Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Highlights

• HETEs are AA metabolites formed by lipoxygenases, cyclooxygenases, and P450 enzymes.

• Oxo-ETEs are formed from HETEs by specific dehydrogenases.

• Receptors have been identified for 5-oxo-ETE (OXE receptor) and 12S-HETE.

• 5-Oxo-ETE is an eosinophil chemoattractant that may be involved in asthma and allergy.

• 12S-HETE promotes tumor cell proliferation and may be involved in cancer and diabetes.

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”.

Introduction

Arachidonic acid (AA) is a key polyunsaturated fatty acid (PUFA), which serves as the precursor for a wide variety of lipid mediators that are involved in many physiological and pathophysiological processes. The initial step in the formation of these mediators is introduction of oxygen, which can be catalyzed by lipoxygenases, cyclooxygenases, or cytochrome P450 enzymes. In the cases of lipoxygenases and cyclooxygenases, AA is first converted to hydroperoxy products (HpETEs, hydroperoxyeicosatetraenoic acids), which can serve as precursors for different intermediates such as prostaglandin (PG) H₂ or leukotriene (LT) A₄ or biological mediators such as hepoxilins [172], lipoxins (LXs) [9], and eoxins [36] (Fig. 1). PGH₂ is converted by specific synthases to PGs D₂, E₂, F_2α, and I₂ and thromboxane (TX) A₂ [221], all of which have a variety of biological effects mediated by the DP_1–2, EP_1–4, FP, IP, and TP prostanoid receptors [97]. LTA₄ is enzymatically converted to either the potent neutrophil chemoattractant LTB₄ or to LTC₄, the precursor of LTD₄, a potent proinflammatory mediator in asthma [80]. The actions of LTB₄ are mediated by the BLT₁ receptor, whereas those of LTD₄ are mediated by the cysLT₁ and cysLT₂ receptors. LTA₄ can also serve as a precursor for the 12-LO- or 15-LO- catalyzed formation of LXA₄, which interacts with the ALX receptor, and LXB₄ [215].

Alternatively, HpETEs generated by lipoxygenases and cyclooxygenases can be reduced by peroxidases to monohydroxy fatty acids (HETEs, hydroxyeicosatetraenoic acids), which are the subject of the present review. Since the initial oxygenase-catalyzed abstraction of a hydrogen atom is from a methylene group situated between two double bonds, the hydroperoxyl group in HETEs formed in this way is always adjacent to a conjugated diene system (Fig. 2). The hydroperoxyl/hydroxyl groups of HpETEs and HETEs formed by lipoxygenases are usually, but not always, in the S-configuration.

In contrast to lipoxygenases, cytochrome P450 enzymes can introduce a hydroxyl group in a variety of positions, resulting in products that in most cases lack a conjugated diene chromophore (e.g. 20-HETE). Rather than hydroperoxy-fatty acids, the initial products of these reactions are hydroxy-fatty acids formed by the introduction of a single oxygen atom from O₂ bound to Fe^3 + at the active site of the enzyme [104]. A mixture of R and S HETE enantiomers is usually formed by cytochrome P450 enzymes, with the R enantiomer tending to predominate, especially in the case of 12-HETE [29], [169].

Oxoeicosatetraenoic acids (oxo-ETEs), also sometimes referred to as KETEs (keto-ETEs), can be formed by the oxidation of HETEs by different positionally-selective dehydrogenases (Fig. 1). Alternatively, they can be formed either enzymatically or non-enzymatically directly from HpETEs. Although not studied in as much detail as LTs and PGs, HETEs and oxo-ETEs have a variety of biological effects and may be implicated in a number of diseases including asthma, cancer, and diabetes. Because of the large number of publications in this area, this review is of necessity rather selective and will be restricted to metabolites of arachidonic acid, even though monohydroxy fatty acids derived from other PUFA are certainly of interest. 5-Oxo-ETE and 12S-HETE have a number of interesting properties and these, in particular those related to 5-oxo-ETE, will be the major focus. Other HETEs and oxo-ETEs will be discussed in less detail.