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Detection of F2-Isoprostanes and F4-Neuroprostanes in Clinical Studies

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Detection of F2-Isoprostanes and F4-Neuroprostanes in Clinical Studies Mini Review Detection of F2-isoprostanes and F4-neuroprostanes in Clinical Studies Hsiu-Chuan Yen Graduate Institute of Medical Biotechnology Department of Medical Biotechnology and Laboratory Science Chang Gung University, Taoyuan, Taiwan Detecting stable products of oxidative damage is the most reliable approach to access oxidative stress in vivo. F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs) are the most specific markers of lipid peroxidation, which is superior to other markers of oxidative damage for clinical studies in many ways. F2-IsoPs is formed from peroxidation of arachidonic acid that is abundant in all kind of cells, while F4-NPs is derived from docosahexaenoic acid enriched in neurons. Moreover, F2-IsoPs is known to exhibit biological activities, such as vasoconstriction and platelet aggregation. Gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) is the reference method and the method with highest sensitivity to quantify F2-IsoPs and F4-NPs. F2-IsoPs is not only a widely used gold marker of lipid peroxidation detectable in all types of body fluids, but also a cause of diseases due to its biological activities, a marker to evaluate severity or predict out- come of diseases, or a tool to monitor the effectiveness of antioxidant therapy. Clinical studies de- tecting F4-NPs are little because cerebrospinal fluid or brain tissues are needed, but it is more useful than F2-IsoPs in selectively evaluating neuronal oxidative damage. This paper will discuss the above issues with emphasis on the advantages and considerations in clinical studies. Key words: Lipid peroxidation, Gas chromatography/negative-ion chemical-ionization mass spectrometry, Body fluid, Neuron The best way to access oxidative stress in humans is to detect specific and stable markers of oxidative dam- Introduction age using reliable methods. There have been many markers of oxidative damage and various methods for Increased production of reactive species, especially reac- each marker with different advantages and disadvantages tive oxygen species and reactive nitrogen species, or [1]. However, since the discovery of F2-isoprostanes decreased antioxidant capacity can result in the status of (F2-IsoPs) as the most specific marker of lipid peroxda- oxidative stress, which has the tendency to cause oxida- tion by Jason Morrow and Jackson Roberts at Vanderbilt tive damage. Oxidative damage to important macro- University in 1990 in humans [2], F2-IsoPs analyzed by molecules, DNA, lipid, or protein, may lead to distur- mass spectrometry has been well recognized as the most bances of normal physiological functions, which plays reliable marker of oxidative damag and widely applied an important role in pathogenesis of various human dis- in various clinical studies [3,4]. Moreover, in addition to eases or mechanisms of toxicity induced by xenobiotics. F4-neuroprostanes (F4-NPs), various products of lipid Many of these basic concepts can be found in the book peroxidation related to or similar to formation of F2-IsoPs, of Halliwell and Gutteridge [1]. There is increasing de- including F3-IsoPs, D/E form of IsoPs and NPs, A/J form mand for accessing oxidative stress in humans, which of IsoPs and NPs, isothromboxanes, isofurans and neu- has become an important issue in the field of clinical rofurans, isoketals and neuroketals, F2-dihomo-IsoPs, laboratory science. However, inappropriate markers and and urinary metabolites of 15-F2t-IsoP, are also generated nonspecific assays were often employed in the literature. from different polyunsaturated fatty acids or via different Received: March 9, 2010 Address for correspondence: Hsiu-Chuan Yen, Ph.D., Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan 333, Taiwan. Tel: +886-3-2118800 ext. 5207, Fax: +886-3-2118692, Email: [email protected] J Biomed Lab Sci 2010 Vol 22 No 1 1 Dectection of F2-isoprostanes and F4-neuroprostanes mechanisms with different significance [5,6]. This re- of F2-IsoPs [11,14]. On the other hand, enantiomer of view paper will only focus on F2-IsoPs and F4-NPs be- PGF2α, ent-PGF2α, could be generated from IsoP path- cause they are more important in clinical studies. Clini- way and might account for most of PGF2α found in urine, cal utilities of F2-IsoPs and F4-NPs will be discussed by which was thought to be exclusively from the COX path- including our work on the studies of aneurysmal su- way. It should be noted that PGF2α and ent-PGF2α could barachnoid hemorrhage (aSAH) and traumatic brain in- be differentiated under the analysis of special liquid jury (TBI) in humans [7-9]. chromatography/mass spectrometry (LC/MS), but not GC/NICI-MS [15]. The terminology for F2-IsoPs or 15-F2t-IsoP has Formation and Nomenclature of F2-IsoPs been confusing especially in the early years after the and F -NPs 4 discovery of F2-IsoPs. It was not more unified until the nomenclature system of Taber et al. for IsoPs was ap- F2-IsoPs is a group of prostaglandin (PG)F2-like com- proved by the Eicosanoid Nomenclature Committee, pounds that are generated from arachidonic acid (AA, which was also sanctioned by the International Union of C20:4 ω-6), an abundant polyunsaturated fatty acid pre- Pure and Applied Chemistry (IUPAC) [3,16]. This no- sent in all kinds of cell membranes, via free radical- menclature system named four major regioisomers as 5-, catalyzed lipid peroxidation. It was proved to be inde- 12-, 8, and 15-series regioisomers, which corresponded pendent of action of cyclooxygenase (COX) because to I-IV regioisomers initially categorized by Morrow et human subjects receiving COX inhibitors did not have al. [2] and provided principles to name different isomers. lower levels of these compounds in body fluids. F2-IsoPs However, many publications or companies still used was named because it has F-type prostane rings similar different old terms of 15-F2t-IsoP, such as 8-iso-PGF2α to PGF2α [2,10,11]. At beginning, it was in fact an acci- and 8-epi-PGF2α, without updates in this aspect. The dental discovery of Morrow et al. when plasma samples chemical structure of 15-F2t-IsoP is almost identical to stored at -20℃ for several months were subjected to that of PGF2α except the stereochemistry as shown by routine analysis by gas chromatography/negative-ion Figure 1. Based on the system of Taber et al., 15-F2t-IsoP chemical-ionization mass spectrometry (GC/NICI-MS) should be pronounced as “15-F-2-transe-isoprostane” for 9α,11β-PGF2, a metabolite of PGD2. Unknown and it was designated in this way because two side PGF2-like compounds, identified as peaks adjacent to chains are oriented trans in respect to hydroxyl groups that of 9α,11β-PGF2 of GC chromatograms, were found on the cyclopentane ring [16]. On the other hand, the in those plasma samples at the levels that were approxi- group of FitzGerald has developed a different nomen- mately 50-fold higher than that in fresh plasma. Freeze- clature system and kept using this system is their publi- thaw cycles of plasma also increased the levels of those cations. That system was developed by Rokach et al and compounds [10]. named four regioisomers as types VI, V, IV, and III re- F2-IsoPs is initially generated on phospholipids on gioisomers [17], which corresponded to 5-, 12-, 8, and tissues or lipoproteins in plasma as esterified form from 15-series regioisomers of Taber et al. [16]. Moreover, esterified fatty acids and can be released into surround- iPF2α-III denotes 15-F2t-IsoP in the system of Rokach et ing body fluids or circulation as free form mediated by al. [17]. phospholipase A2-like activities. Detection of F2-IsoPs in In 1998, Roberts et al. further proved the presence body fluids therefore can reflect the levels of lipid per- of F4-NPs, which was derived from free radical-mediated oxidation in tissues [11,12]. Stafforini et al. identified lipid peroxidation of docosahexaenoic acid (DHA, C22:6 that intracellular and plasma platelet-activating factor ω-3), both in vitro and in vivo with the same principle as acetylhydrolases (PAH-AH) could be responsible for the the formation of F2-IsoPs from AA. Eight different re- hydrolysis of F2-IsoPs from phospholipids [13]. More- gioisomers for F4-NPs, 4-, 7-, 10-, 11-, 13-, 14-, 17- and over, there are four regioisomers of F2-IsoPs, which are 20-series, were predicted [18]. In this paper, the authors denoted as 5-, 12-, 8, and 15-series regioisomers based showed that F4-NPs was generated in a greater amount on the number of carbon atom of side chains on which than F2-IsoPs from equal amounts of AA and DHA, re- the hydroxyl group is localized. Quantity of 5- and spectively. In addition, esterified F4-NPs was barely de- 15-series regioisomers is much higher than that of other tectable in 1 ml of human plasma, while free F4-NPs in two regioisomers both in vitro and in vivo. Although normal human cerebrospinal fluid (CSF) could be de- each regioisomer theoretically consists of eight racemic tected and the levels were elevated in that of patients diastereomers, 15-F2t-IsoP is the most abundant isomer with Alzheimer’s disease (AD). The nomenclature sys- 2 J Biomed Lab Sci 2010 Vol 22 No 1 2 Fig. 1. Chemical structure of PGF2α, 15-F2t-IsoP, and the deuterium (D)-labeled 15-F2t-IsoP, [ H4]-15-F2t-IsoP. tem for NPs has also been proposed by Taber and Rob- specimen with limited amount and low concentrations. erts [19]. Furthermore, by using a unique LC/MS ap- GC/NICI-MS is also the reference method for analyzing proach, Yin et al.
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