Handbook of Vitamin C Research

70Yasuo Kagawa, Shizu Higasa, Masaru Tsujimura et al.substrates produced during Phase I detoxification by P450. Among the various genes thatencode GSTs, GSTP1 is expressed most abundantly in the lung and brain, as well as invarious cancers [36, 37]. The polymorphic GSTP1 gene encodes GST , which removesoxidized carcinogens forming DNA-adducts, such as benzo-[a]-pyrene. The polymorphic sitein the DNA sequence is characterized by an A to G transition at nucleotide 313 (pointmutation in exon 5). The codon variant results in the amino acids Ile105 or Val105 in GSTat the electrophilic ―H‖-site level. The variant GSTP1 GG genotype is associated with lowerenzymatic activity and higher DNA adduct levels in human lymphocytes when comparedwith the AA genotype [57].GSTP1 is a ubiquitous ―disease modifying‖ gene that affects susceptibility to cancer,Parkinson‘s disease and chronic obstructive pulmonary disease through oxidative stress [39].The odds ratio of lung cancer risk in individuals aged about 50 years with the GG genotype is2.67, as compared with individuals having AA [36]. In a meta-analysis of bladder cancersusceptibility, the odds ratio for GSTP1 GA when compared with GSTP1 AA was 1.54 (p =0.001), and the association was strongest in Asian countries [37].It is noteworthy that the GA heterozygotes in GSTP1 showed increased malondialdehyde levels (p = 0.04) and lower reduced glutathione levels (p = 0.019) when comparedwith AA homozygotes [38]; thus, the G allele of GSTP1 is associated with imbalancedoxidative stress in patients [38]. This may be the cause of the differences in VC metabolismshown in Table 2 and Figure 2 and Figure 3, via rapid DAsA reduction by glutathione andpassive DAsA transport.There are many xenobiotic enzymes that can affect VC metabolism. However, among 22polymorphisms in the genes involved in Phase I oxidation of pyrene to 1-hydroxypyrene byCYP1A1 and CYP2E1, and Phase II conjugation of 1-hydroxylpyrene by GSTP and GSTM,only GSTP1 A313G and glucuronyl-transferase UGT1A1 T3263G show high levels (p G and GSTP1 I105V were as follows: 4.20 and 5.12, 5.11 and3.92, 4.93 and 2.91, respectively [79].From the above evidence, the effects of polymorphism in xenobiotic enzymes on AsAmetabolism are thus evident. However, differences in oxidative stress based on AsA intakeare also large (Table 1). Furthermore, the differences in oxidative stress between Mongoliansand Japanese are clearly not attributable to gene variant frequencies in SOD2, SOD3, GSTP1and GSTP2, which are very similar in both ethnic groups.(5) Dehydroascorbatase: Crystallographic Structure, and AntixenobioticPropertiesThe irreversible step of VC catabolism is the formation of 2, 3-diketo-L-gulonate bydehydroascorbatase [EC 3.1.1.17] [3, 46, 80] or by non-enzymatic delactonization, followedby the formation of oxalate or CO 2 [1, 3, 46]. The nutritional activity of orally ingested