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Journal of the American College of Nutrition, Vol. 26, No. 5, 405-411 (2007)
Published by the American College of Nutrition

Effect of Low Dose Antioxidant Vitamin and Trace Element Supplementation on the Urinary Concentrations of Thromboxane and Prostacyclin Metabolites

Josiane Arnaud, PhD, Muriel Bost, PhD, Dominique Vitoux, MD, José Labarère, MD PhD, Pilar Galan, MD, Henri Faure, PhD, Serge Hercberg, MD, PhD, Jean-Claude Bordet, PhD, Anne-Marie Roussel, PhD and Philippe Chappuis, PhD

SFERETE (Société Francophone d'Etudes et de Recherche sur les Eléments Toxiques et Essentiels) (J.A., M.B., D.V., H.F., S.H., A.-M.R, P.C.)
Département de Biologie Intégrée, CHU de Grenoble, Grenoble (J.A., H.F.), INSERM, U884, Grenoble, F-38000
Univ Grenoble, Grenoble, F-38000 (J.A., A.-M.R)
Trace Elément-Institut pour l'UNESCO, Le Condorcet, Lyon (M.B.), Laboratoire d'Analyse de Traces, Fédération de Biochimie, Hôpital Edouard Herriot, Lyon (M.B.)
Laboratoire de Biochimie A, Hôpital Saint-Louis, Paris (D.V.)
Unité d'Evaluation Médicale, CHU de Grenoble, Grenoble (J.L.), UMR U557 Inserm
U1125 Inra; Cnam; Paris 13 - CRNH d'lle de France - SMBH, Bobigny (P.G., S.H.)
Laboratoire d'Hémostase, Pavillon E, Hôpital Edouard Herriot, Lyon (J.-C.B.)
Laboratoire de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris (P.C.), FRANCE

Address correspondence to: Josiane Arnaud, Département de Biologie Intégrée, CHU de Grenoble, BP 217, 38043 Grenoble cedex 9, France. E-mail: JArnaud{at}chu-grenoble.fr


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: This trial evaluated the effect of antioxidant supplementation on the urinary excretion of 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio, a marker of the pathogenesis of thrombosis and arteriosclerosis.

Methods: This study was a randomised, double-blind, placebo-controlled trial involving 186 presumably healthy volunteers. One hundred received a multi-antioxidant supplementation and 86 a placebo for two years. Blood zinc, selenium, beta-carotene, vitamin C and E and urinary excretion of 11-dehydro TXB2 and 2,3 dinor 6 keto PGF1{alpha} were measured.

Results: Baseline subject characteristics did not differ between the two groups. Blood zinc, selenium, and beta-carotene concentrations significantly increased between baseline and two years in the multi-antioxidant supplementation group supporting subject compliance (p < 0.05). At two years, the median urinary 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio was significantly lower in the multi-antioxidant supplementation group (3.4 versus 2.78, p = 0.015). Serum selenium concentration was the only antioxidant studied that was significantly related to the urinary 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio.

Conclusions: These results support the hypothesis that a low-dose multi-antioxidant supplementation may contributes to a reduction in platelet activation which is beneficial for cardiovascular function.

Key words: antioxidant, vitamins, trace elements, thromboxane, prostaglandins

Abbreviations: BMI = body mass index • EDTA = ethylene diamine tetra acetic acid • GPX = glutathion peroxidase • NaCl = sodium chloride • PG = prostaglandin • PRP = platelet-rich plasma • SD = standard deviation • Se = selenium • SU.VI.M.AX = supplémentation en vitamines et minéraux antioxydants • T0 = at baseline • T2 = after 2 years • TX = thromboxane • Zn = zinc


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Cardiovascular diseases remain the major cause of mortality in the world [1]. In developed countries, about 75% of deaths from cardiovascular diseases are attributable to ischemia [1]. Platelet activation contributes to thrombosis and atherosclerosis and therefore is involved in the development of ischemic diseases [2]. Selenium, vitamin E, vitamin C and ß-carotene deficiencies are associated with an increased risk of ischemic diseases [3–5]. It can be postulated that the oxidative metabolism of arachidonic acid is altered. A peroxidation process would stimulate cyclo-oxygenase activity leading to an increase in the production of thromboxane (TX) A2 and, in contrast, would inhibit prostacyclin synthase activity decreasing the production of prostaglandin (PG) I2 [2,6–10]. Thromboxane A2 is a vasoconstricting and platelet proaggregating factor, whereas PGI2 dilates blood vessels and acts as an inhibitor of platelet aggregation. More than the production of these substances, the imbalance in the ratio of TXA2/PGI2 has been reported to be the major contributing factor in the pathogenesis of thrombosis and atherosclerosis [11]. Antioxidant supplementation may decrease this ratio and therefore reduce platelet hyperactivation [2,7,12]. As thromboxane A2 and PGI2 are short-lived compounds, the determination of urinary 11-dehydro TXB2, a stable metabolite of TXA2 is widely used as a reflection of platelet activation, and urinary 2,3 dinor 6 keto PGF1{alpha}, a stable metabolite of PGI2, is used to determine PGI2 production.

The aim of the present study was to determine whether low daily additional intake of ascorbic acid, vitamin E, ß-carotene, selenium and zinc for 2 years decreased the TXA2/PGI2 ratio.


   METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects were participants in the SU.VI.MAX study, a large-scale French intervention trial designed to assess the efficacy of a daily supplementation of antioxidant micronutrients at non-pharmacological doses for 7.5 years in reducing the incidence of cancers and cardiovascular diseases. The design and main results of this randomised, double-blind, placebo-controlled, primary prevention trial have been published elsewhere [13].

As part of the SU.VI.M.AX trial, 186 presumably healthy volunteers enrolled in the SU.VI.M.AX trial, were randomly selected for the present study. This sample size was higher than 140, the minimum needed sample size assuming an expected difference between groups equal to half of the standard deviation; a two-sided alpha error of 0.05, a power of 0.80 and 10% refusal. All subjects provided informed written consent and the study protocol was approved by a medical ethics committee (Paris-Cochin Hospital, France) and the national committee for the protection of privacy and civil liberties. One hundred subjects were in the antioxidant group and received daily a mixture of 120 mg ascorbic acid, 30 mg vitamin E, 6 mg ß-carotene, 100 µg selenium (as enriched yeast) and 20 mg zinc (as gluconate) [13]. Eighty-six were in the placebo group.

Subject compliance was assessed monthly by the number of pills not taken. At baseline, participants gave their height, weight, age as well as lifestyle, cardiovascular risk factors including smoking status, alcohol consumption, physical activity and declared themselves to be free of any severe pathology. A venous blood sample was obtained from 12 h fasting subjects. Glucose, vitamin C, vitamin E and ß-carotene were determined in plasma, and total cholesterol, triglycerides, apolipoproteins A1 and B, selenium, zinc were determined in serum. For zinc and selenium, blood was collected on trace element controlled Vacutainer® tubes (Pont de Claix, France). For vitamin C, plasma was treated by metaphosphoric acid within 30 min after blood collection. Samples were frozen at –80°C until analysis. Total cholesterol and triglyceride concentrations were measured using an enzymatic method (Technicon DAX 24®, Bayer diagnostics, Tarrytown, NY) and apolipoproteins by immunonephelemetry (Beckman Array®, Fullerton, CA). Glucose was determined using a glucose oxidase method on Reflotron® equipment (Boehringher Mannheim, Mannheim, Germany). Vitamin C was determined by the method of Bourgeois et al. [14]; vitamin E and ß-carotene by high performance liquid chromatography [15], zinc by flame atomic absorption spectrometry [16] and selenium by electrothermal atomic absorption spectrometry [17].

At two years, selenium, zinc, vitamin C, vitamin E and ß-carotene were determined again using the same methods. After chromatographic purification, urinary 11-dehydro TXB2 was determined by enzyme immunoassay (Cayman Chemical, Ann Arbor, Mi, USA) and 2,3 dinor 6 keto PGF1{alpha} by radio immunoassay using an antibody to 6 keto PGF1{alpha} that cross reacts (around 120 %) to 2,3 dinor 6 keto PGF1{alpha} (Biosys, Compiègne, France) [18]. Briefly, urine sample was acidified at pH 3 and loaded with tritiated internal standards ([3H] 2,3 dinor 6 keto PGF1{alpha} was synthetized by incubation of [3H]-6-oxo-PGF1{alpha} with isolated hepatocytes, as previously [19] and [3H]-11-dehydro-TXB2 was from Amersham, les Ulis, France). Then, the sample was applied on reversed phase columns C18 SepPak cartridges (Waters, Milford, MA, USA). The column was washed with 15% ethanol in water and isooctane and the eicosanoids eluted with 7 ml of ethyl acetate:dichloromethane (75:25). After evaporation, the concentrated sample was subjected to thin layer chromatography on a silicagel G 60 (Merck, Darmstadt, Germany) using ethyl acetate:isooctane:acetic acid:H2O (130:30:20:100, V/V) solvent mixture [18]. Gel fractions corresponding to eicosanoids were scraped, and eicosanoids were eluted from the gel with acetonitril:water (9:1). After drying, the samples were resuspended in the buffers used for immunoassays. These methods have been validated by comparison with GCMS [20]. Glutathione peroxidase activity was also determined in platelets as a relevant selenium functional index [21] using a previously described method [22]. For this analysis, blood was collected on EDTA as anticoagulant (Vacutainer® tubes, Pont de Claix, France). Platelet-rich plasma (PRP) was separated by centrifugation of the blood at 190 g for 10 min at ambient temperature. PRP was diluted with one volume of a buffer pH 6.5 containing 129 mM trisodium citrate, 30 mM glucose, 120 mM NaCl and 10 mM EDTA. After centrifugation at 800g for 10 min at ambient temperature, supernatant was eliminated and sedimented platelets were resuspended into 10 ml of the buffer. The suspension was centrifuged at 800 g for 10 min at ambient temperature and the sedimented platelets were homogenized in 200 µl deionised water using ultra-sound probe and immediately frozen at –196°C.

Participants with missing data were not excluded from the analysis. Incomplete questionnaires and insufficient available biological samples were the main reasons for missing values. Statistical analyses were based on the intention-to-treat principle. They were performed using Statview software (SAS Institute, Inc, Cary, North Carolina, USA). Results were expressed as frequencies, medians (range) or means ± standard deviations (SD). Baseline characteristics of the two study groups were compared using two-sample Student's t test after logarithm transformation when necessary and chi-square test. Changes in antioxidant concentrations between baseline and two years were compared using analysis of covariance adjusted for baseline concentrations [23]. Linear multiple regression analysis was used to test the relationship between 11-dehydro TXB2/2,3 dinor 6 keto PG F1{alpha} ratio and the antioxidant status. P < 0.05 was considered as significant.


   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Baseline participant characteristics did not differ significantly between the 2 groups (Table 1). Sub-deficient concentrations [24] of blood selenium (<0.75 µmol/l), zinc (<10.7 µmol/l), vitamin C (<11 µmol/l) and vitamin E (<16.2 µmol/l), were observed in 2, 10, 1 and 0 volunteers respectively.


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  		Table 1. Baseline Characteristics of the Population at the Beginning of the Study

 
Significant increase in blood zinc, selenium, and ß-carotene concentrations between baseline and two years in the antioxidant supplementation study group supported participant compliance (Table 2). Platelet glutathione peroxidase activity was significantly increased in the antioxidant group (p < 0.01, Table 2). No significant difference in urinary 11-dehydro TX B2 and 2,3 dinor 6 keto PG F1{alpha} concentrations was detected between the two study groups at two years (Fig. 1a and 1b). However, the median urinary 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio was significantly lower in the multi-antioxidant supplementation study group at two years (3.4 versus 2.78, p = 0.01; Fig. 1c). Among the five serum or plasma antioxidants measured, serum selenium concentration was the only one that was significantly related to the urinary 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio in multiple linear regression analysis (Table 3). When using selenium functional index, the five measured antioxidants failed to demonstrate a significant relationship with urinary 11-dehydro TXB2 and 2,3 dinor 6 keto PGF1{alpha} concentrations (Table 3).


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  		Table 2. Changes in Antioxidant Status at Baseline (T0) and after 2 Years (T2) of Daily Antioxidant Supplement at Moderate Doses

 

Figure 1
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  		Fig. 1. Effect of antioxidant supplement for 2 years on urinary 11-dehydro TXB2 2,3 dinor 6 keto PGF1{alpha}, and their ratio.

Fig. 1a: Effect of antioxidant supplement for 2 years on urinary 11-dehydro TXB2.

Fig. 1b: Effect of antioxidant supplement for 2 years on urinary 2,3 dinor 6 keto PGF1{alpha}.

Fig. 1c: Effect of antioxidant supplement for 2 years on urinary 11-dehydro TXB2/2,3 dinor 6 keto PG F1{alpha} ratio.

 

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  		Table 3. Multiple Linear Regression Analysis to Predict Urinary 11-dehydro TXB2/ 2,3 dinor 6 keto PGF1{alpha} Ratio1

 

   DISCUSSION
 
Compliance during the-2 year supplementation period was supported by a significant increase in blood ß-carotene, zinc and selenium concentrations. Due to the limited number of subjects recruited and appropriate initial status, no significant change was detected for plasma vitamin E and C concentrations, whereas in a sub-sample of 1000 SU.VI.M.AX volunteers [25] or in the entire SU.VI.M.AX population [13], a significant increase in these two parameters was observed in the antioxidant group compared to placebo group after 2 years follow-up.

The results of this randomised, double blind, placebo-controlled trial suggest that a low-dose multi-antioxidant supplementation in presumably healthy subjects may reduce the urinary 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio that has been reported to be a predictor of platelet activation, although it remains conflicting. However, no significant decrease in urinary 11-dehydro TXB2, a commonly used in vivo index of platelet activation was observed. These results suggest a weak effect of the vitamin and mineral supplementation but remain noteworthy as baseline characteristics of the participants suggested that they had a low risk of cardiovascular diseases. Alcohol consumption was within the range which reduces the risk of coronary heart diseases [26]. Among volunteers, 10% only were smokers, 45% had stopped smoking and 2.8% were obese (BMI ≥ 30). They were not considered to have a high risk of diabetes [27] nor of dyslipidemia given the fact that even though they had a slightly elevated total cholesterol, their apolipoprotein A1 concentrations were high and their apolipoprotein B/apolipoprotein A1 ratio was within the reference range [27].

Our results are in accordance with those of different trials conducted in healthy subjects within the lower range of normal antioxidant status, evaluating selenium [7,12], vitamin E [2], vitamin C [28,29] or a multi-antioxidant supplement [30] on platelet function. However, some studies reported no effect on platelet function after vitamin E [8,31], vitamin C [2], ß-carotene [2] or selenium [32] supplementation in subjects with baseline antioxidant status in the higher range of reference values. This may result from the fact that baseline antioxidant status is a main confounding factor, the greatest modification being observed in people with lowest basal concentration. Baseline antioxidant status of our participants, as assessed by the determination of vitamins and trace elements in blood, was within the reference ranges [24]. However, 10% had low serum zinc values and serum selenium was lower than the concentration for optimal glutathione peroxidase activity and immunity [21,33]. Moreover, after two years of supplementation, a significant increase in blood zinc, selenium and ß-carotene concentrations but no significant change was detected for plasma vitamin E and C concentrations. This may confirm an appropriate vitamin E and C status at baseline but inadequate ß-carotene, zinc and selenium status. Finally, the significant difference in platelet glutathione activity between the two groups confirms the functional selenium deficit [21]. Other confounding factors such as supplement dose, duration, chemical form, platelet function index used may modify the results. Patrignani et al. [34] reported no detectable effect of vitamin E supplementation on platelet function in smokers but evidenced an inverse correlation between plasma baseline vitamin E concentrations and urinary 11-dehydro TXB2 while our study shows only a decrease in the ratio of TXA2/PGI2 metabolites on supplementation. In their trial, vitamin E supplementation varied from 300 to 1200 mg/d for 3 weeks, a daily dose 10 to 40 times higher than ours. The effect of zinc supplementation varies largely as zinc stimulates platelet aggregation by different mechanisms [35,36] but oxidation of lipoproteins is prevented which limits atherogenesis [36]. Regarding selenium, the efficacy of the chemical form used in the supplement must also be considered. High doses of selenite have been shown to increase the TXB2/6-keto-PGF1{alpha} ratio in placenta, an effect that would activate blood coagulation, whereas selenate or Ebselen, an organic form of selenium showing glutathione peroxidase activity, did not have any effect [37]. It is difficult to compare these in vitro results with our in vivo study in which selenium was used as yeast and the effect on PG synthesis was measured in urine.

A multi-antioxidant supplement was used in our study. The potential beneficial effect may be the result of antioxidant interactions, as already demonstrated for vitamin E and C [4,38,39] and for selenium and vitamin E [40,41]. Our results also suggest that serum selenium concentration is the most contributive determinant of 11-dehydro TXB2/2,3 dinor 6 keto PGF1{alpha} ratio, even if we cannot rule out a global effect of all the antioxidants used in our formula. Antioxidants, and among them selenium, as part of glutathione peroxidase reduce lipid peroxidation and therefore counteract its effect on phospholipase A2, cyclo-oxygenase, and prostacyclin synthase, consequently modulating thromboxane and prostacyclin synthesis as summarized in Fig. 2 [3,10]. The discrepancy between the two linear regression models may be related to the observation that platelet glutathione peroxidase activity reaches a plateau when selenium intakes are higher than 90 µg/d which correspond to a plasma concentration of approximately 1.25 µmol/l [21,33].


Figure 2
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  		Fig. 2. Proposed scheme for the effect of antioxidant on arachidonic acid and hence on thromboxane/prostacyclin ratio.

 

   CONCLUSION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 CONCLUSION
ACKNOWLEDGMENTS
 REFERENCES
 
Our findings support the potential efficacy of low-dose antioxidant supplementation in decreasing the TXA2/PGI2 ratio in healthy adults and confirm that the TXA2/PGI2 ratio may be more sensitive than metabolites alone for demonstrating a beneficial effect of supplementation on platelet activation. This may be of interest considering the role of the TXA2/PGI2 imbalance in the pathogenesis of thrombosis and atherosclerosis, although the observed effect is weak as evidenced by the lack of significant differences in urinary 11-dehydro TXB2 or 2,3 dinor 6 keto PGF1{alpha} concentrations and that the involvement of eicosanoids in atherosclerosis can not be summarised as the TXA2/PGI2 ratio. In addition no statistically significant differences in cardiovascular disease incidence have been evidenced in the SU.VI.M.AX trial which included 13017 adults followed for 7.5 years [13]. This discrepancy merits further study as it may reflect either a long gap between biological and clinical signs, the effect of confounding factors or a possible dose-effect due a long-term supplementation. The practical implications of these results for optimal antioxidant intake recommendations for prevention of cardiovascular diseases in the general population remained to be demonstrated.


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
REFERENCES
 
This work was supported by a grant from "Centre Evian pour l'Eau", Bourg-la-Reine, France and from the French Society for Clinical Biology.

We are grateful to the staff of the SU.VI.M.AX study, to all those who helped in carrying out this study and to the volunteers who participated in this trial. We thank Susan Gamon for providing assistance with translation.


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by grants from "Centre Evian pour l'Eau" and French Society for Clinical Biology (SFBC).

Received May 17, 2005. Accepted September 12, 2006.


   REFERENCES
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 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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