Handbook of Vitamin C Research

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46Yasuo Kagawa, Shizu Higasa, Masaru Tsujimura et al.in rat, Pauling proposed that the optimum intake is 2.3 g/day. This is the problem ofRDA vs. optimal nutrition. Optimal nutrition is wider in scope than RDA that coversgenetic polymorphisms, long-term health outcome during the lifespan, and xenobiotics.Humans (VC auxotrophs) have relatively low plasma AsA levels and high serum uricacid levels compared to most VC-synthesizing mammals (VC autotrophs) due to genedefects in L-gulonolactone oxidase (GLO [EC 1.1.3.8]) and uricase (urate oxidase) [EC1.7.3.3], respectively. Extrapolation of metabolic data of VC autotrophs to estimatehuman optimal nutrition is limited because of the compensatory mechanism for the GLOdefect in VC auxotrophs, including DAsA transport by GLUT1, and specific mutationsin uricase and dehydroascorbatase. Beneficial effects of long-term VC supplementationremain controversial, perhaps because of 1. genetic heterogeneity in study populations,and 2. the balance of antioxidant and pro-oxidant activities of VC depending on thexenobiotic conditions. Thus, in addition to the biochemical studies on AsA and DAsA,human genetic analysis on VC-loading experiments and epidemiological survey areneeded. There are marked interindividual differences (coefficient of variation >45%) inthe metabolism of VC. This difference is evident during oral loading with 1 mmol AsAor DAsA in subjects consuming a diet low in VC (less than 5 mg/day) for 3 days beforeloading in the cross-over experiment. Since tubular maximum reabsorption of AsA(TmAsA) and glomerular filtration rate (GFR) are similar among subjects, degradationsteps of VC may be involved in the personal difference. The metabolisms of three mostimportant water-soluble antioxidants in mammals i.e. VC, urate and glutathione aredifferent in humans and other animals. The effects of polymorphism A313G (Ile105Val)in the gene for glutathione S-transferase P1 (GSTP1) [EC 2.5.1.18], one of the mostactive xenobiotic enzymes in the second phase of detoxification, on human VCmetabolism were thus studied. In an epidemiologic survey of Mongolians (n = 164) withvery low VC intake, serum VC concentration was only 28%, and the level of reactiveoxygen metabolites was 128%, when compared with those in Japanese. The variantfrequency of GSTP1 among Japanese subjects (n = 210) was AA, 71.0%; GA, 27.0%and GG, 1.9%. In Mongolian subjects (n = 93), it was AA, 62.4%; GA, 36.6%; and GG,1.1%.In VC loading experiments, at 24 h after administration of 1 mmol of VC to youngwomen (n = 17; age, 21.0 ± 1.1 y, glomerular filtration rate, GFR = 90 ml/min), total VCexcretion (46.7 ± 18.1 mg) by AA homozygotes of GSTP1 was greater (p < 0.0069) thanthat (28.2 ± 14.0 mg) by GA heterozygotes. One hour after administration of VC, bloodtotal VC levels were also significantly different (p < 0.0036) between the homozygotesand heterozygotes. The results of background experiments were as follows: (1) the VClevel in 24-h urine after VC loading did not differ between the two orally administered Cforms (AsA and DAsA); (2) VC excretion between 0 and 3 h after VC loading wassignificantly higher (p < 0.05) for DAsA, while those between 3 and 6, 6 and 9, 9 and 12,and 12 and 24 h after VC loading were significantly higher (p < 0.05 or p < 0.01) forAsA; and (3) blood VC concentrations and the increase in VC at 1 h after VC loadingwere significantly higher (p < 0.05 and p < 0.01, respectively) in the DAsA group than inthe AsA group. The difference between AsA and DAsA dynamics in (2) and (3) may beexplained by the sodium-dependent active transport of AsA by SVCT1 and 2, andpassive transport of DAsA by glucose transporters (GLUTs) in the presence ofglutathione. The large species differences in DAsA metabolism are partly explained bythe low activity of human dehydroascorbatase, which has a unique structure, as deducedby X-ray crystallography, and a unique sequence of 299 amino acids. The anti-oxidantand anti-xenobiotic roles of monodehydroascorbate radicals both in vivo and in vitro areimportant. ROS are generated mainly in mitochondria but DAsA transported throughGLUT1 into mitochondria is converted into AsA and prevents oxidative stress. Finally
Human Specific Vitamin C Metabolism… 47RDA and optimal nutrition are discussed from the standpoint of human specificmetabolism of VC including prevention against ROS produced by exercise andpathological conditions.Abbreviations(Standard abbreviations of International Union of Biochemistry and Molecular Biologyare omitted)AsA: ascorbic acidCMV: cytomegalovirusDAsA: dehydroascorbic acidDG: dietary goalEAR: estimated average requirementEC: Enzyme Commission numbersGFR: glomerular filtration rateGLO: L-gulonolactone oxidase [EC 1.1.3.8]GLUT: glucose transporterGSH: reduced glutathione: 5-L-glutamyl-L-cysteinyl-glycineGSSG: oxidized glutathioneGSTO: omega class glutathione transferaseGSTP: glutathione S transferase P [EC 2.5.1.18]KO: knockout (mice)8OhdG: 8-oxo-7,8-dihydro-2‘-deoxyguanosineRDA: recommended dietary allowanceROM: reactive oxygen metabolitesROS: reactive oxygen speciesSD: standard deviationSOD: superoxide dismutase [EC 1.15.1.1]SVCT: sodium vitamin C co-transporterTmAsA: tubular maximum reabsorption of ascorbic acidUL: tolerable upper limitVC: vitamin CIntroductionIn this review article, the biomedical significance of human specific vitamin C (VC)metabolism [1-8] and the effects of polymorphisms in xenobiotic enzymes [5, 8] will bepresented based on our experimental results [3-9] to seek optimal human nutrition for VC.VC is a potent antioxidant [10-12] and a cofactor in reactions catalyzed by Cu + -dependentmonooxygenases (such as dopamine- -hydroxylase [EC 1.14.16.2]) and Fe 2+ -dependentdioxygenases (such as collagen prolyl 4-hydroxylase [EC 1.14.11.2]) [1]. Redox homeostasisis an intricate balance between oxidative and reductive events in the cell and VC plays an
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ContentsPrefaceChapter IChapter IIC
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PrefaceThe 6-carbon lactone known a
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Prefaceixbalance of antioxidant and
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Prefacexiprovided or is contradicto
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Vitamin C: Dietary Requirements, Di
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Oxidative DamageVitamin C: Dietary
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Pro-Oxidant vs. Antioxidant Effects
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186Magdalena Stevanović and Dragan
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In: Handbook of Vitamin C Research
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Molecular Bases of the Cellular Han
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Vitamin C: Daily Requirements, Diet
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262Alan M. Preston, Luis Vázquez Q
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Percent of Study Group Selecting Di
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The Role of Vitamin C in Human Repr
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300Mustafa NazıroğluKeywords: Vit
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302Mustafa NazıroğluNO is synthes
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304Mustafa Nazıroğlu‗recycling
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306Mustafa Nazıroğluagents, such
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308Mustafa NazıroğluFuture Direct
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310Mustafa Nazıroğlu[21] Basu, TK
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312Mustafa Nazıroğlu[59] Cengiz M
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314Samar Al Sayegh Petkovšek and B
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(mgg -1 )320Samar Al Sayegh Petkov
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330Antonio J. López-Farré, José
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Vitamin C in the Treatment of Endot
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Vitamin C Intake by Japanese Patien
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Reciprocal Effects of Ascorbate on
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378Akihito Ishigamicontrols (12,13)
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380Akihito IshigamiFigure 3. Vitami
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382Akihito IshigamiFuture of the SM
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The Importance of Food Processing o
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IndexAA , 249abdominal cramps, 243a
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Index 391atherosclerotic plaque, 23
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Index 393catalase, 6, 13, 169, 181,
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Index 395cyclooxygenase-2, 337, 341
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Index 397endometrium, 286, 294endon
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Index 399GCS, 18gel, x, 87, 92, 121
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Index 401hyperglycaemia, 223hypergl
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Index 403kinetics, 71, 120, 124, 14
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Index 405metastases, 182metastasis,
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Index 407nitrate, 14, 88, 179, 234,
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Index 409phosphodiesterase, 344, 35
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Index 411recovery, vii, 1, 5, 7, 8,
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Index 413steady state, 63, 76, 78st
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Index 415UV, 156, 191, 201, 204, 22
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Handbook of Vitamin C Research

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