Living organisms developed complex antioxidant mechanisms to protect themselves from potential damage of oxidizing species, such as reactive oxygen species (ROS), and almost all organisms control free radical levels by a fine equilibrium, namely RedOx balance.1–3 The harmful effects of elevated ROS levels can be counteracted by several antioxidant enzymes and substances.1,3–5

The ensemble of such enzymes and substances with antioxidant potential represent the antioxidant network, which is specific for each living organism, cell, tissue and organs. Halliwell and Gutteridge provided a definition of antioxidants, which are substances able to compete with oxidizable substrates, delaying or hampering their oxidation.6 Depending on the nature and the mechanisms through which they work antioxidants can be classified as: 

Enzymatic antioxidant defences include superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), while non-enzymatic antioxidants are represented by ascorbic acid (Vitamin C), α-tocopherol (Vitamin E), glutathione (GSH), carotenoids, flavonoids, and other antioxidants

Direct antioxidants are represented by those chemical species and/or systems that are able to donate one or more than one electron both in vivo and in vitro. The main antioxidants belonging to this class are represented by vitamins (Vit. A, E, C); β-carotene; lipids (omega-3, omega-6, squalene); amino acids and thiols (taurine, arginine, histidine, cysteine, etc…); peptide (carnosine, glutathione); and enzyme (lactoferrin, transferrin, SOD, CAT, GSH transferase, GSH reductase, etc…). Once these substances/systems donate its/their electron(s) they become pro-oxidant species and they need to be re-generated in order to recover their primary function. This is a relevant aspect since:

  • if administered at high doses they can exacerbate the oxidative stress, since the organism will not be able to re-generate them once consumed; 
  • when used as modulators in food supplements it is desirable to administer the direct antioxidants in the right association that will be able to “auto-regenerate” the main antioxidants species. 

Indirect antioxidants are represented by those substances/systems that indirectly elevate the production of NADH antioxidants equivalent, they mainly act as cofactors in different metabolic pathways such as the Pentose Phosphate Pathway (PPP) or are involved in relevant transformation processes, such as the conversion of homocysteine (pro-oxidant) to cysteine (antioxidant). In this case vitamins of the B group and poly-glucosamine are good example of natural indirect antioxidants. Indirect antioxidants can be also represented by those drugs that as a side-effects act on cellular reactivity, such as NSAIDs, steroids, statins, and ACE-inhibitors.


1.          Sies, H. & Jones, D. P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21, 363–383 (2020).

2.         Liguori, I. et al. Oxidative stress, aging, and diseases. CIA Volume 13, 757–772 (2018).

3.         Ursini, F., Maiorino, M. & Forman, H. J. Redox homeostasis: The Golden Mean of healthy living. Redox Biol 8, 205–215 (2016).

4.        Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology 39, 44–84 (2007).

5.        Dröge, W. Free Radicals in the Physiological Control of Cell Function. Physiological Reviews 82, 47–95 (2002).

6.        Halliwell, B. & Gutteridge, J. M. C. The definition and measurement of antioxidants in biological systems. Free Radical Biology and Medicine 18, 125–126 (1995).