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Inhibition of Neutrophil Leukotriene B₄ Production by a Novel Synthetic N-3 Polyunsaturated Fatty Acid Analogue, -Oxa 21:3n-3 ¹

Brenton S. Robinson^*, Deborah A. Rathjen^2,*,||, Neil A. Trout^*,, Christopher J. Easton^¶ and Antonio Ferrante^3,*,,

^* Department of Immunopathology, Women’s and Children’s Hospital, North Adelaide, South Australia, Australia; and Department of Pediatrics, University of Adelaide, South Australia, Australia; School of Pharmaceutical, Molecular and Biosciences, University of South Australia, Australia; Department of Chemistry, Flinders University of South Australia, Bedford Park, South Australia, Australia; ^¶ Research School of Chemistry, Australian National University, Canberra, Australian Capital Territory, Australia; and ^|| Peptech Ltd., North Ryde, New South Wales, Australia

We recently reported the synthesis and anti-inflammatory properties of a novel long chain polyunsaturated fatty acid (PUFA) with an oxygen atom in the -position, -oxa-21:3 n-3 (Z,Z,Z)-(octadeca-9,12,15-trienyloxy) acetic acid). Our data, from studies aimed at elucidating the mechanism of its action, show that pretreatment of human neutrophils with the -oxa-PUFA substantially depresses the production of leukotriene B₄ (LTB₄) in response to calcium ionophore, A23187, comparable to standard leukotriene inhibitors such as zileuton and nordihydroguaiaretic acid. Interestingly, the n-6 equivalent, -oxa 21:3 n-6, is also a strong inhibitor of LTB₄ production. In contrast, naturally occurring PUFA only slightly reduce, for eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids, or increase, for arachidonic acid (20:4n-6), the formation of LTB₄. The parent -oxa-21:3n-3 molecule, rather than its derivatives (methyl ester, saturated, monohydroperoxy, or monohydroxy forms), is exclusively responsible for attenuation of LTB₄ formation. -Oxa-21:3n-3 inhibits the conversion of [³H]20:4n-6 to [³H]5-hydroxyeicosatetraenoic acid and [³H]LTB₄ by neutrophils in the presence of calcium ionophore and also suppresses the activity of purified 5-lipoxygenase, but not cyclooxygenase 1 and 2. -Oxa-21:3n-3 is taken up by neutrophils and incorporated into phospholipids and neutral lipids. In the presence of calcium ionophore, the leukocytes convert a marginal amount of -oxa-21:3n-3 to a 16-monohydroxy--oxa-21:3n-3 derivative. After administration to rodents by gavage or i.p. injection, -oxa-21:3n-3 is found to be incorporated into the lipids of various tissues. Thus, -oxa-21:3n-3 has the potential to be used in the treatment of inflammatory diseases, which are mediated by products of the lipoxygenase pathway.

This article has been cited by other articles:

				M. Costabile, C. S. T. Hii, M. Melino, C. Easton, and A. Ferrante The Immunomodulatory Effects of Novel {beta}-Oxa, {beta}-Thia, and {gamma}-Thia Polyunsaturated Fatty Acids on Human T Lymphocyte Proliferation, Cytokine Production, and Activation of Protein Kinase C and MAPKs J. Immunol., January 1, 2005; 174(1): 233 - 243. [Abstract] [Full Text] [PDF]