Handbook of Vitamin C Research

4Kelsey H. Fisher-Wellman and Richard J. Bloomerand thus potential to damage the surrounding tissues are relatively minor in comparison toother radicals [1]. In essence, biological systems appear to favor the formation of AFR(albeit a radical species) at the expense of other, more harmful radicals (e.g., alkoxyl andhydroxyl radical). Moreover, both the AFR and DHA are capable of being recycled back intovitamin C by way of thirodoxin reductase or other currently unidentified enzymes (AFRreductase,DHA-reductase) [2]. Lastly, as mentioned earlier, the toxicity of vitamin C isquite low, as even high doses appear well tolerated [4].Clearly vitamin C is an effective antioxidant within biological systems; however, itsability to also reduce catalytic metals such as iron and copper (Fe 3+ and Cu 2+ to Fe 2+ andCu 1+ ) has led some to speculate that vitamin C might also possess prooxidant properties invivo [1]. Mixtures of vitamin C with copper or iron have been used for decades to induce invitro oxidative modifications of lipids, proteins and DNA [1]. In the presence of transitionmetals, hydrogen peroxide is rapidly converted to the harmful hydroxyl radical (via theFenton reaction), which is capable of promoting extensive oxidative damage to virtuallyevery biomolecule known [12]. However, considerable controversy exists as to whether thismechanism is relevant in vivo [13,14], as the body possesses an efficient capability tosequester such metals via the presence of an extensive concentration of metal bindingproteins such as ferritin and transferrin [15]. In fact, transferrin iron-binding capacity inplasma is three times greater than the amount of iron needing to be transported [15]. Bindingof transition metals to their respective transport protein inhibits their ability to initiate lipidperoxidation, inhibit certain antioxidants, or lead to the formation of hydroxyl radical [15].In accordance with the ―crossover‖ effect, prooxidant/antioxidant status is primarilymediated by the concentration and form of catalytic metals present, with low concentrationsof vitamin C being required for pro-oxidant conditions, whereas high concentrations appearto result in antioxidant effects [9]. In the presence of vitamin C, catalytic metals will initiateradical chain reactions [16]; however, the extent of radicals formed and damage done iscontingent upon the concentration of vitamin C [9]. As the vitamin C concentration islowered, the initiation processes are slowed to an extent, but more importantly, the rate of theantioxidant reactions of vitamin C are also slowed; thus the radical chain length will belonger and more oxidative damage will occur (albeit at a slower rate) [9]. In opposition, highconcentrations of vitamin C in the presence of catalytic metals will indeed result in rapidinduction of radical formation; however, the excess availability of vitamin C willconcomitantly terminate this process, thus preventing extensive further RONS production andoxidative damage.Taken together, with low levels of catalytic metals, vitamin C will almost always serve asan antioxidant. However, under conditions in which excess availability of transition metalsare present (such as the performance of muscle damaging exercise or the presence of certaindiseased conditions), excess vitamin C may be problematic and thus contraindicated [9], as isthe case in individuals suffering from thalassaemia or haemochromatosis (pathologicalconditions associated with iron overload) [16]Related to the effects of supplementation on disease, vitamin C has been shown todecrease lipid peroxidation, as well as protect extracellular low density lipoprotein frommetal catalyzed oxidation [10,11] when the concentration of vitamin C is greater than 40μmol/L [11]. For these reasons, coupled with the aforementioned role of vitamin C in