The controversy around antioxidants and prooxidants

“Free radicals are atoms, molecules or ions with unpaired electrons that are highly unstable and active towards chemical reactions with other molecules. They derive from three elements: oxygen, nitrogen and sulfur, thus creating reactive oxygen species (ROS), reactive nitrogen species (RNS) and reactive sulfur species (RSS). Free radical production occurs as a normal byproduct of metabolism within the mitochondria of cells. In addition, external factors such as smoking, environmental chemicals, medications, pesticides and industrial solvents, can promote free radical production. An excessive production of free radicals can lead to oxidative stress and cellular damage. Estimates suggest that an average human cell is targeted by free radicals 10,000 times each day, with the main targets being cellular proteins, DNA, RNA, sugar and lipids (1). Damage to these molecules has been linked to an increased risk of developing chronic diseases such as cancer, cardiovascular diseases, neurological and metabolic disorders (2).

Thus, maintaining a balance between the production and neutralization of free radicals is critical. To deal with this, the body has developed an efficient endogenous system, which includes two major groups: enzyme-based antioxidants and non- enzyme-based antioxidants. The enzyme-based systems include glutathione peroxidase, catalase, and superoxide dismutase, while endogenous non-enzyme-driven antioxidants consist of vitamin A, coenzyme Q10, uric acid and glutathione (3). While these systems are remarkably adept at managing free radical production in the body, they do not suffice. This is where dietary antioxidants contribute to maintaining the concentration of free radicals at manageable levels. The major natural dietary antioxidants include vitamins C and E, carotenoids such as lycopene, beta-carotene, lutein and zeaxanthin, minerals, including zinc and selenium, flavonoids and phenolic antioxidants. These all participate to support the body’s own antioxidant systems. The antioxidants act in various ways: as inhibitors of free radical oxidation reactions (preventive antioxidants) by inhibiting formation of free lipid radicals; by interrupting the propagation of the autoxidation chain reaction (chain breaking antioxidants); as singlet oxygen quenchers; through synergism with other antioxidants; as reducing agents which convert hydroperoxides into stable compounds; as metal chelators that convert metal prooxidants (iron and copper derivatives) into stable products; and finally as inhibitors of pro- oxidative enzymes (lipooxigenases).

Prooxidants are defined as chemicals that induce oxidative stress, usually through the formation of reactive species or by inhibiting antioxidant systems. Free radicals are considered prooxidants, but surprisingly, antioxidants can also have prooxidant behavior; it all depends on their concentration and the nature of neighbouring molecules (4). The controversy around dietary antioxidants arises because the capacity to display antioxidant and prooxidant behaviour depends on various factors. Numerous studies have shown the beneficial effects of antioxidants, in a few thousand papers, but, many others have demonstrated otherwise. It seems that the originally propagated concept of free radicals being toxic molecules and antioxidants being those compounds that could neutralize the negative effects of free radicals is an oversimplification. Free radicals and their prooxidants effects have been suggested as being necessary for vital metabolic activities, including cellular signaling, cellular growth and differentiation, the destruction of infected and malignant cells, and the killing of pathogenic organisms (5, 6). Therefore, it is likely that striking the right balance of free radical production to antioxidant defenses is critical to optimal health, and that an excess of free radicals, as well as an excess of antioxidants, may have deleterious effects on metabolic function (7). In addition, common misconceptions regarding antioxidants – such as “antioxidants cure all disease”, “the more antioxidants the better” and “any antioxidant will do” – can be identified (8). Managing expectations by focusing on sound research, and not hyping these critical nutritional compounds as cure-alls or panaceas, will allow clinicians and individuals to use antioxidants wisely as a part of a comprehensive health regimen.

The research around antioxidants has grown exponentially, but there are still certain limitations that need to be considered before the real potential of these molecules is unleashed. Several antioxidant assays, trying to measure the antioxidant capacity of food, have limitations and interferences which still pose difficulties when comparing results between different procedures and researchers. Five simple questions that should not be ignored but should be promptly answered when analyzing antioxidant activity have been proposed: 1) What are the true protective properties of antioxidants and what is the antioxidant protecting against? 2) What substrates are oxidized and what products are inhibited? 3) What is the location of the antioxidant in the system? 4) What is the effect of other interacting components? 5) What conditions are relevant to real-life applications? Responding to these questions beforehand could be the first step to narrow down conflicting results. It is true that adequate antioxidant consumption through diet and supplements is beneficial and displays a useful role in human health. The academic community should search deeper into the kinetics and in vivo mechanisms of antioxidants to uncover the optimal concentrations or desired functions in order to push forward the prevention of cancer, neurodegenerative and cardiovascular diseases.”

Based on: Carocho M. and Ferreira I. A review on antioxidants, prooxidants and related controversy: Natural and synthetic compounds, screening and analysis methodologies and future perspectives. Food and Chemical Toxicology. 2013; 51:15–25.

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