Lipoxin A4
From DrugPedia: A Wikipedia for Drug discovery
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| Lipoxin A4
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| Systematic (IUPAC) name | |
| (5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid | |
| Identifiers | |
| CAS number | |
| ATC code | ? |
| PubChem | |
| Chemical data | |
| Formula | C20H32O5 |
| Mol. mass | 352.47 |
| SMILES | & |
| Synonyms | LXA4 |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
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| Legal status | |
| Routes | ? |
Lipoxins are a series of anti-inflammatory mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation. They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4).
Contents |
[edit] General Properties
*Molecular Weight
352.47
*Molecular Formula
C20H32O5
*IUPAC NAME
(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid
*Canonical Smiles
CCCCCC(C=CC=CC=CC=CC(C(CCCC(=O)O)O)O)O
*Isomeric Smiles
CCCCC[C@@H](C=CC=C/C=C/C=C/[C@H]([C@H](CCCC(=O)O)O)O)O
[edit] PhysioChemical Properties
*Melting Point
*LogP
*Water Solubility
[edit] History
Lipoxins were first described by Serhan, Hamberg and Samuelsson in 1984.<ref name=Serhan /> They reported that the lipoxins stimulated superoxide anion (O2−) generation and degranulation at submicromolar concentrations—as potent as LTB4.
[edit] Biosynthesis
Lipoxins are derived enzymatically from arachidonic acid, an ω-6 fatty acid. An analogous class, the resolvins, is derived from EPA and DHA, ω-3 fatty acids.<ref name=Serhan>Template:Cite web Original description of lipoxins.</ref> Another analogous class, the epi-lipoxins, is formed by non-enzymatic peroxidation.
[edit] Biological activity
Lipoxins, as well as certain peptides, are high affinity ligands for the lipoxin A4 receptor (LXA4R), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the LXA4R inhibits chemotaxis, transmigration, superoxide generation and NF-κB activation.<ref name=Chiang>Template:Cite web </ref>
Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization.<ref name=Chiang /> The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase proteins, bacterial peptides, HIV envelope proteins and neurotoxic peptides.
Similarly to the leukotrienes, LXA4 will form the cysteinyl-lipoxins LXC4, LXD4 and LXE4.<ref name="pmid7706749">Powell WS, Chung D, Gravel S (1995). "5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration". J. Immunol. 154 (8): 4123–32. PMID 7706749.</ref> At subnanomolar concentrations, LXA4 and LXB4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.<ref name="pmid8690917">Papayianni A, Serhan CN, Brady HR (1996). "Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells". J. Immunol. 156 (6): 2264–72. PMID 8690917. Retrieved on 2007-11-01.</cite></ref>
Lipoxins are high affinity antagonists to the cysteinyl leukotriene receptor type 1 (CysLT1) to which several leukotrienes (LTC4, LTD4 and LTE4) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug montelukast (Singulair).<ref name=Drazen><cite style="font-style:normal">Drazen J., Israel E., and O'Byrne P. (1999). "Treatment of Asthma with Drugs Modifying the Leukotriene Pathway". PMID 9895400. Retrieved on 2006-04-28.</cite></ref>
[edit] In resolution
During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis).<ref name="pmid12239238"><cite style="font-style:normal">Mitchell S, Thomas G, Harvey K, et al (2002). "Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo". J. Am. Soc. Nephrol. 13 (10): 2497–507. doi:. PMID 12239238.</cite></ref> During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4, which promote the resolution phase of inflammation.<ref name=McMahon>Template:Cite web Invited review article.</ref>
[edit] Lipoxin analogues
Stable synthetic analogues of LXs and aspirin-triggered 15-epi-LXA4s (ATLs) can mimic many of the desirable anti-inflammatory, "pro-resolution" actions of native LXs.<ref name="pmid11478982"><cite style="font-style:normal">McMahon B, Mitchell S, Brady HR (2001). "Lipoxins: revelations on resolution". Trends Pharmacol. Sci. 22 (8): 391–5. doi:. PMID 11478982.</cite></ref>
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