Serum Metabolomic Response to Low- and High-Dose Vitamin E Supplementation in Two Randomized Controlled Trials

Abstract

Background: Vitamin E is an essential micronutrient and critical human antioxidant previously tested for cancer preventative effects with conflicting clinical trial results that have yet to be explained biologically.

Methods: We examined baseline and on-trial serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and for 100 men administered 50 IU ATA or placebo daily in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC). Over 970 metabolites were identified using ultrahigh-performance LC/MS-MS. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E versus those receiving placebo in VEAPS as compared with ATBC.

Results: Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta/gamma-tocopherol were significantly altered by ATA supplementation in both trials (all P values ≤5.1 × 10-5, the Bonferroni multiple comparisons corrected statistical threshold). Serum C22 lactone sulfate was significantly decreased in response to the high-dose vitamin E in VEAPS (β = -0.70, P = 8.1 × 10-6), but not altered by the low dose in ATBC (β = -0.17, P = 0.4). In addition, changes in androgenic steroid metabolites were strongly correlated with the vitamin E supplement-associated change in C22 lactone sulfate only in the VEAPS trial.

Conclusions: We found evidence of a dose-dependent vitamin E supplementation effect on a novel C22 lactone sulfate compound that was correlated with several androgenic steroids.

Impact: Our data add information on a differential hormonal response based on vitamin E dose that could have direct relevance to opposing prostate cancer incidence results from previous large controlled trials.

Trial registration: ClinicalTrials.gov NCT00114387 NCT00342992.

Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Diagram of sex steroid metabolism and hormone metabolite correlations with C22 lactone sulfate (X-12063). Bold values indicate statistical significance of the correlation reaching the Bonferroni multiple comparisons corrected statistical threshold.