Review articleF2-isoprostanes: sensitive and specific non-invasive indices of lipid peroxidation in vivo
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.
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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 iPF2α-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 iPF2α-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 iPF2α-III. Systemic infusion of iPF2α-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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