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 sub classes, and we have shown that two inhibitors of CoA-IT (SK&F 98625 a nd SK&F 45905) block this movement. In this report, we use these inhib itors to further characterize the role of CoA-IT in the production of lipid mediators. SK&F 98625 (diethyl oxo-2,3-dihydro-imidazol-1-yl)hep tane-phosphonate) and SK&F 45905 -3-trifluoromethylphenyl)ureido]-4-tr ifluoromethyl phenoxy]-4,5-dichlorobenzenesulfonic acid) inhibited CoA -IT activity (IC50 values of 9 mu M and 6 mu M, respectively). Neither compound had any effect on cyclooxygenase, 14-kDa PLA(2) or acetyltra nsferase activities at concentrations below 20 mu M. However, SK&F 459 05 inhibited 85-kDa PLA, activity (IC50 = 3 mu M), and both compounds inhibited 5-lipoxygenase activity (IC50 values of 2-4 mu M). In ionoph ore-stimulated neutrophils, SK&F 98625 and SK&F 45905 blocked the libe ration of arachidonic acid from phospholipids, which suggests that the movement of arachidonate into specific phospholipid pools is a prereq uisite for release. Both compounds also inhibited the production of pl atelet-activating factor in ionophore-stimulated neutrophils and antig en-stimulated mast cells. This inhibition of platelet-activating facto r and arachidonic acid release was not mimicked by an inhibitor of 5-l ipoxygenase, 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 sever al inflammatory cells and to block signs of inflammation in ears of ph orbol ester-challenged mice. Taken together, these results show that b lockade of CoA-IT, which leads to inhibition of arachidonate remodelin g between phospholipids, results in the attenuation of platelet-activa ting factor production, arachidonic acid release and the formation of eicosanoid products.