How can a chemically well established antioxidant work differently when in the body

Is There An Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible. Readers are invited to e-mail ascenzi@uniroma3.it if they have questions to contribute or if they can provide answers to questions that are provided here from time to time. In the latter case, instructions will be sent to interested readers. Answers should be, whenever possible, evidence-based and provide relevant references. Paolo Ascenzi The idea that an antioxidant can work as nonantioxidant in the human body looks indeed like a molecular ‘‘to be or not to be’’. Indeed, it is not a dilemma, but an opportunity. Let us proceed with some order. Oxidation reactions are essential for life, being responsible, among others, for the liberation of free energy from lipid and carbohydrates for its subsequent storage in form of adenosine triphosphate. Oxidation reactions can also be disadvantageous when creating chemical modifications of phospholipid, protein, DNA, and regulatory molecules. Increased, uncontrolled oxidations may be part of the pathogenesis of many human ailments such as cancer, atherosclerosis heart disease, stroke, cataracts, Parkinson’s disease, Alzheimer’s disease, and arthritis. However, it is not clear whether the excess oxidations are a cause or consequence of the disease. Uncontrolled oxidation reactions may be detrimental for cells especially via the formation of free radicals and associated chain reactions (1–3). Antioxidants are molecules that retard or prevent the oxidation of other compounds. Not only soluble antioxidants but also complex enzymatic systems such as catalase, superoxide dismutase and some peroxidases may be used by cells to avoid undesired oxidations. A number of molecules are provided with chemically established antioxidant properties, among them are the well-known tocopherols, tocotrienols, ascorbic acid, glutathione, uric acid, bilirubin, lipoic acid, ubiquinol, and polyphenols. Other molecules are also considered to possess antioxidant properties such as carotenes, estrogens, melatonin, etc. On the assumption that increased oxidative damage represents an important part of human disease initiation and progression, antioxidant supplements have been automatically adopted as health promoters. The euphoric application of this paradigm has created a huge popularity for all antioxidants as food additives, in cosmetic products and in pharmaceutical preparations. Such an enthusiasm has a cost and is costing to the consumers many billions of $ each year and, with the purpose of providing scientific evidence for their action, has resulted in a large number of needed (and highly expensive) intervention studies. Unfortunately, most of the clinical trials carried out to test the in vivo efficacy of antioxidants could not measure any benefit of antioxidant administration (4). The following are three important relevant studies. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) (5) involved Finnish men who were heavy