No abstract

Oxidative stress has been proposed as a key contributor to lifestyle- and age-related diseases. Because free radicals play an important role in various processes such as immune responses and cellular signaling, the body possesses an arsenal of different enzymatic and non-enzymatic antioxidant defense mechanisms. Oxidative stress is, among others, the result of an imbalance between the production of various reactive oxygen species (ROS) and antioxidant defense mechanisms including vitamin E (α-tocopherol) as a non-enzymatic antioxidant. Dietary vitamins, such as vitamin C and E, can also be taken in as supplements. It has been postulated that increasing antioxidant levels through supplementation may delay and/or ameliorate outcomes of lifestyle- and age-related diseases that have been linked to oxidative stress. Although supported by many animal experiments and observational studies, randomized clinical trials in humans have failed to demonstrate any clinical benefit from antioxidant supplementation. Nevertheless, possible explanations for this discrepancy remain underreported. This review aims to provide an overview of recent developments and novel research techniques used to clarify the existing controversy on the benefits of antioxidant supplementation in health and disease, focusing on α-tocopherol as antioxidant. Based on the currently available literature, we propose that examining the difference between antioxidant activity and capacity, by considering the catabolism of antioxidants, will provide crucial knowledge on the preventative and therapeutical use of antioxidant supplementation in oxidative stress-related diseases.

Background & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (a-tocopherol, a-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between a-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. a-TOH metabolites in blood (a-TOH and a-CEHC-SO 3) and urine [sulfate (SO 3) and glucuronide (GLU) of both a-TLHQ (oxidized) and a-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MSeMS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of a-TOH metabolites and measures of glucose homeostasis. Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood a-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (a-TLHQ-SO 3 /GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher a-TLHQ-SO 3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary a-TLHQ to a-CEHC ratio as a measure of oxidized-over-enzymatic conversion of a-TOH. Conclusion: Higher urinary levels of oxidized a-TOH metabolites as well as higher oxidized-to-enzymatic a-TOH metabolite ratio, but not circulating a-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating a-TOH, estimates of the conversion of a-TOH might be informative in relation to health and disease.

Background: Intake, either as dietary components or as supplements, and blood concentrations of vitamin E, C, lycopene and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot not be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically-influenced antioxidant levels in blood and ischemic stroke using Mendelian Randomization (MR). Methods: For each circulating antioxidant (vitamin E, C, lycopene, β-carotene and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, genetic instrumental variables were generated from earlier genome wide association studies. We used summary statistics for SNP-stroke associations from three European-ancestry cohorts (cases/controls): MEGASTROKE (67,162/454,450), UK Biobank (2,404/368,771) and FinnGen study (8,046/164,286). MR analyses were performed on each exposure per outcome cohort using inverse-variance weighted analyses, and subsequently meta-analyzed. Results: In a combined sample of 1,065,119 individuals (77,612 cases), none of the genetically-influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (95% CI) ranged between 0.94 (95% CI: 0.85 to 1.05) for vitamin C and 1.04 (95% CI: 0.99 to 1.08) for lycopene. For metabolites, odds ratios ranged between 1.01 (95% CI: 0.98 to 1.03) for retinol and 1.12 (95% CI: 0.88 to 1.42) for vitamin E. Conclusion: This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.

The antioxidant vitamin E (α-tocopherol, α-TOH) protects lipids from oxidation by reactive oxygen species. We hypothesized that lifestyle factors associate with vitamin E metabolism marked by urinary α-tocopheronolactone hydroquinone (α-TLHQ) and α-carboxymethyl-hydroxychroman (α-CEHC levels), as potential reflection of lipid oxidation. We conducted a cross-sectional study in the Netherlands Epidemiology of Obesity Study. Serum α-TOH, and urinary α-TLHQ and α-CEHC were quantified by liquid chromatography coupled with tandem mass spectrometry. Information on the lifestyle factors (sleep, physical activity (PA), smoking and alcohol) were collected through questionnaires. Multivariable linear regression analyses were performed to assess the associations between the lifestyle factors and α-TOH measures. A total of 530 participants (46% men) were included with mean (SD) age of 56 (6) years. Of the examined lifestyle factors, only poor sleep was associated with a higher serum α-TOH (mean difference: 4% (95% CI: 1, 7%)). Current smoking was associated with higher urinary α-CEHC (32%: (14%, 53%)), with evidence of a dose–response relationship with smoking intensity (low pack years, 24% (2, 52%); high pack years, 55% (25, 93%)). Moderate physical activity was associated with a lower α-TLHQ relative to α-CEHC (−17%: (−26, −6%), compared with low PA). Only specific lifestyle factors associate with vitamin E metabolism. Examining serum α-TOH does not provide complete insight in vitamin E antioxidant capacity.