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Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators.

Publication ,  Journal Article
Winkler, JD; Fonteh, AN; Sung, CM; Heravi, JD; Nixon, AB; Chabot-Fletcher, M; Griswold, D; Marshall, LA; Chilton, FH
Published in: J Pharmacol Exp Ther
September 1995

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.

Duke Scholars

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

September 1995

Volume

274

Issue

3

Start / End Page

1338 / 1347

Location

United States

Related Subject Headings

  • Urea
  • Phospholipids
  • Phospholipases A2
  • Phospholipases A
  • Pharmacology & Pharmacy
  • Organophosphorus Compounds
  • Mice, Inbred CBA
  • Mice
  • Inflammation Mediators
  • Inflammation
 

Citation

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ICMJE
MLA
NLM
Winkler, J. D., Fonteh, A. N., Sung, C. M., Heravi, J. D., Nixon, A. B., Chabot-Fletcher, M., … Chilton, F. H. (1995). Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators. J Pharmacol Exp Ther, 274(3), 1338–1347.

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

September 1995

Volume

274

Issue

3

Start / End Page

1338 / 1347

Location

United States

Related Subject Headings

  • Urea
  • Phospholipids
  • Phospholipases A2
  • Phospholipases A
  • Pharmacology & Pharmacy
  • Organophosphorus Compounds
  • Mice, Inbred CBA
  • Mice
  • Inflammation Mediators
  • Inflammation