Handbook of Vitamin C Research

Impact of Vitamin C on Exercise-Induced Oxidative Stress 9peroxide, peroxynitrite) species all with various physiological functions and/or consequences[24].Superoxide radical is the one electron reduction of molecular oxygen and is produced asa byproduct of normal cellular metabolism [59]. As oxygen undergoes a series of oneelectronreductions with cytochrome c oxidase in complex IV of the mitochondrial electrontransport chain, superoxide radical, hydrogen peroxide, hydroxyl radical and finally, water,are produced [59]. This is due to the preference of molecular oxygen to accept its electronsone at a time [12]. Although the reduction of oxygen is a very efficient process, it seems thatsome of the electrons transferred may ―leak‖ to oxygen prematurely, resulting in theproduction of superoxide [24]. The process of energy production via oxidativephosphorlation and subsequent formation (―leakage‖) of superoxide intracellularly is aconstant process. It is believed that approximately 1-3% of all electrons in the transportchain may ―leak‖ to generate superoxide, rather than contributing to the reduction of oxygento water [24]. As such, it could be inferred that any situation that results in increased transferof electrons through the electron transport chain could potentially result in increasedformation of superoxide anion, resulting in an acute state of oxidative stress. One situation inwhich electron transfer is increased includes the performance of physical exercise. This issueis addressed in detail in a later section.Superoxide can also be produced enzymatically by way of several oxidase enzymes, suchas xanthine oxidase or NAD(P)H oxidase. Xanthine oxidase generates superoxide, primarilyin response to conditions of ischemia followed by reperfusion, by catalyzing the oxidation ofhypoxanthine to xanthine and xanthine to uric acid [60]. Intentional production ofsuperoxide also occurs as a component of the respiratory burst (accelerated oxygen uptake) ofphagocytic cells, such as neutrophils, macrophages, and lymphocytes [12]. This mechanismserves to protect the body against invading bacteria and is mediated by the enzyme NAD(P)Hoxidase, which is present in the plasma membrane of these cells [59]. This protectivemechanism can become problematic however, if phagocytic cells become activated in thewrong location or to excessive extents, thus releasing excess superoxide radical andpotentially resulting in cellular damage or disease progression [12].In either case, superoxide, arising either metabolically or during respiratory burst, isconsidered to be the ―primary‖ RONS produced in biological systems, which can theninteract with other molecules to form ―secondary‖ RONS via enzyme or metal catalyzedprocesses [24]. In fact, most of the damage caused by superoxide is done by initiatingsecondary sources of RONS formation, as well as by acting as a potent proinflammatory andproatherogenic signaler [61]. Superoxide can combine with nitric oxide to form the harmfulradical species, peroxynitrite, which is a long-lived oxidant with the potential to damageDNA [62], as well as lead to the formation of hydroxyl radical [27]. Moreover, thedismutation of superoxide and subsequent formation of hydrogen peroxide may also lay thefoundation for the formation of a much more reactive and harmful radical (hydroxyl radical)via the Fenton reaction, further demonstrating the primary role of superoxide formation ininitiating a series of downstream reactions that result in secondary RONS production andcellular damage [27].