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5-Oxo-eicosatetraenoic acid (5-oxo-6''E'',8''Z'',11''Z'',14''Z''-eicosatetraenoate or 5-oxo-ETE; some early studies termed it 5-KETE (K for its 5-Ketone, i.e. 5-oxo, residue) is the most potent naturally occurring member of the 5-HETE family of arachidonic acid metabolites; these metabolites stimulate a variety of cell types including particularly the human eosinophil by binding to the OXER1 receptor.〔Biochim Biophys Acta. 2015 Apr;1851(4):340-55. doi: 10.1016/j.bbalip.2014.10.008〕 Preclinical studies suggest that 5-oxo-ETE may be a mediator of human allergy and/or certain inflammatory and non-inflammatory pathophysiological responses.〔Biochim Biophys Acta. 2015 Apr;1851(4):340-55. doi: 10.1016/j.bbalip.2014.10.008. Epub 2014 Oct 29. Review.〕〔Prog Lipid Res. 2013 Oct;52(4):651-65. doi: 10.1016/j.plipres.2013.09.001〕〔Biochem Pharmacol. 2015 Aug 1;96(3):247-55. doi: 10.1016/j.bcp.2015.05.009〕 == 5-Oxo-ETE production == Cells make 5-oxo-ETE by a) oxygenating arachidonic acid with arachidonate 5-lipoxygenase (ALOX5) to form 5(''S'')-hydroperoxy-eicosatetraenoic acid (5(''S'')-HpETE); b) reducing 5(''S'')-HpETE with cellular peroxidases to form 5(''S'')-hydroxy-eicosatetraeonic acid (5(''S'')-HETE), and (c) oxidizing 5(''S'')-HETE with microsome-bound nicotinamide adenine dinucleotide phosphate (NADP+)-dependent dehydrogenase (5-Hydroxyeicosanoid dehydrogenase or 5-HEDH) to form 5-oxo-ETE (see 5-HETE). (5-HEDH has little or no such effect on the ''R'' stereoisomer of 5(''S'')-HETE viz., 5(''R'')-HETE.) 5-Oxo-ETE can also be made form either 5(''S'')-HpETE (and possibly 5(''R'')-HpEPE) by the action of cytochrome P450 (CYP) enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2S1.; from 5(''S'')-HETE (and probably 5(''R'')-HETE) by the non-enzymatic attack with heme or various other dehydrating agents; and from the conversion of 5-(''S'')-HpETE and 5(''R'')-HpETE to 5-oxo-ETE by the action of a mouse macrophage 50-60 kilodalton cytosolic protein. The contribution of the latter three pathways to the physiological production of 5-oxo-ETE has not been fully studied; most attention has focused on the 5-HEDH pathway. 5-HEDH acts reversibly with the direction of its 5-(''S'')-HETE and 5-oxo-ETE interconversions determined by ambient NADPH/NADP+ ratios〔Biochem J. 2007 Apr 1;403(1):157-65〕〔Free Radic Biol Med. 2011 May 15;50(10):1297-304. 〕 Cells containing high levels of NADPH compared to NADP+ make little or no 5-oxo-ETE from endogenous 5-HETE and rapidly convert exogenous 5-oxo-ETE to 5-(''S'')-HETE whereas cells containing low levels of NADPH compared to NADP+ convert sizable portions of 5-(''S'')-HETE to 5-oxo-ETE.〔Biochim Biophys Acta. 2014 Oct 29. pii: S1388-1981(14)00217-0. doi: 10.1016/j.bbalip.2014.10.008. (ahead of print ) Review〕 Since most cells normally maintain high NADPH/NADP+ ratios, they make little or no 5-oxo-ETE from 5(''S'')-HETE and rapidly convert exogenous 5-oxo-ETE to 5-(''S'')-HETE.〔Biol Chem. 1992 Sep 25;267(27):19233-41>〕〔J Biol Chem. 1998 Dec 4;273(49):32535-41〕 However, cells undergoing aging, senescence, apoptosis, oxidative stress, or other conditions that raise their levels of reactive oxygen species (e.g. superoxide anion, oxygen radicals, and peroxides) either physiologically (e.g. human phagocytes engulfing bacteria) or pathologically (e.g. oxidatively challenged B-lymphocytes) use up NADP+, have low NADPH/NADP+ ratios, and therefore readily convert 5(''S'')-HETE to 5-oxo-ETE.〔J Biol Chem. 2004 Sep 24;279(39):40376-84〕〔Free Radic Biol Med. 2007 Mar 1;42(5):654-64〕〔Free Radic Biol Med. 2009 Jul 1;47(1):62-71. 〕〔Free Radic Biol Med. 2011 May 15;50(10):1297-304. doi: 0.1016/j.freeradbiomed.2011.02.010〕〔Biosci Rep. 2014 May 23;34(3). pii: e00108. doi: 10.1042/BSR20130136〕〔Biochim Biophys Acta. 2015 Apr;1851(4):340-55. doi: 10.1016/j.bbalip.2014.10.008. Epub 2014 Oct 29. Review〕 Thus, many pathological conditions, including those involving oxidative stress such as occurs in rapidly growing cancers, may be important promoters of 5-oxo-ETE accumulation in vivo. Human neutrophils, monocytes, eosinophils, B-lymphocytes, dendritic cell, platelets, airway epithelial cells and smooth muscle cells, vascular endothelial cells, and skin keratinocytes have been found and/or suggested to make 5-oxo-ETE from endogenous or exogenous 5-HETE, particularly under conditions of oxidative stress; cell lines derived from human cancers such as those from breast, prostate, lung, colon, and various types of leukemia have likewise been shown to be producers of 5-oxo-ETE.〔Prog Lipid Res. 2013 Oct;52(4):651-65. doi: 10.1016/j.plipres.2013.09.001.〕 The production of 5-oxo-ETE by these cells often involves transcellular metabolism wherein cells of one type make 5(''S'')-HETE and release it to nearby cells of a second type which then oxidize the 5(''S'')-HETE to 5-oxo-ETE. This sharing of responsibilities, at least in in vitro studies, typically involves the limited number of cell types that express active 5-lipoxygenase and therefore act as donors that deliver 5(''S'')-HETE to the far larger number of cell types that contain 5-HEDH and/or possess lower NADPH/NADP+ ratios than the donor cells. The transcellular production of 5-oxo-eicosatetraenoates has been demonstrated in vitro with human neutrophils as the 5(''S'')-HETE producers and human PC-3 prostate cancer cells, platelets, and monocyte-derived dendritic cells as the oxidizing cells.〔Inflamm Res. 2000 Nov;49(11):633-8〕〔Prog Lipid Res. 2013 Oct;52(4):651-65. doi: 10.1016/j.plipres.2013.09.001. Epub 2013 Sep 19. Review〕 It is theorized that this transcellular metabolism occurs in vivo and provides a mechanism for controlling 5-oxo-ETE production by allowing it to occur of be greatly augmented at sites were 5-lipoxygenase-containg cells congregate with cell types possessing 5-HEDH and favorable NADPH/NADP+ ratios; such sites might include those involving allergy, inflammation, oxidative stress, and rapidly growing cancers. An isomer of 5-oxo-ETE ,5-oxo-(7''E'',9''E'',11''Z'',14''Z'')-eicosatetraenoic acid, forms non-enzymatically as a byproduct of hydrolyses of the 5-lipooxgenase metabolite, Leukotriene A4. This byproduct differs from 5-oxo-ETE not only in the position and geometry of its double bounds but also in its activity: it stimulates human neutrophils apparently by acting on one or more LTB4 receptors rather than OXER1.〔Biochim Biophys Acta. 2000 Feb 24;1484(1):51-8〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「5-oxo-eicosatetraenoic acid」の詳細全文を読む スポンサード リンク
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