Nutrients with an antioxidant role
The potential beneficial effects of antioxidants in protecting against disease have been used as an argument for recommending increasing intakes of several nutrients above those derived by conventional methods. If it is possible to quantify such claims, antioxidant properties should be considered in decisions concerning the daily requirements of these nutrients. This section examines metabolic aspects of the most important dietary antioxidants—vitamins C and E, the carotenoids, and several minerals—and tries to define the populations which may be at risk of inadequacy to determine whether antioxidant properties per se should be, and can be, considered in setting a requirement. In addition, pro-oxidant metabolism and the importance of iron are also considered.
Members of the Food and Nutrition Board of the National Research Council in the United States recently defined a dietary antioxidant as a substance in foods which significantly decreases the adverse effects of reactive
oxygen species, reactive nitrogen species, or both on normal physiological function in humans (1). It is recognized that this definition is somewhat narrow because maintenance of membrane stability is also a feature of antioxidant
function (2) and an important antioxidant function of both vitamin A (3) and zinc (4). However, it was decided to restrict consideration of antioxidant function in this document to nutrients which were likely to interact more directly with reactive species.
The need for biological antioxidants
It is now well established that free radicals, especially superoxide (O2.-), nitric oxide (NO.), and other reactive species such as hydrogen peroxide (H2O2), are continuously produced in vivo (5–7). Superoxide in particular is produced by leakage from the electron transport chains within the mitochondria and microsomal P450 systems or formed more deliberately, for example, by activated phagocytes as part of the primary immune defence in response to foreign substances or to combat infection by microorganisms . Nitric oxide is produced from l-arginine by nitric oxide synthases, and these enzymes areVITAMIN AND MINERAL REQUIREMENTS IN HUMAN NUTRITION
Found in virtually every tissue of the mammalian body, albeit at widely different levels . Nitric oxide is a free radical but is believed to be essentially a beneficial metabolite and indeed it may react with lipid peroxides and function
as an antioxidant. Nitric oxide also serves as a mediator whereby macrophages express cytotoxic activity against microorganisms and neoplastic cells . If nitric oxide is at a sufficiently high concentration, it can react rapidly with superoxide in the absence of a catalyst to form peroxynitrite. Peroxynitrite is a potentially damaging nitrogen species which can react through several different mechanisms, including the formation of an intermediate
through a reaction with a hydroxyl radical .
To cope with potentially damaging reactive oxidant species (ROS), aerobic tissues contain endogenously produced antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase as well as
several exogenously acquired radical-scavenging substances such as vitamins E and C and the carotenoids . Under normal conditions, the high concentrations of SOD maintain superoxide concentrations at a level too low to
allow the formation of peroxynitrite. It is also important to mention the antioxidant,reduced glutathione (GSH). GSH is ubiquitous in aerobic tissues, and although it is not a nutrient, it is synthesized from sulfhydryl-containing amino acids and is highly important in intermediary antioxidant metabolism . Integrated antioxidant defences protect tissues and are presumably in equilibrium with continuously generated ROS to maintain tissues metabolically intact most of the time. Disturbances to the system occur when production of ROS is rapidly increased, for example, by excessive exercise, high exposure to xenobiotic compounds (such as an anaesthetic, pollutants, or unusual food), infection, or trauma. Superoxide production is increased by activation of
NADPH oxidases in inflammatory cells or after the production of xanthine oxidase, which follows ischaemia. The degree of damage resulting from the temporary imbalance depends on the ability of the antioxidant systems to
respond to the oxidant or pro-oxidant load. Fruits and vegetables are good sources of many antioxidants, and it is reported that diets rich in these foods are associated with a lower risk of the chronic diseases of cancer (15) and heart disease . Hence, it is believed that a healthful diet maintains the exogenous antioxidants at or near optimal levels thus reducing the risk of tissue damage. The most prominent representatives of dietary antioxidants are
vitamin C, tocopherols, carotenoids, and flavonoids (17–19). Requirements for flavonoids are not being considered at this time, as work on this subjectis still very much in its infancy. In contrast, several intervention studies have
been carried out to determine whether supplements of the other nutrients can provide additional benefits against diseases such as those mentioned above. The components of biological tissues are an ideal mixture of substrates
for oxidation. Polyunsaturated fatty acids (PUFAs), transition metals, and oxygen are present in abundance but are prevented from reaction by cellular organization and structure. PUFAs are present in membranes but are always
found with vitamin E. Transition metals, particularly iron, are bound to both transport and storage proteins; abundant binding sites on such proteins prevent overloading the protein molecule with metal ions. Tissue structures, however, break down during inflammation and disease, and free iron and
other transition metals have been detected during these periods . Potentially damaging metabolites can arise from interactions between transition metals and the ROS described above. In particular, the highly reactive
hydroxyl radical can be formed by the Fenton and Haber-Weiss reactions with an iron-salt catalyst) .
Pathologic conditionsgreatly increase the concentrations of both superoxide and nitric oxide, and the formation of peroxynitrite has been demonstrated in macrophages, neutrophils, and cultured endothelium . During inflammation or other forms of stress and disease, the body adopts new measures to counter potential pro-oxidant damage. The body alters the transport and distribution of iron by blocking iron mobilization and absorption, and stimulating iron uptake from plasma by liver, spleen, and macrophages . Nitric oxide has been shown to play a role in the coordination of iron traffic by mimicking the consequences of iron starvation and leading to the cellular uptake of iron . The changes accompanying disease are generally termed the acute-phase response and are, generally, protective