Elsevier

Atherosclerosis

Volume 147, Issue 1, November 1999, Pages 1-10
Atherosclerosis

Review article
F2-isoprostanes: sensitive and specific non-invasive indices of lipid peroxidation in vivo

https://doi.org/10.1016/S0021-9150(99)00257-9Get rights and content

Abstract

Isoprostanes are members of a complex family of lipids, isomers of the conventional enzymatically derived prostaglandins (PG), which are produced in vivo primarily, if not exclusively, by a free radical-catalyzed peroxidation of polyunsaturated fatty acids. Most of the work has been focused upon a group of isomers of the enzyme-derived PGF, called F2-isoprostanes (F2-iPs). Because of their mechanism of formation, chemical stability and the rapid development of sensitive methods for their measurement, they have the attraction as non-invasive indices of oxidant stress in vivo. Altered generation of F2-iPs has been reported in a variety of clinical settings putatively associated with oxidant stress. These include atherosclerosis, chronic obstructive pulmonary disease and Alzheimer’s disease. Furthermore, the measurement of specific F2-iPs may provide a sensitive biochemical basis for rational dose-selection of natural and synthetic inhibitor of lipid peroxidation. Although F2-iPs possess biological activities in vitro and in vivo, much remains to be learned about their role and as mediators of the cellular effects of lipid peroxidation and oxidant stress.

Introduction

Isoprostanes are a family of prostaglandin (PG) isomers that are produced from oxidative modification of polyunsaturated fatty acids (PUFA) through a free radical-catalyzed mechanism. Their generation in vitro from auto-oxidation of PUFA was first demonstrated by Pryor and by Porter over 25 years ago [1], [2] and subsequently by others [3], [4]. However, it was only in 1990 that Morrow et al. reported that these compounds were also produced in vivo in humans [5]. Since then, a large body of evidence has been accumulated indicating that isoprostanes can be reliably monitored through non-invasive analytical approaches that yield sensitive and specific markers of lipid peroxidation in vitro and in vivo.

Section snippets

Mechanism of formation

Unlike the classic PGs that are formed through the action of PG endoperoxide synthase (colloquially known as cyclooxygenase or COX) enzyme and require free arachidonic acid, isoprostanes can be formed also from this fatty acid when is esterified in the membrane phospholipids. Compounds analogous to the isoprostanes may be formed from other PUFA, including eicosapentaenoic acid and docosahexaenoic acid [6], [7]. Free radical derived isomers of other PGs, leukotrienes and eicosaenoic acids have

Nomenclature

The increasing interest in the isoprostanes as indices of oxidant stress and as biological active compounds has resulted in the chemical synthesis of several of them [20], [21], [22]. As a result, a need for a systematic nomenclature that can also account for isoprostanes originating from all the common PUFA precursors has become more and more evident. Roberts et al. first proposed to abbreviate the name isoprostanes as ‘IsoP’s’, to avoid confusion with the definition of IP for inositol

Biological implications

Perhaps the most important aspect of the discovery of F2-iPs is the fact that measurement of these compounds in biological fluids might afford a quantitative index of lipid peroxidation and oxidant stress in vivo. It has been recognized for a long time that the difficulty in assessing free radical generation in vivo has been caused by the unavailability of reliable non-invasive methods. Traditional assays, such as thiobarbituric reactive substance (TBARS) or lipid hydroperoxides, suffer from

Metabolism

Only limited information is available as for the metabolism of F2-iPs. Previously, it has been demonstrated that in the rat the t1/2 of the clearance of iPF-III from circulation was ∼16 min. Furthermore, the creation of a porta caval shunt and ligation of the hepatic artery in the same animal, which completely eliminated clearance of this iP by the liver, prolonged the t1/2 only from 16 to 21 min [33]. Administration of labeled iPF-III to primates and one human suggested that close to 20%

Quantification of isoprostanes

As discussed earlier, F2-iPs were discovered as a result of free radical or autoxidation of arachidonic acid. Thus, precautions must be taken to prevent artifactual formation of them by autoxidation in samples during processing and storage. We found that autoxidation does not occur in lipid containing samples, e.g. plasma, that are immediately snap frozen in liquid nitrogen and stored at −80°C up to 8 months. Similar considerations apply for tissue samples. We have shown that autoxidation is

F2-isoprostanes as mediators of oxidant stress

F2-iPs are not simply markers of lipid peroxidation but also possess biological activity. Indeed, they could be mediators of the cellular effects of oxidant stress. Most of the information on their biological activity has been gathered on the few that are available in synthetic form, particularly iPF-III. Systemic infusion of iPF-III in the rat caused a potent renal vasoconstriction, with reduction of glomerular filtration rate and renal blood flow by 40%, but no change in systemic blood

F2-isoprostanes as indices of oxidant stress

There is considerable evidence that lipid and phospholipid oxidation is a feature of oxidant stress in vivo. Several lipid oxidation products have been identified and reported in animal models and human clinical situations putatively associated with increased oxidant stress. A description of this extensive literature is beyond the scope of this review. A number of excellent reviews are available with regard to this aspect [57], [58], [59].

Conclusions

F2-iPs are a new class of biologically active products of arachidonic acid metabolism. Their analysis continues to be refined, but enough data have been accumulated that clearly indicate them as a credible and non-invasive approach for studying lipid peroxidation in vivo. In addition to being valuable markers of oxidant stress, their measurement may provide a criterion and a sensitive biochemical basis for rational dose selection of natural and synthetic antioxidants in clinical settings, where

Acknowledgements

I wish to thank Garret A. FitzGerald for his comments to this manuscript. This work was in part supported by a grant from the National Institute of Health (MO1RR00040).

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