Document Detail


Arachidonate-derived dihomoprostaglandin production observed in endotoxin-stimulated macrophage-like cells.
MedLine Citation:
PMID:  17135246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Eicosanoids, including the prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids, epoxyeicosatetraenoic acids, and related compounds, are biosynthetic, bioactive mediators derived from arachidonic acid (AA), a 20:4(n-6) fatty acid. We have developed a comprehensive and sensitive mass spectral analysis to survey eicosanoid release from endotoxin-stimulated RAW 264.7 macrophage-like cells that is capable of detecting over 70 diverse eicosanoids and eicosanoid metabolites, should they be present. We now address the question: Are biologically significant eicosanoids being overlooked? Herein, we illustrate a general approach to diverse isotope metabolic profiling of labeled exogenous substrates using mass spectrometry (DIMPLES/MS), demonstrated for one substrate (AA) and its resultant products (eicosanoids). RAW cells were incubated in medium supplemented with deuterium-labeled AA. When the cells are stimulated, two sets of eicosanoids are produced, one from endogenous AA and the other from the supplemented (exogenous) deuterium-labeled form. This produces a signature mass spectral "doublet" pattern, allowing for a comprehensive and diverse eicosanoid search requiring no previous knowledge or assumptions as to what these species may be, in contrast to traditional methods. We report herein observing unexpected AA metabolites generated by the cells, some of which may constitute novel bioactive eicosanoids or eicosanoid inactivation metabolites, as well as demonstrating differing metabolic pathways for the generation of isomeric prostaglandins and potential peroxisome proliferator-activated receptor activators. Unexpectedly, we report observing a series of 1a, 1b-dihomologue prostaglandins, products of adrenic acid (22:4(n-6)), resulting from the two-carbon elongation of AA by the RAW cells.
Authors:
Richard Harkewicz; Eoin Fahy; Alexander Andreyev; Edward A Dennis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-11-29
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-29     Completed Date:  2007-04-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2899-910     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0601, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Arachidonic Acids / metabolism*
Cell Line
Deuterium
Dinoprost / analogs & derivatives*,  metabolism
Dinoprostone / analogs & derivatives*,  metabolism
Eicosanoids / metabolism
Endotoxins / pharmacology*
Epoprostenol / analogs & derivatives*,  metabolism
Kinetics
Macrophages / drug effects,  metabolism*
Mass Spectrometry
Mice
Prostaglandins / metabolism*
Software
Grant Support
ID/Acronym/Agency:
GM069338/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Arachidonic Acids; 0/Eicosanoids; 0/Endotoxins; 0/Prostaglandins; 26198-80-1/1a,1b-dihomoprostaglandin E2; 35121-78-9/Epoprostenol; 363-24-6/Dinoprostone; 551-11-1/Dinoprost; 57944-39-5/1a,1b-dihomoprostaglandin F2; 7782-39-0/Deuterium; 99286-22-3/dihomo-prostaglandin I(2)
Comments/Corrections
Erratum In:
J Biol Chem. 2007 Sep 28;282(39):29068

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