Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000) / Chapter Skim
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5 Vitamin C
5 Vitamin C
Pages 95-185
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From page 95... ...
Evidence for in vivo antioxidant functions of ascorbate include the scavenging of reactive oxidants in activated leukocytes, lung, and gastric mucosa, and diminished lipid peroxidation as measured by urinary isoprostane excretion. To provide antioxidant protection, a Recommended Dietary Allowance (RDA)
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From page 96... ...
Because of its reducing power, the vitamin can recluce most physiologically relevant reactive oxygen species (Buettner, 1993~. As such, the vitamin functions primarily as a cofactor for reactions requiring a recluceci iron or copper metalloenzyme and as a protective antioxiciant that operates in the aqueous phase both intra- and extracellularly (Englarci and Seifter, 1986; Halliwell and Whiteman, 1997; Tsao, 1997~.
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From page 97... ...
97 CH2OH HOCH O O Has O' a Ascorbyl Radical (A.-) -e +e CH2OH HOCH O O HI Dehydroascorbate valves either monooxygenase or clioxygenase activities (Levine et al., 1996b)
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From page 98... ...
The one- and two-electron oxidation products of ascorbate are relatively nontoxic and easily regenerated by the ubiquitous recluctants glutathione and NADH or NAD-PH. The relatively high tissue levels of ascorbate provide substantial antioxidant protection: in the eye, against photolytically generated free-radical damage; in neutrophils, against ROS produced during phagocytosis; and in semen, against oxidative damage to sperm deoxyribonucleic acid (DNA)
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From page 99... ...
Physiology of Absorption, Metabolism, and Excretion Absorption and Transport Intestinal absorption of ascorbic acid occurs through a socliumclepenclent active transport process that is saturable and close clependent (Rumsey and Levine, 1998; Tsao,1997~. At low gastrointestinal ascorbate concentrations, active transport predominates, while simple diffusion occurs at high concentrations.
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From page 100... ...
Tissue-specific cellular transport systems allow for wicle variation of tissue ascorbate concentrations. High levels are maintained in the pituitary and adrenal glancis, leukocytes, eye tissues and humors, and the brain, while low levels are found in plasma and saliva (Hornig, 1975~.
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From page 101... ...
In the United States, low blood ascorbate concentrations are more prevalent in men, especially elderly men, than in women and are more prevalent in populations of lower socioeconomic status (LSRO/FASEB, 1989~. Infantile scurvy is rarely seen, because human milk provides an acloquate supply of vitamin C and infant formulas are fortified with the vitamin.
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From page 102... ...
(1996) showing that supplementation of smokers with 2.0 g vitamin C for ~ clays was associated with a significant reduction in urinary isoprostanes, an indicator of oxidative stress.
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From page 103... ...
Studies with guinea pigs and monkeys show that the concentration of ascorbate in the leukocytes more accurately reflects liver and body pool ascorbate than floes the concentration in plasma or erythrocytes (Omaye et al., 1987~. The vitamin is transported into leukocytes by an energy-clepenclent transport system that concentrates the vitamin some twenty-five-, forty-, and eightyfold over plasma levels in neutro
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From page 104... ...
d LDL oxidizability is measured by the lag time and propagation rate of in vitro lipid peroxidation. e VLDL = very low-density lipoprotein.
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From page 105... ...
VITAMIN C 105 tg/d) Duration Plasma Change Findings 2 wk 2.0-fold ~ Plasma and LDLb TBARSC 4 wk 2.3-fold ~ Plasma and LDL TBARS 14 d Not reported LDL oxidation d, no change 10 d Not reported ~ VLDLe and LDL oxidation (4 hour TBARS)
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From page 106... ...
TABLE 5-3 Vitamin C and Enclothelium-Depenclent Vasoclilation in Humans Reference Subjects Vitamin Heitzer et al., 1996 10 chronic smokers 18 mg/n 10 control subjects (infusic Levine et al., 1996 46 coronary artery disease patients 2,000 me (20 placebo) (oral)
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From page 107... ...
correlation between gastric mucosa ascorbyl radical concentration and ROS activity ~ Nitrotyrosine in gastric mucosa (measure of RNSC activity) `1 In viva nitrosation by urinary nitrosoproline products Vitamin C Dose Findings 18 mg/min (infusion)
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From page 108... ...
Exposure of nine apparently healthy adults to 2,000 parts per billion (ppb) of ozone, an environmental pollutant, for 2 hours resulted in increased myeloperoxiciase and clecreaseci ascorbate concentrations in bronchoalveolar ravage fluid.
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From page 109... ...
Results of the latter study involving supplementation of apparently healthy individuals with both vitamin C and iron are discussed in the section "Tolerable Upper Intake Levels." Inverse correlations of lymphocyte ascorbate and glutathione con
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From page 110... ...
centrations with oxiclizeci DNA bases in another study of 105 apparently healthy adults suggest that these two intracellular antioxiciants protect human lymphocytes against oxiciative damage (Lemon et al., 1999)
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From page 111... ...
. Urinary Markers of DNA Damage Urinary excretion of DNA oxidant damage products, which is thought to represent the balance of total body DNA damage and repair has been measured in the studies shown in Table 5-~.
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From page 112... ...
found. Thus, urinary markers of DNA damage cannot be used to determine vitamin C requirements.
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From page 113... ...
(1997) reported no effects on DNA damage but increased chromosome aberrations.
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From page 114... ...
a DNA = deoxyribonucleic acid. b H202 = hydrogen peroxide.
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From page 115... ...
2 wk No effect on DNA damage (comet assay) ~ Chromosome aberrations after bleomycin treatment Single dose ~ Lymphocyte DNA strand breaks in both groups after ex viva H202b oxidant stress (comet assay)
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From page 116... ...
after in viva supplementation of apparently healthy men with 1,500 mg/day of vitamin C for 1 week. Summary For the three studies shown in Table 5-4 in which only vitamin C intake was varied, some markers of cellular DNA damage showoci no change with increased vitamin C intake, two markers clecreaseci, and one increased.
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From page 117... ...
, the studies involved apparently healthy free-living populations supplemented with from 200 mg/ciay to 6 g/ciay of vitamin C in aciclition to clietary vitamin intake. Hence, the results relate largely to the pharmacological range of vitamin C intakes rather than the nutritional range of intakes usually provicleci from food alone.
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From page 118... ...
Therefore, ciata from currently available immune function studies cannot be used to estimate the vitamin C requirement. Other Indicators Co1111agen Metabolism Ascorbic acid is required along with iron as a cofactor for the post-translational hyciroxylation of praline and lysine to effect cross
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From page 119... ...
No change in other cellular or humoral immune functions Mitogen-stimulated in vitro lymphocyte proliferation and DDSb response to skin antigens Mitogen-stimulated in vitro lymphocyte proliferation and DDS response. No changes in serum immunoglobulins No change in Mitogen-stimulated in vitro lymphocyte proliferation or DDS response No change in PMN chemotaxis or response to experimental .
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From page 120... ...
Epiclemiological studies have failed to demonstrate an association between vitamin C intake and periodontal disease (Alvares, 1997; Russell, 1967~. Controlled experimental studies of patients with gingivitis and apparently healthy adults with vitamin C intakes of ~ to 1,500 mg/ciay have shown mixed results with regard to the influence of vitamin C status on periodontal integrity (Leggott et al., 1986, 1991; Vogel et al., 1986; Woolfe et al., 1984~.
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From page 121... ...
A prospective study of 1,605 Finnish men showoci that those with increased plasma vitamin C (greater than 11.4 ~mol/L t0.2 mg/dL1) had a 60 percent decreaseci risk of coronary heart disease (Nyyssonen et al., 1997a)
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From page 122... ...
The First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study cohort of more than 11,000 adults showoci a reduction in cardiovascular disease of 45 percent in men and 25 percent in women whose vitamin C intakes were approximately 300 mg/ciay from food and supplements (Enstrom et al., 1992~. Sahyoun et al.
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From page 123... ...
(1981) found high plasma vitamin C concentrations to be associateci with clecreaseci cervical cancer risk.
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From page 124... ...
Similarly, ciata from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study of more than 10,000 men and women inclicateci that clietary vitamin C intakes greater than 133 mg/ciay were inversely associateci with lung cancer risk (Yong et al., 1997~. There was no aciclitional protective effect of vitamin C supplements.
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From page 125... ...
Despite the epiclemiological associations and the evidence that gastric juice vitamin C is protective against nitrosation and oxidant damage, the two vitamin C supplementation studies conclucteci to ciate have not shown a subsequent decrease in gastric cancer inciclence (Blot et al., 1993; O'Toole and Lombard, 1996~. Although many of the above studies suggest a protective effect of vitamin C against specific cancers by site, the ciata are not consistent or specific enough to estimate a vitamin C requirement baseci on cancer.
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From page 126... ...
Asthma and Obstructive Pulmonary Disease It is suspected that vitamin C may decrease the risk of asthma and other related pulmonary conditions (Hatch, 1995~. Two cross-sectional studies suggest that high plasma vitamin C concentrations or intakes protect or perhaps enhance respiratory function in men but not in women (Ness et al., 1996)
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From page 127... ...
in 5,182 Dutch residents aged 55 to 95 years Jama et al., 1996~. Another study of 442 men and women, age ci 65 to 94 years, reported that higher plasma ascorbate levels were associateci with better memory performance (Perrig et al., 1997~.
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From page 128... ...
and the ratio of GSH/GSSG, both indicators of oxiciative stress, were significantly clecreaseci (Henning et al., 1991~. In apparently healthy adults supplemented with 500 mg/day of ascorbic acid, erythrocyte glutathione rose significantly Johnston et al., 1993~.
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From page 129... ...
. In aciclition, the finclings of clecreasecT ceruloplasmin ferroxidase activity due to high physiologic ascorbate concentrations have been attributed to an artifact of nonphysiological assay pH (L0vstacT, 1997~.
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From page 130... ...
still finci that smokers have lower plasma vitamin C concentrations than nonsmokers. This inclicates that smoking per se predisposes to lower vitamin C status.
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From page 131... ...
were not different between smokers and nonsmokers; however, DNA damage clue to ex viva H2O2 aciclition was significantly greater in smokers than in nonsmokers. Vitamin C at 1 g/ciay clecreaseci ex vivo DNA damage by about 20 percent in both groups (Panayioticlis and Collins, 1997~.
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From page 132... ...
Environmental or siclestream tobacco smoke provokes oxidant damage similar to mainstream cigarette smoke (Bermuclez et al., 1994; Pryor et al., 1983~. Plasma ascorbate concentrations of passive smokers were intermediate between those of active smokers and nonsmokers who were not exposed to environmental tobacco smoke, despite similar vitamin C intakes (Tribble et al., 1993)
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From page 133... ...
, higher fruit consumption by women contributeci to but clici not entirely account for their higher plasma and leukocyte ascorbate levels compared to men (Burr et al., 1974~. However, the latter fincling of higher leukocyte ascorbate in women compared to men was not confirmed in a subsequent study, which found no gentler differences in leukocyte ascorbate concentrations (Evans et al., 1982)
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From page 134... ...
The vitamin C content of human milk appears to decline cluring the first year of life so that by the twelfth month of lactation the vitamin C content is about 8 to 12 percent lower (Karra et al., 1986; Salmenpera, 1984)
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From page 135... ...
Although limited ciata are available for typical vitamin C intakes from foocis by infants feci human milk, mean vitamin C intakes from solid foods are 22 mg/day for formula-fed infants (Montalto et al., 1985~. For purposes of developing an AI for this age group, it is assumed that infants who are feci human milk have intakes of solici food similar to formula-feci infants of the same age group (Specker et al., 1997~.
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From page 136... ...
b Values were estimated from graphs. c Lack of correlation between maternal intake and breast milk concentration of vitamin C in human milk.
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From page 137... ...
There was no significant difference in milk content between the two groups. Also measured plasma concentration of ascorbic acid found no significant difference n = 168 Gambian women n= 200 healthy nonsmoking mothers and full-term infants Infants were exclusively fed human milk for at least 3 mo (range 3-12 mo)
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From page 138... ...
This is comparable to the value calculated above utilizing human milk and solici food. The 1994 to 1996 CSFII ciata for infants 7 through 12 months of age ranged from 21 to 293 mg/day, with median 106 mg/day of vitamin C (Appendix Table D-1 ~ .
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From page 139... ...
Values recommencleci here are baseci on an amount of vitamin C that is thought to provicle antioxiciant protection as cleriveci from the correlation of such protection with neutrophil ascorbate concentrations. It is recognizeci that there are no human ciata to quantify clirectly the close-response relationship between vitamin C intake anci in vivo
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From page 140... ...
with seven apparently healthy males reported plasma, neutrophil, and urinary ascorbate concentrations cluring vitamin C clepletion and repletion to stoutly state. Thus, there are wicle uncertainties in the ciata utilized to estimate the vitamin C requirements.
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From page 141... ...
FIGURE 5-2 The effect of varying extracellular ascorbate concentrations on inhibition of superoxide produced by activated neutrophils. The range of normal human plasma ascorbate concentrations is shown within the arrows.
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From page 143... ...
, this criterion should provide for acloquate in vivo antioxidant protection to body tissues while minimizing excess urinary vitamin excretion. Vitamin C intakes greater than the urinary excretion threshold provide little or no increase in the ascorbate body pool (Baker et al., 1969; Kallner et al., 1979~.
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From page 144... ...
Seven apparently healthy male volunteers, age ci 20 to 26 years, were stuclieci as in-patients for 4 to 6 months. Subjects were clepleteci by being feci a cliet containing less than ~ mg/ciay vitamin C
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From page 145... ...
(1979) previously reported that the body pool of vitamin C was saturated at an intake of 100 mg/day in healthy non-smoking men; thus, an average intake at the EAR of 75 mg/ciay would not provide body pool saturation of vitamin C
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From page 146... ...
This fincling is not surprising since the NHANES III vitamin C plasma concentrations are for both smokers and nonsmokers, and it is known that plasma vitamin C concentrations are recluceci by about 40 percent in male smokers (Pelletier, 1977; Weber et al., 1996~. In aciclition, as cliscusseci in the earlier section "Environmental Tobacco Smoke," exposure of nonsmokers to environmental tobacco smoke can result in a decline in plasma ascorbate concentrations (Tribble et al., 1993; Valkonen and Kuusi, 1998~.
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From page 147... ...
/day of vitamin C Adults Ages 5 ~ Years and Older Evidence Considered in Estimating the Average Requirement Some cross-sectional studies have shown that vitamin C status, as measured by plasma and leukocyte ascorbate concentrations, is lower in the elderly, especially institutionalized elderly, than in young adults (Burr et al., 1974; Cheng et al., 1985~. Low blood vitamin C concentrations in institutionalized and chronically ill elderly were normalized to those of active elderly and young adults by increasing their dietary vitamin C intake, suggesting that the low levels were primarily clue to poor intake (Newton et al., 1985~.
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From page 148... ...
However, the vitamin C requirement of the elderly may be increased clue to the oxiciative stress of inflammatory and infectious conditions often found in this population (Cheng et al., 1985~. As previously cliscusseci, older adults have similar or lower plasma ascorbate concentrations than young adults.
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From page 149... ...
/day of vitamin C Pregnancy Evidence Considered in Estimating the Average Requirement Plasma vitamin C concentration decreases with the progression of pregnancy, probably secondary to hemoclilution (Morse et al., 1975) as well as active transfer to the fetus (Choi and Rose, 1989~.
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From page 150... ...
. It has been reported that plasma vitamin C in pregnant smokers ex80 mg (454 ~nol)
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From page 151... ...
Maternal vitamin C intake in excess of 200 mg/ciay resulted in increased urinary excretion of vitamin C but clici not increase the content of the vitamin in human milk (Byerley and Kirksey, 1985~. It is thought that a regulatory mechanism in the mammary glanci prevents the elevation of milk vitamin C concentrations beyond that level seen when urinary execration increases representing blood saturation (Byerley and Kirksey, 1985~.
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From page 152... ...
More precise ciata were obtaineci from an experimental stucly of 17 apparently healthy male smokers who were administered radiolabeled tracer ascorbic acid at steacly-state intakes of 30 to 180 mg/ciay to allow kinetic calculations of ascorbate metabolism and body pools. Results were compared with a similar protocol for nonsmokers (Kallner et al., 1979, 1981~.
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From page 153... ...
Hypovitaminosis C (plasma ascorbate concentrations less than 23 ~mol/L t0.5 mg/ciL]
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From page 154... ...
/day and median total intake (including supplements, see Appendix Table C-2) is about 120 mg (682 ~mol)
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From page 155... ...
Total vitamin C intakes from food plus supplements from the Third National Health and Nutrition Examination Survey (NHANES III) are found in Appendix Table C-2.
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From page 156... ...
(1981) reported significant increases in mean urinary oxalate excretion in 39 apparently healthy adults consuming 1, 3, 6, and 9 g/day of ascorbic acid.
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From page 157... ...
~1996a) reported significantly increased uric acid excretion above the normal range following ascorbic acid intakes of 1 g/ciay or more in 7 apparently healthy male subjects.
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From page 158... ...
could increase iron stores above recommencleci levels in apparently healthy inclivicluals. They found that vitamin C intakes clici not increase the number of high iron absorbers, and limited ciata involving ascorbic acid intakes above 100 mg/ciay showoci no change in iron absorption values.
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From page 159... ...
Controlled human studies in which supplemental vitamin C was acicleci to the meals of apparently healthy adults for periods of up to 2 years showed little or no change in iron status measures including serum ferritin (Cook et al., 1984; Hunt et al., 1994~. Data on ironascorbate combinations in the plasma of normal healthy adults and preterm infants with high plasma ascorbate levels showoci that high plasma ascorbate concentrations in the presence of reclox-active iron clici not cause either lipid or protein oxidation.
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From page 160... ...
Supplementation of apparently healthy volunteers with vitamin C and iron resulteci in increases in some DNA damage markers, decreases in others, and a rise in total DNA base damage at 6 weeks, which clisappeareci at 12 weeks (Rehman et al., 1998~. Other evidence from in vitro and in viva ciata as well as epiclemiological studies have not shown increased oxiciative DNA damage or increased cancer risk associateci with high intakes of vitamin C (Block, 1991; Fontham, 1994; Fraga et al., 1 99 1; Rifici and Khachaclurian, 1 993)
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From page 161... ...
Summary Baseci on considerations of causality, relevance, and the quality and completeness of the database, osmotic diarrhea and related gastrointestinal disturbances were selected as the critical endpoints on which to base a UL. The in viva ciata do not clearly show a causal relationship between excess vitamin C intake by apparently healthy inclivicluals and other adverse effects (i.e., kidney stone formation, excess iron absorption, recluceci vitamin BE and copper levels, increaseci oxygen clemanci, systemic conditioning, pro-oxiciant effects, dental enamel erosion, or allergic response)
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From page 162... ...
Potential concerns for high vitamin C concentrations in infants stem from isolated reports of anecdotal rebound scurvy, oxidative damage, and hemolysis (Ballin et al., 1988; Cochrane, 1965; Powers et al., 1995~. To prevent high levels of intake, the only source of intake for infants should be that available from food and formula.
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From page 163... ...
should not be used to treat ADD. It is unlikely that the increases in serum aminotransferases were clue to the high acsorbic acid intake since no such effects of high vitamin C intakes have been reported by other investigators.
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From page 164... ...
Byerley and Kirksey (1985) noted that the vitamin C composition of human milk was not affected by maternal vitamin C intake ranging from 156 to 1,123 mg/ciay and that urinary excretion increased as intake increased over 200 mg/ciay, suggesting that mammary tissue becomes saturated with vitamin C
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From page 165... ...
RESEARCH RECOMMENDATIONS FOR VITAMIN C · Despite the many known biochemical roles of ascorbic acid, no reliable biochemical or physiologically baseci functional measures of vitamin C nutriture have been established. As a result, vitamin C intake requirements in adults have been baseci on estimates of body pool or tissue ascorbate cleemeci acloquate to provide antioxidant protection.
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From page 166... ...
, it is critically important to conduct large-scale studies with children using state-of-the-art biomarkers to assess their vitamin C requirement. · Many studies that provicleci vitamin C supplements to apparently healthy well-nourisheci populations were investigating pharmacological (at or above the point where body tissues are saturateci)
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From page 167... ...
Am J Clin Nutr 24:444-454. Ballin A, Brown EJ, Koren G
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From page 168... ...
Am ~ Clin Nutr 51:837-845. Blanchard l, Tozer TN, Rowland M
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From page 169... ...
Amy Clin Nutr69:10861087. Casanueva E, Polo E, Tejero E, Meza C
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From page 170... ...
Hum Nutr Clin Nutr 38C:463-471. Davies HE, Gruffudd S
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From page 171... ...
Am ~ Clin Nutr 34:13561361. Elneihoum AM, Falke P
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From page 172... ...
Am ~ Clin Nutr 36:332-339. Garry Pl, Vanderjagt Dl, Hunt WC.
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From page 173... ...
Can oxidative DNA damage be used as a biomarker of cancer risk in humans? Free Radic Res 29:469-486.
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From page 174... ...
Amy Clin Nutr 51:644-648. Hinds MW, Kolonel LN, Hankin JH, Lee J
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From page 175... ...
Am ~ Clin Nutr 48: 1436-1442. Jacob RA, Kelley DS, Pianalto FS, Swendseid ME, Henning SM, Zhang FEZ, Ames EN, Fraga CG, Peters OH.
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From page 176... ...
Am ~ Clin Nutr 43:495-503. Katsuki H
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From page 177... ...
1999. Glutathione and ascorbate are negatively correlated with oxidative DNA damage in human lymphocytes.
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From page 178... ...
Am ~ Clin Nutr 65:959-963. Lykkesfeldt l, Christen S
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From page 179... ...
Am J Clin Nutr 28:1000-1013. Moser U
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From page 180... ...
Am ~ Clin Nutr 44:257-264. Omaye ST, Schaus EE, Kutnink MA, Hawkes WC.
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From page 181... ...
Am ~ Clin Nutr 65:503-507. Pryor WA.
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From page 182... ...
Euri Clin Nutr 51 :472477. Sasaki A, Kondo K, Sakamoto Y
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From page 183... ...
1995. Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects.
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From page 184... ...
Am J Clin Nutr 42:522-530. Urivetzky M, Kessaris D, Smith AD.
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From page 185... ...
1991. Role of oxidized low density lipoprotein in atherogenesis.
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