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

Abstract

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.

• Authors: J D Winkler, A N Fonteh, C M Sung, J D Heravi, A B Nixon, M Chabot-Fletcher, D Griswold, L A Marshall, F H Chilton
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 274 Issue 3 Pg. 1338-47 (Sep 1995) ISSN: 0022-3565 [Print] United States
• PMID: 7562506 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-4-(trifluoromethyl)phenoxy)-4,5-dichlorobenzenesulfonic acid
• Benzenesulfonates
• Enzyme Inhibitors
• Imidazoles
• Inflammation Mediators
• Organophosphorus Compounds
• Phospholipids
• SK&F 98625
• Urea
• Acyltransferases
• arachidonyl transacylase
• Phospholipases A
• Phospholipases A2

Topics

• Acyltransferases (antagonists & inhibitors)
• Animals
• Benzenesulfonates (pharmacology)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Inflammation (metabolism)
• Inflammation Mediators (metabolism)
• Mice
• Mice, Inbred CBA
• Organophosphorus Compounds (pharmacology)
• Phospholipases A (antagonists & inhibitors, metabolism)
• Phospholipases A2
• Phospholipids (biosynthesis)
• Urea (analogs & derivatives, pharmacology)