Inhibition of neutrophil leukotriene B4 production by a novel synthetic N-3 polyunsaturated fatty acid analogue, beta-oxa 21:3n-3.
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.
Department of Immunopathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Brenton S
BS
Robinson
Deborah A
DA
Rathjen
Neil A
NA
Trout
Christopher J
CJ
Easton
Antonio
A
Ferrante
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002788:Cholesterol Esters; D004075:Diglycerides; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D010743:Phospholipids; C439390:beta-Oxa 21-3n-3 fatty acid; D007975:Leukotriene B4; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase