Handbook of Vitamin C Research

50Yasuo Kagawa, Shizu Higasa, Masaru Tsujimura et al.part of a normal diet. Metabolism of VC is increased to detoxify xenobiotics as will bediscussed in section (4).In order to evaluate the VC item in the RDAs for Japanese, following the plan of theVitamin C Research Committee, Vitamin Society of Japan, we have performed depletionrepletionstudies in humans [4]. We selected human subjects instead of other animals becausehumans are unable to synthesize VC [1, 22, 25], and are unable to decompose uric acid [24,25]. Uric acid, despite being a major antioxidant in human plasma, is both correlated withand predictive of development of cardiovascular disease, conditions associated with oxidativestress [25]. The pro-oxidative effects of uric acid are thought to be involved in cardiovasculardisease [24]. VC, as well as vitamin E (VE), is known to be one of the major physiologicalantioxidants based on in vivo experiments [11, 12, 33], in vitro chemical reactions [1, 14-16,34] and numerous epidemiological studies on the incidence of cardiovascular diseases andintake of these antioxidants [10, 33].We have surveyed Mongolian individuals, whose average lifespan (male, 62 years;female, 69 years; WHO World Health Report, 2005) is much shorter than that of Japanese(male, 79 years; female, 85 years), perhaps because of lower blood VC and VE whencompared to levels in Japanese [6], and higher levels oxidative stress [9]. However,interventional trials on the long-term administration of these vitamins have been controversial[10, 33]. For example, in the large (14,641 males), 10-year Physicians' Health Study IIrandomized controlled trial, VC supplementation (500 mg/day) did not reduce the risk ofmajor cardiovascular events [33]. These data provide no support for the use of thesesupplements for the prevention of cardiovascular disease in middle-aged and older men [10,33]. The other antioxidant tested, VE (400 IU/day), was associated with an increased risk ofstroke (HR, 1.74 [95% CI, 1.04 - 2.91]) [10, 33]. The discrepancy in the preventive effects ofantioxidants may partly result from genetic heterogeneity in the study populations, whichlimits generalization to other populations. Another cause of the discrepancy may be the prooxidantproperty of VC depending on the condition [20, 21].(3) Polymorphism of Xenobiotic Enzymes and VC MetabolismThe completion of the Human Genome Project in 2003, after RDAs for VC had beendetermined [28, 29], made it possible to find the genetic contributions to diseases and analyzewhole-genome samples for genetic variations that contribute to their onset [32]. In geneticepidemiology, a genome-wide association study (GWAS) is an examination of geneticvariation across a given genome, designed to identify genetic associations with observabletraits [32]. If genetic variations are more frequent in people with the disease, the variationsare said to be "associated" with the disease. The associated genetic variations are thenconsidered pointers to the region of the human genome where the disease-causing problemresides. Since the entire genome is analyzed for the genetic associations of a particulardisease, this technique allows the genetics of a disease to be investigated in a non-hypothesisdrivenmanner. In human studies, this might include interindividual difference in VCmetabolism [5, 8]. Polymorphisms in genes involved in VC/VE uptake, distribution,metabolism and molecular action may be important determinants for the protective effects of