![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
JD Winkler, AN Fonteh, CM Sung, JD Heravi, AB Nixon, M Chabot-Fletcher, D Griswold, LA Marshall and FH Chilton
Division of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
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.
This article has been cited by other articles:
|
|
 |
|
  A. J. Tonks, A. Tonks, R. H. K. Morris, K. P. Jones, and S. K. Jackson Regulation of platelet-activating factor synthesis in human monocytes by dipalmitoyl phosphatidylcholine J. Leukoc. Biol., July 1, 2003; 74(1): 95 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Winkler, C.-M. Sung, M. Chabot-Flecher, D. E. Griswold, L. A. Marshall, F. H. Chilton, W. Bondinell, and R. J. Mayer beta -Lactams SB 212047 and SB 216754 Are Irreversible, Time-Dependent Inhibitors of Coenzyme A-Independent Transacylase Mol. Pharmacol., February 1, 1998; 53(2): 322 - 329. [Abstract] [Full Text]
|
|
|
|
 |
|
 L. A. Marshall, B. Bolognese, J. D. Winkler, and A. Roshak Depletion of Human Monocyte 85-kDa Phospholipase A2 Does Not Alter Leukotriene Formation J. Biol. Chem., January 10, 1997; 272(2): 759 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Boilard and M. E. Surette Anti-CD3 and Concanavalin A-induced Human T Cell Proliferation Is Associated with an Increased Rate of Arachidonate-Phospholipid Remodeling. LACK OF INVOLVEMENT OF GROUP IV AND GROUP VI PHOSPHOLIPASE A2 IN REMODELING AND INCREASED SUSCEPTIBILITY OF PROLIFERATING T CELLS TO CoA-INDEPENDENT TRANSACYLASE INHIBITOR-INDUCED APOPTOSIS J. Biol. Chem., May 11, 2001; 276(20): 17568 - 17575. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
