doi: 10.1161/01.ATV.0000020757.27916.DD
© 2002 American Heart Association, Inc.
Letters to the Editor |
Physiological Variations of Isoprostanes: A Step Forward?
Pharmacology Laboratory, Grenoble University Hospital, France
To the Editor:
Ide et al1 recently reported that 15-F2t-IsoP urinary levels were higher in healthy young men compared with healthy premenopausal women, showing that lipid peroxidation is increased in the former group. Isoprostanes appear to be specific and sensitive biomarkers of lipid peroxidation2 and are widely used in clinical trials. Unlike the 5-series and the 15-F2t-IsoP metabolites, our knowledge of the physiological variations of 15-F2t-IsoP is increasing, essential criteria before assessing this biomarker in pathological states. The study by Ide et al provides important but incomplete information concerning the physiological variations of 15-F2t-IsoP in humans. This study was meticulously performed, using a validated assay.3 The numerous exclusion criteria (smoking, hypertension, dyslipidemia, diabetes, alcoholism, medication including vitamins and oral contraceptives) give weight to the validity of the results, because few biases are likely to have been introduced. Furthermore, four potential limitations of the study that the authors outline in the discussion can reasonably be ruled out: the confounding effects of exercise or of diet, the enzyme dependent production of 15-F2t-IsoP, and the lack of measurement of 15-F2t-IsoP metabolites in their study. Extreme endurance exercise increases 15-F2t-IsoP levels in humans, but moderate exercise does not.4–6 Similarly, F2-isoprostane levels are not modified by the lipid content of the diet.7–9 In addition, the cyclo-oxygenase–dependent formation of 15-F2t-IsoP that was demonstrated in vitro is negligible in humans in clinical settings.10 Lastly, the measurement of 15-F2t-IsoP metabolites together with the parent compound provides an integrated index of 15-F2t-IsoP formation,11 but there is no evidence that the metabolite levels alone are a better marker of oxidative stress.
The major criticism that should be made is that whereas the distribution of isoprostanes in women seems to follow normality, this is not the case for men, in whom the median 15-F2t-IsoP level is obviously lower than the mean. Because the differences observed between men and women are driven by 3 men, this may lead to the hypothesis that a subgroup of men, but not men in general, has a higher 15-F2t-IsoP urinary level. Furthermore, it should be pointed out that the measurement of isoprostanes was obtained from a small subgroup of patients, in whom median should be used rather than mean for describing 15-F2t-IsoP urinary levels. Interestingly, anti-oxidant vitamin supplementation led to a significant reduction of 15-F2t-IsoP levels in men but not in women. Such data further support the hypothesis proposed by Patrignani et al12 that the basal rate of lipid peroxidation is the major determinant of the response to anti-oxidant vitamin supplementation.
In conclusion, this study suggests a sex difference in the basal rate of lipid peroxidation, but it does not enable a definitive conclusion concerning the physiological variations of 15-F2t-IsoP in men and women. Confirmation of these preliminary results in another clinical trial including a large number of men and women with isoprostane measurement as the primary endpoint is required. However, from now on, it seems unavoidable to match patients in terms of sex in clinical studies with 15-F2t-IsoP as a biomarker.
References
- Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihashi M, Tamai H, Takeshita A. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol. 2002; 22: 438–442.
[Abstract/Free Full Text] - Roberts LJ, Morrow JD. Measurement of F2-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med. 2000; 28: 505–513.[CrossRef][Medline] [Order article via Infotrieve]
- Ohashi N, Yoshikawa M. Rapid and sensitive quantification of 8-isoprostaglandin F2
in human plasma and urine by liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr B Biomed Sci Appl. 2000; 746: 17–24.[CrossRef][Medline]
[Order article via Infotrieve]
- Mori TA, Dunstan DW, Burke V, Croft KD, Rivera JH, Beilin LJ, Puddey IB. Effect of dietary fish and exercise training on urinary F2-isoprostane excretion in non–insulin-dependent diabetic patients. Metabolism. 1999; 48: 1402–1408.[CrossRef][Medline] [Order article via Infotrieve]
- Childs A, Jacobs C, Kaminski T, Halliwell B, Leeuwenburgh C. Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise. Free Radic Biol Med. 2001; 31: 745–753.[CrossRef][Medline] [Order article via Infotrieve]
- Mastaloudis A, Leonard SW, Traber MG. Oxidative stress in athletes during extreme endurance exercise. Free Radic Biol Med. 2001; 31: 911–922.[CrossRef][Medline] [Order article via Infotrieve]
- Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A. 1990; 87: 9383–9387.
[Abstract/Free Full Text] - Richelle M, Turini ME, Guidoux R, Tavazzi I, Metairon S, Fay LB. Urinary isoprostane excretion is not confounded by the lipid content of the diet. FEBS Lett. 1999; 459: 259–262.[CrossRef][Medline] [Order article via Infotrieve]
- Gopaul NK, Zacharowski K, Halliwell B, Anggard EE. Evaluation of the postprandial effects of a fast-food meal on human plasma F2-isoprostane levels. Free Radic Biol Med. 2000; 28: 806–814.[CrossRef][Medline] [Order article via Infotrieve]
- Cracowski JL, Devillier P, Durand T, Stanke-Labesque F, Bessard G. Vascular biology of the isoprostanes. J Vasc Res. 2001; 38: 93–103.[CrossRef][Medline] [Order article via Infotrieve]
- Chiabrando C, Valagussa A, Rivalta C, Durand T, Guy A, Zuccato E, Villa P, Rossi JC, Fanelli R. Identification and measurement of endogenous beta-oxidation metabolites of 8-epi-Prostaglandin F2. J Biol Chem. 1999; 274: 1313–1319.
[Abstract/Free Full Text] - Patrignani P, Panara MR, Tacconelli S, Seta F, Bucciarelli T, Ciabattoni G, Alessandrini P, Mezzetti A, Santini G, Sciulli MG, Cipollone F, Davi G, Gallina P, Bon GB, Patrono C. Effects of vitamin E supplementation on F2-isoprostane and thromboxane biosynthesis in healthy cigarette smokers. Circulation. 2000; 102: 539–545.
[Abstract/Free Full Text]
Physiological Variations of Isoprostanes: A Step Forward? Response to Letter to the Editor
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Discovery Research Laboratory, Tanabe Seiyaku Co, Ltd, Toda, Japan
We are grateful to Drs Cracowski, Stanke-Labesque, and Bessard for thoughtful comments and appreciate the great interest in our recent article on the difference in oxidative stress between healthy young men and women.1
First, we have to admit that the number of healthy individuals for the measurement of 8-iso-PGF2 is small in this study. It is clearly needed to confirm our results in larger number of the study subjects. However, our conclusion is considered to be valid because thiobarbituric acid–reacting substances (TBARS) data also supported this notion. Moreover, the rate of cellular respiration, which is probably the dominant source of reactive oxygen species in the physiological state, might be higher in men and lead to greater oxidative stress.2 Second, even though a putative 2,3-dinor-5,6-dihydro-iPF2-III, a metabolite of 8-iso-PGF2 (iPF2-III), is a better marker of in vivo oxidative stress,3 the addition of other biomarkers of oxidative stress such as 8-hydroxydeoxyguanosine (8-OHdG)4 or plasma oxidized LDL (Ox-LDL)5 would increase the strength and relevance of the results obtained by using 8-iso-PGF2. Finally, the doctors’ comments regarding the overlap between the majority of two groups in terms of both TBARS and 8-iso-PGF2 levels are quite incisive. These data are consistent with those by Patrignani et al,6 indicating that the basal rate of lipid peroxidation is the major determinant of the response to antioxidant vitamin supplementation.
Despite the increasing knowledge of the role of reactive oxygen species in atherogenesis, it remains uncertain whether oxidative stress is of clinical significance in the pathophysiology of atherosclerotic cardiovascular diseases in humans. Moreover, the postulated beneficial effects of antioxidant supplementation on these patients remain also to be confirmed. Biomarkers of in vivo oxidative stress such as 8-iso-PGF2 offer a valuable tool for investigating these crucial issues. The present study suggests that sex may imply potential effects on these markers adding to other well-known risk factors including hypercholesterolemia, diabetes mellitus, and cigarette smoking.
Acknowledgments
We thank Hiroyuki Tsutsui for providing us details from his study.
References
- Ide T, Tsutsui H, Ohashi N, Hayashidani S, Suematsu N, Tsuchihashi M, Tamai H, Takeshita A. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol. 2002; 22: 438–442.
- Meijer GA, Westerterp KR, Saris WH, ten Hoor F. Sleeping metabolic rate in relation to body composition and the menstrual cycle. Am J Clin Nutr. 1992; 55: 637–640.
[Abstract/Free Full Text] - Patrono C, FitzGerald GA. Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol. 1997; 17: 2309–2315.
[Abstract/Free Full Text] - Kasai H. Analysis of a form of oxidative DNA damage, 8-hydroxy-2[prime]- deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis. Mutat Res. 1997; 387: 147–163.[CrossRef][Medline] [Order article via Infotrieve]
- Tsutsui T, Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Ohnishi M, Kinoshita M. Plasma oxidized low-density lipoprotein as a prognostic predictor in patients with chronic congestive heart failure. J Am Coll Cardiol,. 2002; 39: 957–962.
[Abstract/Free Full Text] - Patrignani P, Panara M, Tacconelli S, Seta F, Bucciarelli T, Ciabattoni G, Alessandrini P, Mezzetti A, Santini G, Sciulli MG, Cipollone F, Davi G, Gallina P, Bon GB, Patrono C. Effects of vitamin E supplementation on F2-isoprostane and thromboxane biosynthesis in healthy cigarette smokers. Circulation. 2000; 102: 539–545.
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