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Emma A. Meagher, MD; Orla P. Barry, PhD; John A. Lawson, BS; Joshua Rokach, PhD; Garret A. FitzGerald, MD

JAMA. 2001;285:1178-1182.

Context  Oxidative stress may play a role in the development or exacerbation of many common diseases. However, results of prospective controlled trials of the effects of antioxidants such as vitamin E are contradictory.

Objective  To assess the effects of supplemental vitamin E on lipid peroxidation in vivo in healthy adults.

Design  Randomized, double-blind, placebo-controlled trial conducted March 1999 to June 2000.

Setting  A general clinical research center in a tertiary referral academic medical center.

Participants  Thirty healthy men and women aged 18 to 60 years.

Interventions  Participants were randomly assigned to receive placebo or -tocopherol dosages of 200, 400, 800, 1200, or 2000 IU/d for 8 weeks (n = 5 in each group), followed by an 8-week washout period.

Main Outcome Measures  Three indices of lipid peroxidation, urinary 4-hydroxynonenal (4-HNE) and 2 isoprostanes, iPF₂-III and iPF₂-VI, measured by gas chromatography/mass spectrometry and compared among the 6 groups at baseline, 2, 4, 6, and 8 weeks, and 1, 3, and 8 weeks after discontinuation.

Results  Circulating vitamin E levels increased in a dose-dependent manner during the study. No significant effect of vitamin E on levels of urinary 4-HNE or either isoprostane was observed. Mean (SEM) baseline vs week 8 levels of iPF₂-III were 154 (20.1) vs 168 (22.3) pg/mg of creatinine for subjects taking placebo; 165 (19.6) vs 234 (30.1) pg/mg for those taking 200 IU/d of vitamin E; and 195 (26.7) vs 213 (40.6) pg/mg for subjects taking 2000 IU/d. Corresponding iPF₂-VI levels were 1.43 (0.6) vs 1.62 (0.4) ng/mg of creatinine for subjects taking placebo; 1.64 (0.3) vs 1.24 (0.8) ng/mg for those taking 200 IU/d of vitamin E; and 1.83 (0.3) vs 1.94 (0.9) ng/mg for those taking 2000 IU/d. Baseline vs week 8 levels of 4-HNE were 0.5 (0.04) vs 0.4 (0.05) ng/mg of creatinine for subjects taking placebo; 0.4 (0.06) vs 0.5 (0.02) ng/mg with 200 IU/d of vitamin E; and 0.2 (0.02) vs 0.2 (0.1) ng/mg with 2000 IU/d.

Conclusions  Our results question the rationale for vitamin E supplementation in healthy individuals. Specific quantitative indices of oxidative stress in vivo should be considered as entry criteria and for dose selection in clinical trials of antioxidant drugs and vitamins in human disease.

Author Affiliations: Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia (Drs Meagher, Barry, and FitzGerald and Mr Lawson); and the Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne (Dr Rokach).

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