title: Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid.
abstract: 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".
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626St. Urbain Street, Montreal, Quebec H2X 2P2, Canada. Electronic address: William.Powell@McGill.ca.
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
authors.affiliation: Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rokach
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism; D004194:Disease; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D018055:Receptors, Eicosanoid / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C066652:12-hydroxyeicosatetraenoic acid receptor; D001095:Arachidonic Acids; C501953:GPR31 protein, human; D006893:Hydroxyeicosatetraenoic Acids; C504018:OXER1 protein, human; D047492:Peroxisome Proliferator-Activated Receptors; D018055:Receptors, Eicosanoid; D043562:Receptors, G-Protein-Coupled; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D016718:Arachidonic Acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
keywords: 12-HETE; 5-Oxo-ETE; Asthma; Cancer; Inflammation; OXE receptor