Inhibition of neutrophil leukotriene B4 production by a novel synthetic N-3 polyunsaturated fatty acid analogue, beta-oxa 21:3n-3

• Published in: The Journal of immunology (1950) Vol. 171; no. 9; pp. 4773 - 4779
• Main Authors: Robinson, Brenton S, Rathjen, Deborah A, Trout, Neil A, Easton, Christopher J, Ferrante, Antonio
• Format: Journal Article
• Language: English
• Published: United States 01.11.2003
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arachidonate 5-Lipoxygenase - metabolism; Calcimycin - pharmacology; Cholesterol Esters - metabolism; Diglycerides - metabolism; Enzyme Inhibitors - pharmacology; Fatty Acids, Unsaturated - metabolism; Fatty Acids, Unsaturated - pharmacology; Humans; Hydroxyeicosatetraenoic Acids - antagonists & inhibitors; Hydroxyeicosatetraenoic Acids - biosynthesis; Leukotriene B4 - antagonists & inhibitors; Leukotriene B4 - biosynthesis; Lipoxygenase Inhibitors; Neutrophil Activation - drug effects; Neutrophils - drug effects; Neutrophils - enzymology; Neutrophils - immunology; Neutrophils - metabolism; Phospholipids - metabolism
• ISSN: 0022-1767
• DOI: 10.4049/jimmunol.171.9.4773

We recently reported the synthesis and anti-inflammatory properties of a novel long chain polyunsaturated fatty acid (PUFA) with an oxygen atom in the beta-position, beta-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 beta-oxa-PUFA substantially depresses the production of leukotriene B(4) (LTB(4)) in response to calcium ionophore, A23187, comparable to standard leukotriene inhibitors such as zileuton and nordihydroguaiaretic acid. Interestingly, the n-6 equivalent, beta-oxa 21:3 n-6, is also a strong inhibitor of LTB(4) 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 LTB(4). The parent beta-oxa-21:3n-3 molecule, rather than its derivatives (methyl ester, saturated, monohydroperoxy, or monohydroxy forms), is exclusively responsible for attenuation of LTB(4) formation. beta-Oxa-21:3n-3 inhibits the conversion of [(3)H]20:4n-6 to [(3)H]5-hydroxyeicosatetraenoic acid and [(3)H]LTB(4) by neutrophils in the presence of calcium ionophore and also suppresses the activity of purified 5-lipoxygenase, but not cyclooxygenase 1 and 2. Beta-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 beta-oxa-21:3n-3 to a 16-monohydroxy-beta-oxa-21:3n-3 derivative. After administration to rodents by gavage or i.p. injection, beta-oxa-21:3n-3 is found to be incorporated into the lipids of various tissues. Thus, beta-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.