expert opinion

Misconceptions about antioxidants

October 1, 2013


Aalt Bast and Guido R. M. M. Haenen, Department of Toxicology, Faculty of Health Medicine and Life Sciences, Maastricht University, The Netherlands

Oxidative damage of fatty acids, proteins, and DNA by reactive oxygen species (ROS) is a common cellular event involved in numerous diseases. Antioxidants react with ROS and neutralize their chemical reactivity. Thus, it has been suggested that antioxidants may avert cellular damage and could be used for preventing and treating diseases, such as atherosclerosis or cancer, which are caused and promoted by a range of factors. Therefore, there has been extensive research into natural dietary antioxidants (such as vitamins E and C and polyphenols) and newly designed antioxidants. Regarding healthful effects, the positive attitude towards antioxidants was based primarily on in vitro experiments. Effective chemical scavenging activity of antioxidants in vitro led to extrapolation that there could be a protective potential in vivo. How-ever, clear pharmacological responses should not be expected from antioxidants. Drugs act on a specific target, such as an enzyme, a receptor, or a transporter. The preferable action of a drug is specific, that is, it acts on a unique target and induces a strong effect. The clinical efficacy of a drug is therefore relatively easy to measure. This contrasts with food and food-derived compounds, such as food supplements. These com-pounds have a multitude of actions. Their action is certainly not specific and their effects on human health are difficult to determine. The efficacy of antioxidants is best tested in terms of their ability to maintain (metabolic) equilibrium within the body (homeostasis). The decay of aerobic life by oxygen leads to disease and can be delayed by appropriate antioxidant measures. What a pity it would be if antioxidant-rich diets or supplements were neglected for their putative beneficial health effects. What a shame it would be if the design and development of new antioxidant drugs were to cease because misconceptions prevail.

Misconception 1: antioxidants cure any disease
Many human studies on prevention of disease development and progression by antioxidants have been conducted; most of them generated inconclusive results. The expectations for antioxidants were set too high and it has been made apparent that these compounds cannot remedy everything. We now realize that high chemical reactivity of the parent compound in vitro is not conclusive evidence that the compound can cure any disease associated with ROS (1).

Misconception 2: antioxidants increase mortality
Articles on antioxidants and mortality have received much attention. For example, a meta-analysis of selec-ted randomized clinical trials concluded that antioxidant supplementation increased all-cause mortality (2). However, this conclusion was refuted after re-examination showed that none of the studies had mortality as a primary outcome (3). Despite the obvious criticism, the general unjustified and unbalanced notion that antioxidants could be highly unsafe remains. Instead of the polarized view whereby antioxidants are either good or bad, a more appropriate approach to evaluating antioxidants would be to discuss big benefits versus high risk (a high benefit-risk ratio). It is important to identify groups who might benefit from antioxidants. We should not place too much credence in unbalanced alarming news.

Misconception 3: the more the better
The Renaissance physician Paracelsus noted more than 500 years ago that every compound has negative effects when the dosage is too high. This also holds for antioxidants. Administration of high doses of antioxi-dants might explain the increased toxicity that is sometimes reported. For example, a daily supplementation with 20 mg of beta-carotene for several years in male heavy smokers has been reported to increase the incidence of lung cancer (4). Note that the estimated average daily intake of beta-carotene is only 2–7 mg (5). Clearly, ‘the more, the better’ is not the case. Identification of an optimal dose with a high benefit-risk ratio is required, along with adequate knowledge of the biotransformation of antioxidants.

Misconception 4: at high doses, antioxidants become pro-oxidant
Antioxidants have the ability to donate electrons. This power reducing quality is essential in neutralizing radicals and other reactive species. In the presence of transition metal ions, electron donation may lead to a pro-oxidant effect. The effect of vitamin C (ascorbic acid) on iron -induced lipid peroxidation in vitro is a very illustrative example of this effect (6). Iron itself induces mild lipid peroxidation and in combination ascorbic acid promotes the lipid peroxidation process by reducing the transition metal ion. At a relatively high con-centration, however, ascorbic acid inhibits lipid peroxidation. Therefore, at low concentrations ascorbic acid behaves as a pro-oxidant but at high concentrations it becomes an antioxidant (7). This contradicts the idea that a high concentration of an antioxidant always has a pro-oxidant effect.

Misconception 5: any antioxidant will do
Antioxidants can be thiols, phenols, and amines and may be either hydrophilic or lipophilic. This diversity gives every antioxidant its unique (bio-)chemical profile, which is reflected in different sites of action and biological activities. Different antioxidants display different biological effects, and for specific pathological conditions the right antioxidant needs to be selected.

Misconception 6: theoretically, antioxidants cannot behave as such
This misconception emanates from the fact that the reaction rate of radicals with (bio-)molecules in the body is very high. This means that in order to protect, antioxidants have to react even faster with radicals, which, it is argued, is impossible. This is correct for extremely reactive hydroxyl radicals. However, lipid peroxyl radicals in membranes, which have a much longer half-life than hydroxyl radicals, can be neutralized by vitamin E (8). Even for hydroxyl radicals, site-specific scavenging, for example by binding to iron and neutra-lizing the radical at the site of formation, may provide protection. In other words, primary protection, that is, preventing the formation of hydroxyl radicals, is possible. Without antioxidants, life in an aerobic environ-ment would be impossible. Antioxidants do act. Their action has been established by determining their effect on biomarkers such as lipids, DNA, or proteins reflecting oxidative damage.

Misconception 7: antioxidant status measures health
Antioxidant status measurements (e.g., oxygen radical absorbance capacity, ORAC) lack specificity (9). However, this could also be an advantage because the measurement comprises the overall activity of several antioxidants at the same time. Antioxidant status might be useful as an indicator of disease severity; however, it does not take into account the unique biochemical profile of specific antioxidants.

Misconception 8: once used, antioxidants are inactive
It seems quite logical that an antioxidant, once oxidized, loses its antioxidant power. This assumption, how-ever, is not entirely correct. Antioxidants function in a network and regeneration of oxidized antioxidants frequently occurs (10).

Misconception 9: natural antioxidants are superior
Chemophobia is widespread (11) and natural antioxidants, frequently denoted by the prefix bio-, are regard-ed to be superior to chemically synthesized antioxidants. For consumers, the word ‘bio’ means natural and is thought to be synonymous with safe. The same school of thought associates the word ‘chemical’ with danger, unjustifiably. The natural and the synthetic vitamin E form RRR-alpha-tocopherol have the same efficacy as a protector against membrane lipid peroxidation, simply because it is the same molecule. This is also true for bio- vitamin C which is bioequivalent to chemically synthesized L-ascorbic acid.

Misconception 10: antioxidant drugs do not work
Many drugs have antioxidant activity even if they are not specifically designed as antioxidants, which may contribute to their therapeutic effects (12). The significance of this antioxidant action depends both on the compound used and the pathology involved. However, it appears to be difficult to establish direct and acute effects of scavenging antioxidant compounds in vivo. The human physiology is already equipped with an elaborate antioxidant network. The effect of antioxidants is particularly clear in situations in which radical formation and subsequent damage are also evident. Antioxidants, for example, can inhibit (cancer) cell proliferation, albeit via various mechanisms. However, it has also been suggested that antioxidants can negatively affect the antitumor action of drugs. Interestingly, although the physiological relevance of the well-described antioxidant action of compounds is frequently disputed, the relatively unsubstantiated notion that antioxidant nutritional supplements cause, rather than prevent, cancer by disturbing oxidant-induced apoptosis of cancer cells is receiving a huge amount of attention (13). The paradox ‘ antioxidants do not work’ because they cannot display antioxidant activity and that they cause toxicity at the same time and even premature mortality via antioxidant activity is contradictory.“

Based on: Bast A. and Haenen G. Ten misconceptions about antioxidants. Trends in Pharmacological Sciences. Published online July 2013.


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