:33753496]
[show Abstract]
Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC4, LTD4, and LTE4, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC4 and its signaling through the CysLT receptor 2 (CysLT2R) in itch. Cysltr2 transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected CYSLTR2 in a broad population of human DRG neurons. Injection of leukotriene C4 (LTC4) or its nonhydrolyzable form NMLTC4, but neither LTD4 nor LTE4, induced dose-dependent itch but not pain behaviors in mice. LTC4-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC4-induced itch was abrogated in mice deficient for Cysltr2 or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for Cysltr1, Trpv1, or mast cells (WSh mice). CysLT2R played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or Alternaria-induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and Cysltr2-/- mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC4 acts through CysLT2R as its physiological receptor to induce itch, and CysLT2R contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch. | Conseil G, Arama-Chayoth M, Tsfadia Y, Cole SPC (2019)
Structure-guided probing of the leukotriene C4 binding site in human multidrug resistance protein 1 (MRP1; ABCC1).
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33, 10692-10704 [PubMed:31268744]
[show Abstract]
The human multidrug resistance protein 1 (hMRP1) transporter is implicated in cancer multidrug resistance as well as immune responses involving its physiologic substrate, glutathione (GSH)-conjugated leukotriene C4 (LTC4). LTC4 binds a bipartite site on hMRP1, which a recent cryoelectron microscopy structure of LTC4-bound bovine Mrp1 depicts as composed of a positively charged pocket and a hydrophobic (H) pocket that binds the GSH moiety and surrounds the fatty acid moiety, respectively, of LTC4. Here, we show that single Ala and Leu substitutions of H-pocket hMRP1-Met1093 have no effect on LTC4 binding or transport. Estrone 3-sulfate transport is also unaffected, but both hMRP1-Met1093 mutations eliminate estradiol glucuronide transport, demonstrating that these steroid conjugates have binding sites distinct from each other and from LTC4. To eliminate LTC4 transport by hMRP1, mutation of 3 H-pocket residues was required (W553/M1093/W1246A), indicating that H-pocket amino acids are key to the vastly different affinities of hMRP1 for LTC4vs. GSH alone. Unlike organic anion transport, hMRP1-mediated drug resistance was more diminished by Ala than Leu substitution of Met1093. Although our findings generally support a structure in which H-pocket residues bind the lipid tail of LTC4, their critical and differential role in the transport of conjugated estrogens and anticancer drugs remains unexplained.-Conseil, G., Arama-Chayoth, M., Tsfadia, Y., Cole, S. P. C. Structure-guided probing of the leukotriene C4 binding site in human multidrug resistance protein 1 (MRP1; ABCC1). | Johnson ZL, Chen J (2017)
Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1.
Cell 168, 1075-1085.e9 [PubMed:28238471]
[show Abstract]
The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several opiates, antidepressants, statins, and antibiotics. In addition, MRP1 regulates redox homeostasis, inflammation, and hormone secretion. Using electron cryomicroscopy, we determined the molecular structures of bovine MRP1 in two conformations: an apo form at 3.5 Å without any added substrate and a complex form at 3.3 Å with one of its physiological substrates, leukotriene C4. These structures show that by forming a single bipartite binding site, MRP1 can recognize a spectrum of substrates with different chemical structures. We also observed large conformational changes induced by leukotriene C4, explaining how substrate binding primes the transporter for ATP hydrolysis. Structural comparison of MRP1 and P-glycoprotein advances our understanding of the common and unique properties of these two important molecules in multidrug resistance to chemotherapy. | Lund SJ, Portillo A, Cavagnero K, Baum RE, Naji LH, Badrani JH, Mehta A, Croft M, Broide DH, Doherty TA (2017)
Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation.
Journal of immunology (Baltimore, Md. : 1950) 199, 1096-1104 [PubMed:28667163]
[show Abstract]
Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R-/- mice, but not CysLT2R-/- mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R-/- mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses. | Jablonka W, Pham V, Nardone G, Gittis A, Silva-Cardoso L, Atella GC, Ribeiro JM, Andersen JF (2016)
Structure and Ligand-Binding Mechanism of a Cysteinyl Leukotriene-Binding Protein from a Blood-Feeding Disease Vector.
ACS chemical biology 11, 1934-1944 [PubMed:27124118]
[show Abstract]
Blood-feeding disease vectors mitigate the negative effects of hemostasis and inflammation through the binding of small-molecule agonists of these processes by salivary proteins. In this study, a lipocalin protein family member (LTBP1) from the saliva of Rhodnius prolixus, a vector of the pathogen Trypanosoma cruzi, is shown to sequester cysteinyl leukotrienes during feeding to inhibit immediate inflammatory responses. Calorimetric binding experiments showed that LTBP1 binds leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) but not biogenic amines, adenosine diphosphate, or other eicosanoid compounds. Crystal structures of ligand-free LTBP1 and its complexes with LTC4 and LTD4 reveal a conformational change during binding that brings Tyr114 into close contact with the ligand. LTC4 is cleaved in the complex, leaving free glutathione and a C20 fatty acid. Chromatographic analysis of bound ligands showed only intact LTC4, suggesting that cleavage could be radiation-mediated. | Dvash E, Har-Tal M, Barak S, Meir O, Rubinstein M (2015)
Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage.
Nature communications 6, 10112 [PubMed:26656251]
[show Abstract]
Endoplasmic reticulum (ER) stress and major chemotherapeutic agents damage DNA by generating reactive oxygen species (ROS). Here we show that ER stress and chemotherapy induce leukotriene C4 (LTC4) biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2) in cells of non-haematopoietic lineage. ER stress and chemotherapy also trigger nuclear translocation of the two LTC4 receptors. Acting in an intracrine manner, LTC4 then elicits nuclear translocation of NADPH oxidase 4 (NOX4), ROS accumulation and oxidative DNA damage. Mgst2 deficiency, RNAi and LTC4 receptor antagonists abolish ER stress- and chemotherapy-induced ROS and oxidative DNA damage in vitro and in mouse kidneys. Cell death and mouse morbidity are also significantly attenuated. Hence, MGST2-generated LTC4 is a major mediator of ER stress- and chemotherapy-triggered oxidative stress and oxidative DNA damage. LTC4 inhibitors, commonly used for asthma, could find broad clinical use in major human pathologies associated with ER stress-activated NOX4. | Cummings HE, Liu T, Feng C, Laidlaw TM, Conley PB, Kanaoka Y, Boyce JA (2013)
Cutting edge: Leukotriene C4 activates mouse platelets in plasma exclusively through the type 2 cysteinyl leukotriene receptor.
Journal of immunology (Baltimore, Md. : 1950) 191, 5807-5810 [PubMed:24244016]
[show Abstract]
Leukotriene C4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT1R], CysLT2R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT2R. Platelets expressed CysLT1R and CysLT2R proteins. LTC4 induced surface expression of CD62P by wild-type mouse platelets in platelet-rich plasma (PRP) and caused their secretion of thromboxane A2 and CXCL4. LTC4 was fully active on PRP from mice lacking either CysLT1R or GPR99, but completely inactive on PRP from CysLT2R-null (Cysltr2(-/-)) mice. LTC4/CysLT2R signaling required an autocrine ADP-mediated response through P2Y12 receptors. LTC4 potentiated airway inflammation in a platelet- and CysLT2R-dependent manner. Thus, CysLT2R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte-platelet complexes that facilitate inflammation. | Quehenberger O, Armando AM, Brown AH, Milne SB, Myers DS, Merrill AH, Bandyopadhyay S, Jones KN, Kelly S, Shaner RL, Sullards CM, Wang E, Murphy RC, Barkley RM, Leiker TJ, Raetz CR, Guan Z, Laird GM, Six DA, Russell DW, McDonald JG, Subramaniam S, Fahy E, Dennis EA (2010)
Lipidomics reveals a remarkable diversity of lipids in human plasma.
Journal of lipid research 51, 3299-3305 [PubMed:20671299]
[show Abstract]
The focus of the present study was to define the human plasma lipidome and to establish novel analytical methodologies to quantify the large spectrum of plasma lipids. Partial lipid analysis is now a regular part of every patient's blood test and physicians readily and regularly prescribe drugs that alter the levels of major plasma lipids such as cholesterol and triglycerides. Plasma contains many thousands of distinct lipid molecular species that fall into six main categories including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenols. The physiological contributions of these diverse lipids and how their levels change in response to therapy remain largely unknown. As a first step toward answering these questions, we provide herein an in-depth lipidomics analysis of a pooled human plasma obtained from healthy individuals after overnight fasting and with a gender balance and an ethnic distribution that is representative of the US population. In total, we quantitatively assessed the levels of over 500 distinct molecular species distributed among the main lipid categories. As more information is obtained regarding the roles of individual lipids in health and disease, it seems likely that future blood tests will include an ever increasing number of these lipid molecules. | Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD (2005)
Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11).
Molecular pharmacology 67, 545-557 [PubMed:15537867]
[show Abstract]
We previously determined that expression of human multidrug resistance protein (MRP) 8, a recently described member of the MRP family of ATP-binding cassette transporters, enhances cellular extrusion of cyclic nucleotides and confers resistance to nucleotide analogs (J Biol Chem 278:29509-29514, 2003). However, the in vitro transport characteristics of the pump have not been determined. In this study, the substrate selectivity and biochemical activity of MRP8 is investigated using membrane vesicles prepared from LLC-PK1 cells transfected with MRP8 expression vector. Expression of MRP8 is shown to stimulate the ATP-dependent uptake of a range of physiological and synthetic lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate. In addition, MRP8 is competent in the in vitro transport of cAMP and cGMP, in accord with the results of our previously reported cellular studies. DHEAS, E(2)17betaG, and methotrexate were transported with K(m) and V(max) values of 13.0 +/- 0.8 microM and 34.9 +/- 9.5 pmol/mg/min, 62.9 +/- 12 microM and 62.0 +/- 5.2 pmol/mg/min, and 957 +/- 28 microM and 317 +/- 17 pmol/mg/min, respectively. Based upon the stimulatory action of DHEAS on uptake of E(2)17betaG, the attenuation of this effect at high DHEAS concentrations and the lack of reciprocal promotion of DHEAS uptake by E(2)17betaG, a model involving nonreciprocal constructive interactions between some transport substrates is invoked. These results suggest that MRP8 participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides and indicate that the pump has complex interactions with its substrates. | Mayatepek E, Meissner T, Gröbe H (2004)
Acute metabolic crisis with extreme deficiency of glutathione in combination with decreased levels of leukotriene C4 in a patient with glutathione synthetase deficiency.
Journal of inherited metabolic disease 27, 297-299 [PubMed:15243994]
[show Abstract]
A 32-year-old man with glutathione synthetase deficiency developing an acute metabolic crisis is described. During this acute episode, intracellular glutathione content in erythrocytes was below the detection limit (<0.3 mmol/L). Leukotriene C4 in CSF and urinary leukotriene E4 were massively decreased, indicating an imparied synthesis of cysteinyl leukotrienes. Clinical recovery after one week was accompanied by a clear improvement of these biochemical parameters. The highly disturbed glutathione synthesis is postulated to be the reason for a deficient synthesis of cysteinyl leukotrienes, which may at least in part be responsible for the severe clinical symptoms. | Bandeira-Melo C, Weller PF (2003)
Eosinophils and cysteinyl leukotrienes.
Prostaglandins, leukotrienes, and essential fatty acids 69, 135-143 [PubMed:12895596]
[show Abstract]
Eosinophils are the main source of the cysteinyl leukotrienes, LTC(4)/D(4)/E(4), which are lipid mediators that play major roles in the pathogenesis of asthma and other forms of allergic inflammation. Here, we review the mechanisms governing eosinophil LTC(4) synthesis, focusing on the distinct intracellular domains that regulate eicosanoid formation and function within eosinophils. Cysteinyl leukotrienes exert their actions by engaging specific receptors. As recently shown, eosinophils express CysLT1 and CysLT2, the only cloned receptors for cysteinyl leukotrienes. Therefore, here we also present some of the new findings regarding the paracrine/autocrine activation of these CysLT receptors on eosinophils, and discuss some data on novel intracrine effects of LTC(4) triggered by a putative third CysLT receptor expressed intracellularly within eosinophils. | Setoguchi H, Nishimura J, Hirano K, Takahashi S, Kanaide H (2001)
Leukotriene C(4) enhances the contraction of porcine tracheal smooth muscle through the activation of Y-27632, a rho kinase inhibitor, sensitive pathway.
British journal of pharmacology 132, 111-118 [PubMed:11156567]
[show Abstract]
1. An unsaturated fatty acid, leukotriene C(4) (LTC(4)), has a potent contractile effect on human airway smooth muscle, and has been implicated in the pathogenesis of human asthma. Using front-surface fluorometry with fura-PE3, the effect of LTC(4) on the intracellular Ca(2+) concentration ([Ca(2+)](i)) and tension were investigated in porcine tracheal smooth muscle strips. 2. The application of LTC(4) induced little or no contraction despite a small and transient increase in [Ca(2+)](i). In the presence of LTC(4), however, the contractions evoked by high K(+) depolarization or a low concentration of carbachol (CCh) were markedly enhanced without inducing any changes in the [Ca(2+)](i) levels, thus indicating that LTC(4) increases the Ca(2+) responsiveness of the contractile apparatus. This LTC(4)-induced increase in Ca(2+) responsiveness could partly be reproduced in the permeabilized preparation of tracheal smooth muscle strips. 3. The LTC(4)-induced enhancement of contraction was accompanied by an increase in myosin light chain (MLC) phosphorylation and was blocked by a rho kinase inhibitor (Y-27632), but not by either a PKC inhibitor (calphostin C) or a tyrosine kinase inhibitor (genistein). 4. These results indicated that, in porcine tracheal smooth muscle, LTC(4) enhances the contraction by increasing the Ca(2+) responsiveness of the contractile apparatus in a MLC phosphorylation dependent manner, possibly through the activation of the rho-rho kinase pathway. | Sjölinder M, Tornhamre S, Claesson HE, Hydman J, Lindgren J (1999)
Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1.
Journal of lipid research 40, 439-446 [PubMed:10064732]
[show Abstract]
Platelets express leukotriene (LT) C4 synthase and can thus participate in the formation of bioactive LTC4. To further elucidate the relevance of this capability, we have now determined the capacity of human platelets to export LTC4. Endogenously formed LTC4 was efficiently released from human platelets after incubation with LTA4 at 37 degrees C, whereas only 15% of produced LTC4 was exported when the cells were incubated at 0 degrees C. The activation energy of the process was calculated to 49.9 +/- 7.7 kJ/mol, indicating carrier-mediated LTC4 export. This was also supported by the finding that the transport was saturable, reaching a maximal export rate of 470 +/- 147 pmol LTC4/min x 10(9) platelets. Furthermore, markedly suppressed LTC4 transport was induced by a combination of the metabolic inhibitors antimycin A and 2-deoxyglucose, suggesting energy-dependent export. The presence in platelets of multidrug resistance-associated protein 1 (MRP1), a protein described to be an energy-dependent LTC4 transporter in various cell types, was demonstrated at the mRNA and protein level. Additional support for a role of MRP1 in platelet LTC4 export was obtained by the findings that the process was inhibited by probenecid and the 5-lipoxygenase-activating protein (FLAP) inhibitor, MK-886. The present findings further support the physiological relevance of platelet LTC4 production. | Koshino T, Takano S, Houjo T, Sano Y, Kudo K, Kihara H, Kitani S, Takaishi T, Hirai K, Ito K, Morita Y (1998)
Expression of 5-lipoxygenase and 5-lipoxygenase-activating protein mRNAs in the peripheral blood leukocytes of asthmatics.
Biochemical and biophysical research communications 247, 510-513 [PubMed:9642160]
[show Abstract]
Leukotrienes are a family of arachidonic acid metabolites with potent biological activities such as bronchoconstriction and leukocyte chemotaxis. Recent evidence has demonstrated that the 5-lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FALP) products of arachidonic acid metabolism, leukotriene C4, D4 and E4, were increased in the serum and the urine of asthmatic patients. Therefore, we examined the expression of 5-LO and FLAP mRNAs in the peripheral blood leukocytes (PBL) of 10 asthmatics and 10 controls. Both 5-LO and FLAP mRNAs of PBL in the asthmatic group were found to be significantly increased compared with those in the control group. These data suggest that up-regulation of 5-LO and FLAP mRNAs might be involved in the increased leukotriene synthesis and play an important role in the pathogenesis of asthma. | O'Byrne PM (1997)
Leukotrienes in the pathogenesis of asthma.
Chest 111, 27S-34S [PubMed:9042024]
[show Abstract]
Asthma is a chronic inflammatory disease that is associated with widespread but variable airflow obstruction. The mechanisms that lead to airflow obstruction in asthma are bronchoconstriction, mucosal edema, increased secretion of mucus, and an inflammatory-cell infiltrate that is rich in eosinophils. Leukotrienes (LTs) B4, C4, D4, and E4 have been shown experimentally to play a role in each of these inflammatory mechanisms and to mimic the pathologic changes seen in asthma. Inhaled LTC4 and LTD4 are the most potent bronchoconstrictors yet studied in human subjects. LTC4 and LTD4 also may cause migration of inflammatory cells into the asthmatic airway. LTs are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, and increased production of LTs has been demonstrated in patients who have asthma. Leukotriene receptor antagonists and specific inhibitors of the 5-LO pathway hold great promise as new therapies to treat asthma. Because LTC4, LTD4, and LTE4 appear to interact with a common LTD4 receptor, selective LTD4 receptor antagonists (eg, pranlukast [SB205312/ONO-1078], zafirlukast [ICI 204,219], MK-571, and MK-679), as well as zileuton (A-64077, a direct inhibitor of 5-LO) have been developed as antiasthma agents. Clinical and experimental studies have demonstrated the efficacy of these compounds in reducing not only the symptoms of asthma, but use of beta 2-agonists and bronchoconstriction induced by exposure to allergens, exercise, aspirin, and cold air. | Damtew B, Spagnuolo PJ (1997)
Leukotriene C4 from vascular endothelium enhances neutrophil adhesiveness.
Prostaglandins, leukotrienes, and essential fatty acids 56, 111-116 [PubMed:9051719]
[show Abstract]
We have examined the synthesis of leukotriene C4 from bovine aortic and pulmonary artery endothelium. Under basal conditions, neither aortic nor pulmonary artery endothelium revealed significant amounts of hydroxy fatty acids. Following incubation with ionophore A23187, several peaks including one which co-migrated with authentic LTC4 could be demonstrated from both aortic and pulmonary endothelium. LTC4 production was maximal after 30 min incubation, was inhibitable by the lipoxygenase inhibitor nordihydroguairetic acid, and was synthesized by bovine endothelium from tritiated arachidonic acid substrate. The putative LTC4 from endothelium was shown to be identical to authentic LTC4 by chromatography and scanning UV spectroscopy. Endothelial-derived LTC4 increased the adherence of bovine aortic endothelium for neutrophils in a concentration dependent pattern similar to authentic LTC4. These data suggest that vascular endothelium may influence leukocyte-endothelial interactions through synthesis of biologically active arachidonic acid metabolites such as LTC4. | Hardcastle JE, Bruch RJ (1997)
Effect of L-aspartyl-L-phenylalanine methyl ester on leukotriene biosynthesis in macrophage cells.
Prostaglandins, leukotrienes, and essential fatty acids 57, 331-333 [PubMed:9384524]
[show Abstract]
Macrophage cells treated with L-aspartyl-L-phenylalanine methyl ester (aspartame) produced leukotrienes and other arachidonic acid metabolites. Leukotriene C4, leukotriene B4, and 15-hydroxyeicosatetraenoic acid were the major metabolites detected. The aspartame-treated macrophage cell cultures produced three times as much arachidonic acid metabolites as did the untreated control cell cultures. Leukotriene C4 was produced in the largest amount by the aspartame-treated cells. | Heimbürger M, Palmblad JE (1996)
Effects of leukotriene C4 and D4, histamine and bradykinin on cytosolic calcium concentrations and adhesiveness of endothelial cells and neutrophils.
Clinical and experimental immunology 103, 454-460 [PubMed:8608646]
[show Abstract]
We compared the effects of leukotrienes B4, C4 and D4 (LTB4, C4 and D4) in vitro, as well as of histamine and bradykinin, on adhesive interactions between cultured umbilical vein endothelial cells (HUVEC) and polymorphonuclear neutrophils (PMN) and on cytosolic calcium transients, [Ca(2+)](i), in vitro. LTB4, but not LTC4 or LTD4 (at 1-100 nM), increased HUVEC adhesiveness for PMN, maximally 2.8 fold; in addition, PMN adhesion was augmented by LTB4 (but not by LTC4 and LTD4) to a plastic surface. Rapid, but smaller increments of HUVEC (but not of PMN) adhesiveness were induced by histamine and bradykinin (at 10 microM). Nonetheless, LTC4 and LTD4 (at 100 nm) induced rapid rises of [Ca(2+)](i) in HUVEC, whereas approximately 100-fold higher concentrations were needed of histamine and bradykinin for similar rises. In PMN LTD4 (and LTB4) induced rapid increases of [Ca(2+)](i), whereas no significant effect was seen with LTC4, histamine or bradykinin. The [Ca(2+)](i) responses to LTC4 and LTD4 were inhibited by the peptidoleukotriene receptor blocker SKF 104,353. Thus, LTB4 and the peptidoleukotrienes display disparate profiles as inducers of adhesion and calcium transients in PMN and HUVEC, indicating discrete differences in the stimulus response coupling for these closely related leukotrienes. | Richter L, Hesselbarth N, Eitner K, Schubert K, Bosseckert H, Krell H (1996)
Increased biliary secretion of cysteinyl-leukotrienes in human bile duct obstruction.
Journal of hepatology 25, 725-732 [PubMed:8938552]
[show Abstract]
Background/aimsThe pathophysiological role of leukotrienes in liver disease is not well understood. Redistribution or enhanced formation in cholestatic states may result in increased hepatic concentrations that are expected to contribute to liver injury. To disclose the potential role of cysteinyl-leukotrienes in chronic liver diseases, we studied biliary and urinary secretion in the model situation of relief of bile duct obstruction.MethodsConcentrations of cysteinyl-leukotrienes were determined in bile and urine of patients with extrahepatic biliary obstruction in the course of therapeutic decompression by endoscopic or transhepatic techniques. Leukotrienes were measured by radioimmunoassay after HPLC separation. Concentrations of bile acids in bile and serum were measured for comparison.ResultsBile collected 2 h after decompression contained high concentrations of leukotrienes (57.5 +/- 22 microM). Biliary secretion decreased over 24 h reaching equilibrium values after 48-72 h (2.8 +/- 1.7 mM and 6.4 +/- 6.6 microM, respectively). Total bile acid concentration in serum followed a similar time course. In contrast, biliary bile acid concentration showed high interindividual variations. Bile contained all leukotriene C4, D4, E4 and NAc-LTE4, but LTC4 was predominant. Urinary leukotriene secretion in cholestasis (199.7 pmol/mmol creatinine) was less than 7% of maximal biliary secretion. It further decreased to 116.4 pmol/mmol creatinine within 72 h. Urine also contained all species of cysteinyl-leukotrienes, but the relative amounts of LTE4 and NAc-LTE4 were higher than in bile.ConclusionsFormation of cysteinyl-leukotrienes is increased in obstructive jaundice resulting in increased urinary excretion before and both biliary and urinary excretion after relief of the obstruction. Predominance of LTC4 suggests that the secreted leukotrienes are newly formed. Increased synthesis and retention of hepatic cysteinyl-leukotrienes may contribute to hepatic and extrahepatic consequences of cholestasis. | Lane SJ, Lee TH (1996)
Mast cell effector mechanisms.
The Journal of allergy and clinical immunology 98, S67-71; discussion S71-2 [PubMed:8939179]
[show Abstract]
Several lines of evidence support the central role of the cysteinyl leukotrienes in aspirin-sensitive asthma, although their cellular source is unknown. The two most likely cells are the mast cell and eosinophil. Compared with aspirin-tolerant patients with asthma, patients with aspirin-sensitive asthma have been found to have a greater infiltration of mast cells and eosinophils in bronchial biopsy samples, although proportions of activated eosinophils were similar. Findings that support the involvement of mast cells include elevated serum histamine and tryptase levels after aspirin challenge in sensitive subjects, in line with a decrease in lung function and increased histamine and leukotriene C4 levels in nasal secretions; release of high-molecular-weight neutrophil chemotactic factor into serum after challenge; and prevention of aspirin-induced bronchoconstriction by pretreatment with cromolyn sodium or nedocromil sodium. These agents are also effective in protecting against bronchoconstriction induced by hyperosmolar stimuli, a challenge that is not associated with increased leukotriene E4 responsiveness but that is followed by increased release of histamine and prostaglandin D2 into bronchoalveolar lavage fluid. Antihistamines are poorly effective at inhibiting aspirin-induced bronchoconstriction but have been shown to attenuate the bronchoconstrictor response to hyperosmolar challenge. The main effector mechanism in hyperosmolar-induced bronchoconstriction appears to be mast cell activation and histamine release. | Cruz JR, Cano F, Razin E, Acheson DW, Keusch GT (1995)
Fecal excretion of leukotriene C4 during human disease due to Shigella dysenteriae.
Journal of pediatric gastroenterology and nutrition 20, 179-183 [PubMed:7714683]
[show Abstract]
Fecal excretion of leukotriene C4 was determined in 26 individuals with dysentery and in 19 healthy controls. Of the patients, five were infected with Shigella dysenteriae type 1, 15 were infected with Shigella flexneri, two were infected with Shigella boydii, and four were infected with Shigella sonnei. Three of the healthy controls were infected with non-dysenteriae Shigellae. All isolates of Shigella dysenteriae type 1 produced Shiga toxin; the other strains were not toxigenic. Patients with dysentery due to Shigella dysenteriae type 1 excreted higher concentrations of leukotriene C4 (median, 3,234 pg/0.05 g of feces) than either ill individuals infected with non-dysenteriae Shigellae (median, 202 pg/0.05 g) or healthy carriers (median, 145 pg/0.05 g) and uninfected controls (median, 129 pg/0.05 g). We propose that Shiga toxin stimulates intestinal mast cells, which release leukotriene C4, contributing to the inflammatory response in Shigella dysenteriae type 1-associated dysentery. | Matsumoto S, Hayashi Y, Kinoshita I, Ikata T, Yamamoto S (1993)
Immunoaffinity purification of prostaglandin E2 and leukotriene C4 prior to radioimmunoassay: application to human synovial fluid.
Annals of clinical biochemistry 30 ( Pt 1), 60-68 [PubMed:8434868]
[show Abstract]
When human synovial fluid as such was subjected to radioimmunoassays of prostaglandin E2 (PGE2) and leukotriene C4 (LTC4), there was no linear increase in PGE2 and LTC4 as the amount of synovial fluid was raised. For removal of substances thus disturbing the assay we developed a method of immunoaffinity purification of PGE2 and LTC4. A monoclonal antibody against PGE2 or LTC4 was coupled to BrCN-activated Sepharose 4B. When synovial fluid mixed with radiolabelled PGE2 or LTC4 was applied to the column of immobilized antibody, the ligand was adsorbed to the column and eluted with a mixture of methanol/water in a recovery of about 80%. The purified material showed a linearity between the amount of the sample and the value of radioimmunoassay. The one-step method was applied to synovial fluid from patients with rheumatoid arthritis, osteoarthritis and other joint diseases. | Aktan S, Aykut C, Yegen BC, Okar I, Ozkutlu U, Ercan S (1993)
The effect of nordihydroguaiaretic acid on leukotriene C4 and prostaglandin E2 production following different reperfusion periods in rat brain after forebrain ischemia correlated with morphological changes.
Prostaglandins, leukotrienes, and essential fatty acids 49, 633-641 [PubMed:8415814]
[show Abstract]
Leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) are the 5-lipoxygenase and cyclooxygenase metabolites of arachidonic acid (AA). They constrict blood vessels and enhance vascular permeability inducing vasogenic edema that may hurt the ischemic penumbra after cerebral ischemia and reperfusion. Nordihydroguaiaretic acid (NDGA) is known as the most potent inhibitor of 5-lipoxygenase in different tissues. Furthermore, it has considerable inhibitory activity against cyclooxygenase. In this study, after developing a global ischemic model in the rat, the levels of LTC4 and PGE2 in the forebrain were measured, following different reperfusion periods after 10 min ischemia including 8 rats for each reperfused group. Sham operations were performed for each corresponding control group (n = 8). AA metabolites were then correlated with neuropathological findings. In the combined reperfused groups both metabolites increased significantly when compared with 10 min, ischemic group (P < 0.05). In the 8 min reperfused group, PGE2 and LTC4 increased significantly compared with each corresponding control group (P < 0.005). These mediators also increased to high levels compared with the 4 min reperfused group (P < 0.05, P < 0.005). PGE2 and LTC4 were reduced significantly at the 15th and 60th min of reperfusion compared with the 8 min reperfused group (P < 0.05, P < 0.005). NDGA (0.1 mg/kg) reduced both metabolites in the 8 min reperfused group significantly (P < 0.05). Brain cortex specimens were taken for light and electromicroscopical investigations. No significant differences were noted between the structural changes in the 4, 8 and 15 min of reperfusion and NDGA administered groups.(ABSTRACT TRUNCATED AT 250 WORDS) | De Servi S, Ricevuti G, Mazzone A, Pasotti D, Bramucci E, Angoli L, Specchia G (1991)
Transcardiac release of leukotriene C4 by neutrophils in patients with coronary artery disease.
Journal of the American College of Cardiology 17, 1125-1128 [PubMed:2007712]
[show Abstract]
Leukotriene C4 is a potent constrictor of smooth muscle in vitro and may induce coronary vasoconstriction in vivo. To study leukotriene C4 release by neutrophils in patients with coronary artery disease, neutrophils were separated from blood samples taken from the coronary sinus and aorta in 20 patients with stable exertional angina and angiographically documented coronary artery narrowings (group I). Eight patients with normal coronary arteries were also studied (group II). To assess leukotriene C4 generation, neutrophils were incubated with calcium ionophore A 23187 (0.25 microM) and the supernatants obtained after centrifugation were analyzed for leukotriene C4 by radioimmunoassay. Patients in group I had a significantly lower release of leukotriene C4 from neutrophils separated from the coronary sinus blood than from those separated from aortic blood (4.33 +/- 0.69 versus 5.92 +/- 0.54 ng/ml, p less than 0.025), whereas patients in group II had a similar release of leukotriene C4 by the neutrophils separated from coronary sinus blood and from aortic blood (6.0 +/- 0.72 versus 6.4 +/- 0.66 ng/ml, p = NS). Moreover, in group I patients, a significant correlation was found (p less than 0.01) between the extent of coronary artery disease (expressed by the Leaman coronary score) and the percent reduction in leukotriene C4 released from neutrophils separated from coronary sinus blood as compared with leukotriene C4 produced by neutrophils separated from aortic blood. These data show that neutrophils from patients with coronary artery disease have a reduced ability to produce leukotriene C4 after stimulation by calcium ionophore A 23187.(ABSTRACT TRUNCATED AT 250 WORDS) | Zijlstra FJ, Wilson JH (1991)
15-HETE is the main eicosanoid present in mucus of ulcerative proctocolitis.
Prostaglandins, leukotrienes, and essential fatty acids 43, 55-59 [PubMed:1652771]
[show Abstract]
Prostaglandins, leukotrienes and mono-hydroxy acid products of arachidonic acid were measured in mucus of freshly recovered morning stools of a patient with an exacerbation of ulcerative proctocolitis. Eicosanoids in ether extracts were separated by high performance liquid chromatography and amounts determined by radioimmunoassay. Four hydroxy-eicosatetraenoic acids were detected, of which the most important one was identified as 15-hydroxy eicosatetraenoic acid (530 ng/g mucus). Leukotriene B4 was also present (21 ng/g mucus) and small amounts of immunoreactive leukotriene C4 (less than 0.8 ng/g mucus). The prostaglandins 6-keto-PGF1 alpha and PGE2 and thromboxane B2 were found in amounts of 3.7, 2.0 and 9.2 ng/g mucus, respectively. | Kloprogge E, de Leeuw AJ, de Monchy JG, Kauffman HF (1989)
Cellular communication in leukotriene C4 production between eosinophils and neutrophils.
International archives of allergy and applied immunology 90, 20-23 [PubMed:2509375]
[show Abstract]
Eosinophilic granulocytes as well as neutrophilic granulocytes produced leukotriene C4 (LTC4) on stimulation with 1 microM A23187 (Ca2+ ionophore). In healthy volunteers, the LTC4 production in eosinophils was about 3 times the production in neutrophils. Within 15 min greater than 90% of the LTC4 was released into the supernatant. Stimulation of eosinophils and neutrophils together resulted in a synergistic increase in LTC4 production of 306 +/- 40%. LTC4 synthesis by hypodense eosinophils was also enhanced if stimulated in the presence of neutrophils. These findings suggest a communication between eosinophils and neutrophils, which may play a role in bronchial asthma. | Schauer U, Eckhart A, Müller R, Gemsa D, Rieger CH (1989)
Enhanced leukotriene C4 production by peripheral eosinophilic granulocytes from children with asthma.
International archives of allergy and applied immunology 90, 201-206 [PubMed:2512259]
[show Abstract]
Granulocytes and mononuclear cells were isolated from the blood of asthmatic and healthy children. Stimulation with ionophore A 23187 induced a significantly higher leukotriene C4 (LTC4) generation from granulocytes of asthmatic children than from granulocytes of healthy controls. In contrast, mononuclear cells from patients and controls did not differ in their ability to produce LTC4. Additional analysis showed that the difference in LTC4 generation of granulocytes was due to increased formation but not to decreased oxidative degradation of LTC4. Analysis of LTC4 generation of purified neutrophils and eosinophils revealed that LTC4 was generated almost exclusively by eosinophils and, in particular, the hypodense population. Granulocytes from patients with a history of severe asthma displayed a higher LTC4 formation than granulocytes from patients with less severe disease. | Sawazaki Y (1989)
[Leukotriene B4, leukotriene C4 and prostaglandin E2 in the serum, synovial fluid and synovium in patients with rheumatoid arthritis].
Nihon Ika Daigaku zasshi 56, 559-564 [PubMed:2558123]
[show Abstract]
This study investigated the presence of arachidonic acid metabolites, (leukotriene B4, leukotriene C4 and prostaglandin E2) in the serum, synovial fluid and synovium of rheumatoid arthritis patients (RA). We obtained the serum, synovial fluid and synovium from 16 female patients with RA during knee operations. Leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) were detected by RIA analysis. In the patients administered steroids, a positive correlation was found between the concentrations of LTB4 and PGE2 in the synovium. In the patients not administered steroids, significant correlations were found between the concentrations of LTB4 in the synovium and serum, and also between the concentrations of LTB4 and LTC4 in the synovium. The levels of immunoglobulins and LTB4 in the serum were determined and a significant correlation was found between the content of IgG and the concentration of LTB4. In the serum, the concentration of LTB4 was elevated in RA patients relative to the control normal subjects, and the difference was statistically significant. In conclusion, these data suggest that LTB4 in the serum reflects the concentration of LTB4 in the synovium. | Sternfeld M, Fink A, Bentwich Z, Eliraz A (1989)
The role of acupuncture in asthma: changes in airways dynamics and LTC4 induced LAI.
The American journal of Chinese medicine 17, 129-134 [PubMed:2633615]
[show Abstract]
A cohort of nine extrinsic asthma patients were treated by means of acupuncture. Patients were followed up for changes in medical treatment, spirometry, skin reactivity to immediate type reactions, total serum IgE levels and reactivity of their leukocytes to leukotriene C4 challenge (LTC4 induced leukocyte adherence inhibition (LAI) assay). Our results show that after acupuncture, treated patients were able to reduce bronchodilator and taper completely corticosteroid therapy. No change in skin reactivity or in IgE levels were noted. However, acupuncture treatment was able to negate, in 66.6%, the positive LTC4 induced responses. | Romero R, Wu YK, Mazor M, Hobbins JC, Mitchell MD (1988)
Increased amniotic fluid leukotriene C4 concentration in term human parturition.
American journal of obstetrics and gynecology 159, 655-657 [PubMed:3421265]
[show Abstract]
The purpose of this study was to determine whether parturition is associated with changes in the amniotic fluid concentration of leukotriene C4, an arachidonate lipoxygenase metabolite. Amniotic fluid was collected from 36 women not in labor and from 30 women in active labor with cervical dilation of greater than or equal to 6 cm. The concentration of leukotriene C4 was determined by radioimmunoassay. The median amniotic fluid concentration of leukotriene C4 was greater in laboring women than in nonlaboring women: 121 pg/ml (range, 52 to 261 pg/ml) versus 73.5 pg/ml (range, 6 to 249 pg/ml), respectively (p = 0.0008). These data are consistent with activation of the lipoxygenase pathway during spontaneous parturition at term. | Paoletti P, Gaetani P, Grignani G, Pacchiarini L, Silvani V, Rodriguez y Baena R (1988)
CSF leukotriene C4 following subarachnoid hemorrhage.
Journal of neurosurgery 69, 488-493 [PubMed:3418380]
[show Abstract]
Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage. | Angi MR, Bettero A, Filippi F, Salvalaio L, Benassi CA (1987)
[Quantitative evaluation of conjunctival irritation by simultaneous determination of histamine, serotonin and leukotriene C4 in tears].
Ophtalmologie : organe de la Societe francaise d'ophtalmologie 1, 509-511 [PubMed:3153930] | Talbot SF, Atkins PC, Goetzl EJ, Zweiman B (1985)
Accumulation of leukotriene C4 and histamine in human allergic skin reactions.
The Journal of clinical investigation 76, 650-656 [PubMed:2411760]
[show Abstract]
To determine whether lipoxygenase products of arachidonic acid metabolism are released in vivo during human allergic cutaneous reactions, we serially assayed chamber fluid placed over denuded skin sites for the presence of both C-6 peptide leukotrienes (e.g., LTC4, LTD4, and LTE4) and leukotriene B4 (LTB4), using radioimmune assay and HPLC separation, and compared it to histamine (assayed radioenzymatically) in 13 atopic and two nonatopic volunteers. Skin chamber sites challenged with ragweed or grass pollen antigen (250-750 protein nitrogen units/ml) for the first hour and phosphate-buffered saline (PBS) for the next 3 h were assayed hourly and compared to sites challenged with PBS alone. As assessed by HPLC, LTC4 composed greater than 85% of the C-6 peptide leukotriene released at any skin site, whereas little LTD4 or LTE4 was detected. LTC4 was present in significantly greater concentrations at antigen sites as compared to PBS-challenged sites throughout the 4-h period. Minimal concentrations of LTB4 were found throughout this time period and were not different at antigen or PBS sites. Histamine was present in significantly greater concentrations at antigen rather than PBS sites, but the pattern of release was different from that of LTC4. Peak histamine release invariably occurred during the first hour and decreased progressively thereafter, whereas the greatest amounts of LTC4 were detected during the 2nd to 4th hours. The amount of LTC4 accumulating at the site was dependent upon the dosage of antigen used in the epicutaneous challenge. We have demonstrated in this study that of the leukotrienes assessed LTC4 is released in the greatest quantity in situ during in vivo allergic cutaneous reactions and that it is present at such sites for at least 4 h after antigen challenge. Since intradermal injection of LTC4 in humans induces wheal and flare responses that persist for hours, our findings support the hypothesis that LTC4 is an important mediator of human allergic skin reactions. | Pönicke K, Förster W (1984)
Influence of leukotriene C4 on aggregation and on malondialdehyde formation of human blood platelets.
Biomedica biochimica acta 43, S459-62 [PubMed:6440558]
[show Abstract]
The effect of leukotriene C4 on arachidonic acid-induced aggregation and on malondialdehyde formation of human blood platelets was studied. LTC4 (7.2 - 48.3 mumol . 1(-1] inhibited the platelet aggregation in a dose-dependent manner (IC50: 30 mumol . 1(-1]. LTC4 prolonged the lag phase between addition of arachidonic acid and onset of aggregation. Simultaneously the malondialdehyde formation was enhanced by LTC4. By using high doses of LTC4 the malondialdehyde formation was nearly complete at the beginning of the delayed platelet aggregation. |
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