Elsevier

Free Radical Biology and Medicine

Volume 43, Issue 10, 15 November 2007, Pages 1388-1393
Free Radical Biology and Medicine

Original Contribution
The relationship between dose of vitamin E and suppression of oxidative stress in humans

https://doi.org/10.1016/j.freeradbiomed.2007.06.019Get rights and content

Abstract

The oxidation hypothesis of atherogenesis has been the focus of much research over the past 2 decades. However, randomized placebo-controlled trials evaluating the efficacy of vitamin E in preventing cardiovascular events in aggregate have failed to show a beneficial effect. Implicit in these trials is that the dose of vitamin E tested effectively suppressed oxidative stress status but this was never determined. We defined the dose-dependent effects of vitamin E (RRR-α-tocopherol) to suppress plasma concentrations of F2-isoprostanes, a biomarker of free radical-mediated lipid peroxidation, in participants with polygenic hypercholesterolemia and enhanced oxidative stress, a population at risk for cardiovascular events. A time-course study was first performed in participants supplemented with 3200 IU/day of vitamin E for 20 weeks. A dose-ranging study was then performed in participants supplemented with 0, 100, 200, 400, 800, 1600, or 3200 IU/day of vitamin E for 16 weeks. In the time-course study, maximum suppression of plasma F2-isoprostane concentrations did not occur until 16 weeks of supplementation. In the dose-ranging study there was a linear trend between the dosage of vitamin E and percentage reduction in plasma F2-isoprostane concentrations which reached significance at doses of 1600 IU (35 ± 2%, p < 0.035) and 3200 IU (49 ± 10%, p < 0.005). This study provides information on the dosage of vitamin E that decreases systemic oxidant stress in vivo in humans and informs the planning and evaluation of clinical studies that assess the efficacy of vitamin E to mitigate disease.

Section snippets

Participants

These studies were approved by the Vanderbilt University Institutional Review Board and all participants gave informed consent. Individuals with polygenic hypercholesterolemia were studied. Men and women who had a total serum cholesterol level higher than 200 mg/dl at the initial screening evaluation were selected for entry into the study. Subjects with any known disease except for minor nonsystemic ailments were excluded, as were individuals who smoked or were taking multivitamins or other

Time-course study

The time course of the effect of daily administration of 3200 IU/day of vitamin E on reduction of plasma concentrations of F2-isoprostanes is shown in Fig. 1. Repeated measures of trend analysis showed a significant overall time effect on suppression of plasma concentrations of F2-isoprostanes by vitamin E (p < 0.001). A significant reduction from mean plasma concentrations of F2-isoprostanes at week 0 (61.7 ± 6.5 pg/ml) did not occur until after 16 weeks of vitamin E supplementation (36.3 ± 

Discussion

This study has defined the clinical pharmacology of vitamin E in humans with increased oxidative stress associated with polygenic hypercholesterolemia. The goal of these experiments was to obtain information regarding the relationship between dose of vitamin E and suppression of oxidative stress in humans and the duration of treatment required to achieve this effect. This information is essential for the interpretation of clinical studies that have been performed exploring the ability of

Acknowledgments

This work was supported by NIH Grants GM42056 (MERIT Award to L.J.R.); HL65709 and HL57986 (to S.F.); HL58427 (to M.F.L.); DK48831, GM15431, and ES13125 (to J.M.); and DK26657.

References (47)

  • G.W. Burton et al.

    Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E

    Am. J. Clin. Nutr.

    (1998)
  • M.G. Traber et al.

    Vitamin E, antioxidant and nothing more

    Free Radic. Biol. Med.

    (2007)
  • S.A. Dillon et al.

    Dietary supplementation with aged garlic extract reduces plasma and urine concentrations of 8-iso-prostaglandin F(2 alpha) in smoking and nonsmoking men and women

    J. Nutr.

    (2002)
  • H. Wiseman et al.

    Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans

    Am. J. Clin. Nutr.

    (2000)
  • J.N. Hathcock et al.

    Vitamins E and C are safe across a broad range of intakes

    Am. J. Clin. Nutr.

    (2005)
  • H. Kappus et al.

    Tolerance and safety of vitamin E: a toxicological position report

    Free Radic. Biol. Med.

    (1992)
  • E.B. Rimm et al.

    Vitamin E consumption and the risk of coronary heart disease in men

    N. Engl. J. Med.

    (2002)
  • M.J. Stampfer et al.

    Vitamin E consumption and the risk of coronary disease in women

    N. Engl. J. Med.

    (1993)
  • D. Steinberg et al.

    Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity

    N. Engl. J. Med.

    (1989)
  • S. Yla-Herttuala et al.

    Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man

    J. Clin. Invest.

    (1989)
  • J. Virtamo et al.

    Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease

    Arch. Intern. Med.

    (1998)
  • G. de Gaetano

    Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project

    Lancet

    (2001)
  • E. Lonn et al.

    Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE)

    Circulation

    (2001)
  • Cited by (212)

    • Highly Reactive Isolevuglandins Promote Atrial Fibrillation Caused by Hypertension

      2020, JACC: Basic to Translational Science
      Citation Excerpt :

      Contemporary antioxidants have been largely ineffective in such diseases, including AF. However, therapeutically used doses of antioxidants such as vitamin E and fish oil are not effective to reduce in vivo measures of oxidative injury (e.g., F2-isoprostanes, widely used sensitive markers of oxidative stress) (57–59). Dicarbonyl scavengers represent an alternative strategy to leave ROS generation intact, but to rapidly scavenge reactive lipid mediators as they form, rendering them inactive, so that they cannot interact with their biological targets.

    View all citing articles on Scopus
    View full text