Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers

doi:10.1016/j.bbalip.2014.11.004

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1851, Issue 4, April 2015, Pages 446-455

https://doi.org/10.1016/j.bbalip.2014.11.004 Get rights and content

Highlights

•
Bio- and chemical syntheses of non-enzymatic cyclic oxygenated derivatives of PUFA are presented.
•
Current evaluation of iso-prostanoids and furanoids in vivo is discussed.
•
Biological activities of those PUFA metabolites are compared.

Abstract

Cyclic oxygenated metabolites are formed in vivo through non-enzymatic free radical reaction of n-6 and n-3 polyunsaturated fatty acids (PUFAs) such as arachidonic (ARA C20:4 n-6), adrenic (AdA 22:4 n-6), α-linolenic (ALA 18:3 n-3), eicosapentaenoic (EPA 20:5 n-3) and docosahexaenoic (DHA 22:6 n-3) acids. These cyclic compounds are known as isoprostanes, neuroprostanes, dihomo-isoprostanes and phytoprostanes. Evidence has emerged for their use as biomarkers of oxidative stress and, more recently, the n-3PUFA-derived compounds have been shown to mediate bioactivities as secondary messengers. Accordingly, this review will focus on the cyclic oxygenated metabolites generated from AdA, ALA, EPA and DHA. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.

Introduction

Free radicals are implicated in a wide variety of human diseases [1] and the consequences are the oxidation of biomolecules, including DNA, proteins and lipids. Among lipids, polyunsaturated fatty acids (PUFAs) have reactive skipped dienes, or methylated interrupted double bonds, that can participate to form acyclic, and subsequently, stable cyclic oxygenated metabolites [2]. Since the discovery of F₂-isoprostanes (F₂-IsoPs) by Morrow et al. in 1990 derived from arachidonic acid (ARA, 20:4 n-6) peroxidation in vivo [3], an important field of research has been developed. Nowadays, elevation of F₂-IsoP levels in biological fluids (e.g. plasma and urines) is recognized as the reference biomarker for lipid peroxidation and oxidative stress [4]. Because of the high reactivity and short life span of free radicals, oxidative stress is evaluated by the measurement of damaged biological products, which can be considered as biomarkers of lipid peroxidation. Beyond their capacity of oxidative stress evaluation, isoprostanes also demonstrate to be biologically active [2], [5], [6].

Docosahexaenoic (DHA, 22:6 n-3) and eicosapentaenoic (EPA, 20:5 n-3) acids, the main n-3 PUFAs, form neuroprostanes (NeuroPs) [7], [8] and EPA-derived isoprostanes [9], respectively, under free radical reactions. Also, the n-6 PUFA adrenic acid (AdA, 22:4) located in brain white matter and other tissues, such as the adrenal gland and kidney, is the precursor of dihomo-isoprostanes (dihomo-IsoPs) [10]. Finally α-linolenic acid (ALA, 18:3 n-3) from plants may be converted into phytoprostanes (PhytoPs) [11].

This review will focus on the isoprostanes, neuroprostanes, dihomo-isoprostanes and phytoprostanes generated from ALA, AdA, EPA and DHA with regard to (i) the synthesis of these new cyclic oxygenated metabolites of PUFA, (ii) the use of such lipid metabolites as biomarkers of oxidative stress in humans, and (iii) data relative to their biological activities in vitro and in vivo.

Section snippets

Biosynthesis of cyclic oxygenated metabolites of PUFA

In 1990, Roberts, Morrow and co-workers discovered novel prostaglandin (PG)-like isomers, which are named isoprostanes. In contrast to PG produced by cyclooxygenases, the mechanism of formation proceeds via a non-enzymatic free radical peroxidation of ARA esterified in phospholipids and not from free ARA [3]. The main structural characteristics compared to PGs are the cis-relationship of the side chains, the large number of potential isomers and the generation of racemic metabolites [12], [13].

Chemical synthesis of cyclic oxygenated metabolites

The total synthesis of cyclic oxygenated metabolites is of greatest importance for the general understanding of their in vivo formation and biological functions, but also to explore their potential diagnostic applications. Different strategies to produce PhytoPs, IsoPs, dihomo-IsoPs and NeuroPs have been reported in the literature by organic chemists around the world (see few reviews [2], [19], [20]). All these strategies developed so far confirmed the biological importance of IsoPs, NeuroPs,

Eicosapentaenoic and docosahexaenoic acids

Among the identified n-3 fatty acids, EPA and DHA are the most notable ones for (patho)physiological functions. They are present in all human tissues at different levels, and DHA is foremost concentrated in the retina and brain. The structural occurrence of multiple double bonds allows the generation of oxygenated metabolites in the presence of free radicals. Oxidation of EPA can generate 6 series of F₃-IsoPs, of which 96 racemic derivatives can be potentially measured in vivo (see above

Bioactive lipids and potential signaling molecules

The biological activities of non-enzymatic-derived cyclic oxygenated metabolites are well recognized but the focus has been mainly on IsoPs (from ARA) [66]. Of the F₂-IsoPs, 15-F_2t-IsoP is the most studied where it is able to induce vasoconstriction and platelet activation. In addition, F₂-IsoPs induces inflammation by expression of adhesion molecules (e.g. ICAM-1) leading to enhanced adhesion of monocytes, mitogenesis of smooth muscle cells and proliferation of fibroblasts. Collectively, they

Conclusions

In this review, we have discussed findings showing that non-enzymatically-derived cyclic oxygenated metabolites of n-3 and n-6 PUFA, i.e. isoprostanes, neuroprostanes, dihomo-isoprostanes and phytoprostanes can be useful oxidative stress biomarkers, especially in neuronal disorders and diseases, but can also exhibit bioactivities contributing to signaling and regulatory events in vivo. There is scope to explore how the relative prevalence of these oxygenated cyclic products of PUFA can

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^☆: This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: Analysis and biological relevance”.

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ReviewNon-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers☆

Highlights

Abstract

Introduction

Section snippets

Biosynthesis of cyclic oxygenated metabolites of PUFA

Chemical synthesis of cyclic oxygenated metabolites

Eicosapentaenoic and docosahexaenoic acids

Bioactive lipids and potential signaling molecules

Conclusions

Free Radic. Biol. Med.

Prostaglandins Other Lipid Mediat.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Lipid Res.

J. Biol. Chem.

J. Biol. Chem.

Methods Enzym.

J. Biol. Chem.

Chem. Phys. Lipids

J. Biol. Chem.

J. Biol. Chem.

J. Nutr.

Food Chem. Toxicol.

Chem. Phys. Lipids

Free Radic. Biol. Med.

Am. J. Pathol.

Neurobiol. Dis.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Clin. Chim. Acta

Free Radic. Biol. Med.

J. Chromatogr. B

NeuroToxicology

Neurobiol. Aging

Exp. Neurol.

Free Radic. Biol. Med.

Neuron

Free Radic. Biol. Med.

Prostaglandins

J. Biol. Chem.

Biochim. Biophys. Acta BBA — Lipids Lipid Metab.

J. Lipid Res.

Free Radic. Biol. Med.

J. Nutr.

J. Lipid Res.

J. Lab. Clin. Med.

Blood

Pharmacol. Ther.

J. Nutr.

J. Biol. Chem.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Curr. Opin. Plant Biol.

Biochimie

Free Radic. Biol. Med.

J. Lipid Res.

Atherosclerosis

Review
Non-enzymatic cyclic oxygenated metabolites of adrenic, docosahexaenoic, eicosapentaenoic and α-linolenic acids; bioactivities and potential use as biomarkers☆