Handbook of Vitamin C Research

64Yasuo Kagawa, Shizu Higasa, Masaru Tsujimura et al.R.DOSEFigure 4. EAR, RDA, Optimal Nutrition and UL, and an example of VC-related genetic polymorphisms[31]. EAR: estimated average requirement for Japanese (12 – 70 years over) [28]. RDA: recommendeddietary allowance for Japanese (12 -70 years over) [28]. UL: tolerable upper intake level SD: standarddeviation of EAR. RDA is defined as EAR + 2SD. OPT. NUTR.: optimal nutrition.SCURVY: scurvyprevention dose.According to the free radical theory of ageing [14], VC and other antioxidantsupplements are expected to prevent age-related diseases, including cardiovascular diseasescaused by oxidative stress and xenobiotics [10, 33, 35]. In fact, in vivo studies [10] andepidemiological surveys, including our Mongolian study showing low VC and VE and highoxidative stress (Table 1) [9], have confirmed the preventive effects of VC and VE onoxidative stress [10]. As shown in the results of VC deficient Mongolians (the lowest line ofTable 1; 8OHdG), oxidation of guanosine yields potentially mutagenic 8-oxo-7,8-dihydro-2‘-deoxyguanosine (8OHdG), which results in GC3TA transversions in 50% of the replicatingDNA [72]. In fact, loading mitochondria with AsA via DAsA treatment conferred protectionagainst H 2 O 2 -induced 8OHG formation [43]. However, the interventional trials on the longtermadministration of VC remain controversial [10, 33]. This discrepancy regarding thepreventive effects of antioxidants may partly be attributed to the genetic heterogeneity ofstudy populations [5, 8], the pro-oxidant property of VC under special conditions [12, 20,21], the unique VC auxotrophy of humans [1, 25], a lack of uric acid catabolism [24] andstudy conditions. VC supplementation in human subjects after a 21-km run revealedbiochemical and ultrastructural indices of muscle damage [73], perhaps because VC exhibitedpro-oxidant properties due to the highly oxidative nature of the monodehydroascorbate