Powell William S, Rokach Joshua
Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901, USA.
Biochim Biophys Acta. 2015 Apr;1851(4):340-55. doi: 10.1016/j.bbalip.2014.10.008. Epub 2014 Oct 29.
Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".
花生四烯酸可被多种不同的酶氧化，包括脂氧合酶、环氧化酶和细胞色素P450，并且由于脂质过氧化作用可转化为复杂的氧化产物混合物。这些反应的初始产物是氢过氧化二十碳四烯酸（HpETEs）和羟基二十碳四烯酸（HETEs）。氧代二十碳四烯酸（oxo-ETEs）可通过各种脱氢酶对HETEs的作用或HpETEs的脱水作用形成。尽管已鉴定出大量不同的HETEs和oxo-ETEs，但本综述将主要聚焦于5-氧代-ETE、5S-HETE、12S-HETE和15S-HETE。其他相关的花生四烯酸代谢产物也将进行较少细节的讨论。5-氧代-ETE是由选择性酶5-羟基类花生酸脱氢酶氧化5-脂氧合酶产物5S-HETE合成的。其作用由选择性OXE受体介导，该受体在嗜酸性粒细胞上高度表达，这表明它在诸如哮喘等嗜酸性粒细胞疾病中可能很重要。5-氧代-ETE似乎还能刺激肿瘤细胞增殖，也可能与癌症有关。高选择性和强效的OXE受体拮抗剂最近已可获得，这可能有助于阐明其病理生理作用。12-脂氧合酶产物12S-HETE通过GPR31受体起作用，促进肿瘤细胞增殖和转移，因此可能是癌症治疗中有前景的靶点。它也可能作为促炎介质参与糖尿病。相比之下，15S-HETE可能在癌症中具有保护作用。除了G蛋白偶联受体（GPCRs）外，更高浓度的HETEs和oxo-ETEs可激活过氧化物酶体增殖物激活受体（PPARs），并可能通过这种机制潜在地调节多种过程。本文是名为“多不饱和脂肪酸的氧化代谢：分析及生物学意义”的特刊的一部分。
