Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators.
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.
Winkler
J D
JD
Division of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Fonteh
A N
AN
Sung
C M
CM
Heravi
J D
JD
Nixon
A B
AB
Chabot-Fletcher
M
M
Griswold
D
D
Marshall
L A
LA
Chilton
F H
FH
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids / Q000096:biosynthesis*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C093344:2-(2-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-4-(trifluoromethyl)phenoxy)-4,5-dichlorobenzenesulfonic acid; D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D018836:Inflammation Mediators; D009943:Organophosphorus Compounds; D010743:Phospholipids; C093303:SK&F 98625; D014508:Urea; D000217:Acyltransferases; C039766:arachidonyl transacylase; D010741:Phospholipases A; D054467:Phospholipases A2