Linked Life Data

7562506

Source:http://linkedlifedata.com/resource/pubmed/id/7562506

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1995-10-25
pubmed:abstractText
The enzyme CoA-independent transacylase (CoA-IT) has been proposed to mediate the movement of arachidonate between specific phospholipid subclasses, and we have shown that two inhibitors of CoA-IT (SK&F 98625 and SK&F 45905) block this movement. In this report, we use these inhibitors to further characterize the role of CoA-IT in the production of lipid mediators. SK&F 98625 (diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydro-imidazol-1-yl)heptane- phosphonate) and SK&F 45905 [2(-)[3-(4-chloro-3-trifluoromethylphenyl)ureido]-4-trifluoromethyl phenoxy]-4,5-dichlorobenzenesulfonic acid) inhibited CoA-IT activity (IC50 values of 9 microM and 6 microM, respectively). Neither compound had any effect on cyclooxygenase, 14-kDa PLA2 or acetyltransferase activities at concentrations below 20 microM. However, SK&F 45905 inhibited 85-kDa PLA2 activity (IC50 = 3 microM), and both compounds inhibited 5-lipoxygenase activity (IC50 values of 2-4 microM). In ionophore-stimulated neurotrophils, SK&F 98625 and SK&F 45905 blocked the liberation of arachidonic acid from phospholipids, which suggests that the movement of arachidonate into specific phospholipid pools is a prerequisite for release. Both compounds also inhibited the production of platelet-activating factor in ionophore-stimulated neutrophils and antigen-stimulated mast cells. This inhibition of platelet-activating factor and arachidonic acid release was not mimicked by an inhibitor of 5-lipoxygenase, zileuton, which indicates that the primary mode of action of SK&F 98625 and SK&F 45905 is via inhibition of CoA-IT. SK&F 98625 and SK&F 45905 were able to decrease prostaglandin production in several inflammatory cells and to block signs of inflammation in ears of phorbol ester-challenged mice. Taken together, these results show that blockade of CoA-IT, which leads to inhibition of arachidonate remodelling between phospholipids, results in the attenuation of platelet-activating factor production, arachidonic acid release and the formation of eicosanoid products.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/2-(2-(3-(4-chloro-3-(trifluoromethyl..., http://linkedlifedata.com/resource/pubmed/chemical/Acyltransferases, http://linkedlifedata.com/resource/pubmed/chemical/Benzenesulfonates, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles, http://linkedlifedata.com/resource/pubmed/chemical/Inflammation Mediators, http://linkedlifedata.com/resource/pubmed/chemical/Organophosphorus Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Phospholipases A, http://linkedlifedata.com/resource/pubmed/chemical/Phospholipases A2, http://linkedlifedata.com/resource/pubmed/chemical/Phospholipids, http://linkedlifedata.com/resource/pubmed/chemical/SK&F 98625, http://linkedlifedata.com/resource/pubmed/chemical/Urea, http://linkedlifedata.com/resource/pubmed/chemical/arachidonyl transacylase
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
274
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1338-47
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators.
pubmed:affiliation
Division of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.