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Journal of the American College of Nutrition, Vol. 20, No. 6, 623-627 (2001)
Published by the American College of Nutrition

Original Research

Plasma-Saturating Intakes of Vitamin C Confer Maximal Antioxidant Protection to Plasma

Carol S. Johnston, PhD, FACN and Sarah K. Cox, MS

Department of Nutrition, Arizona State University East, Mesa, Arizona

Address reprint requests to: Carol Johnston, PhD, Department of Nutrition, Arizona State University East, 7001 E. Williams Field Rd, Mesa, AZ 85212. Email: carol.johnston{at}asu.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective: Supplemental vitamin C has been shown to reduce oxidative damage in vivo, yet the dose-response relationship between vitamin C intake and antioxidant protection is not known. This report examined blood indicators of oxidative stress in subjects consuming graded doses of vitamin C, from 75 to 2000 mg/day.

Methods: Ten healthy, non-smoking men and women (26.1 ± 2.1 years) were recruited from a campus population. During the ten-week study, subjects limited fruit and vegetable consumption (<=3 servings/day) and consumed a multivitamin and mineral pill daily. Beginning at week 3, subjects ingested either a vitamin C (n = 8) or placebo (n = 2) capsule, which were identical in appearance and taste. The content of the vitamin C capsule increased every two weeks (from 250 mg at weeks 3–4 to 500 mg, 1000 mg, and 2000 mg at weeks 5–6, 7–8, 9–10, respectively). Fasting blood samples were collected at two-week intervals and analyzed for vitamin C, total lipid hydroperoxides and Heinz bodies in packed erythrocytes incubated 24 hours at 37°.

Results: Plasma vitamin C rose 55% in vitamin C-supplemented subjects by the end of the ten-week treatment (p < 0.05), and measures of oxidative stress decreased 60% to 90% (8.1 ± 0.6 to 3.5 ± 0.4 nmol/mL and 69.1 ± 7.8% to 6.7 ± 6.0% for total lipid hydroperoxides and Heinz bodies, respectively). Significant decreases in markers of oxidative stress were noted at the 500 mg, 1000 mg and 2000 mg dosages versus placebo. Antioxidant protection was similar at the 1000 mg and 2000 mg dosage.

Conclusions: These data indicate that the antioxidant protection afforded by short-term vitamin C supplementation is maximal at the 500–1000 mg dosage range.

Key words: vitamin C, oxidative stress, lipid peroxides, Heinz bodies


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent reports show that supplemental vitamin C reduces oxidative damage in vivo. Using plasma immunoglobulin carbonyls as an indicator of oxidative stress, Carty et al. [1] demonstrated that healthy subjects with an initial low plasma vitamin C concentration (plasma ascorbate, 29.5 ± 2.3 µM, n = 20) exhibited significantly less oxidative stress (-30%) after vitamin C supplementation (400 mg/d for 10 weeks; mean plasma ascorbate at 10 weeks, 64.2 µM). Compared to these subjects, subjects with higher vitamin C concentrations initially (51.8 ± 5.3 µM, n = 20) exhibited less oxidative stress at baseline, and vitamin C supplementation did not further reduce their immunoglobulin carbonyl concentrations [1]. In a separate study, exposure to cigarette smoke (30 minutes) caused an immediate reduction in plasma vitamin C concentrations (from about 52 µM to 40 µM) and was associated with a 30% increase in serum thiobarbituric acid reactive substances and a 50% reduction in the resistance of LDL to oxidation ex vivo [2]. Acute vitamin C supplementation (3 g orally two hours before smoke exposure) completely protected against the oxidative stress of passive exposure to cigarette smoke in these subjects.

Exposure of low-vitamin C guinea pigs (plasma ascorbate, 40 µM) to cigarette smoke (10 cigarettes/animal/day for seven days) significantly increased protein carbonyl formation in plasma and in lung and heart microsomal proteins [3]. Accumulations of conjugated dienes and malondialdehyde in lung and heart microsomal membranes were also noted in these animals. Identically treated, vitamin C supplemented animals (plasma ascorbate, 56 µM) were protected from the smoke-induced oxidative stress. Together, these data suggest that oxidative stress evident at plasma vitamin C concentrations below 40 µM can be eliminated if plasma vitamin C concentrations are raised to over 50 µM. This is in agreement with epidemiological and experimental investigations that indicate a significant protective effect of vitamin C on risk for free radical-associated disease at plasma concentrations greater than 40 to 50 µM [4,5].

The U.S. Food and Nutrition Board recently evaluated and revised upward the Recommended Dietary Allowance (RDA) for vitamin C, from 60 mg/day to 75 and 90 mg daily for adult women and men, respectively [6]. At intakes near 90 mg/day, plasma vitamin C concentrations range from 35 to 45 µM [7–9]. Hence, vitamin C ingestion at the recommended dosages may not maintain plasma vitamin C concentrations at or above 50 µM, the level associated with reductions in oxidative stress. Currently there are no data quantifying directly the dose-response relationship between vitamin C intake and in vivo antioxidant protection [6]. The present report examined blood indicators of oxidative stress in healthy, nonsmoking men and women consuming graded doses of vitamin C, from 75 to 2000 mg/day.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and experimental protocol. Ten healthy, non-smoking men (n = 4) and women (n = 6), aged 26.1 ± 2.1 years, were recruited from a campus population. Subjects were normal weight (body mass index, 23.3 ± 1.1 kg/m2), and none had renal or hepatic disease, diabetes, heart disease or hypertension, or took prescription medications or nutritional supplements. Subjects provided informed consent, and the study was conducted in accordance with the guidelines of the University Human Subjects Institutional Review Board at Arizona State University.

Throughout the 10-week experimental period, subjects were free-living and consumed self-selected diets, but were instructed to limit fruit and vegetable consumption. Subjects were allowed two to three servings of vitamin C-rich fruits and vegetables per week, and up to three servings of any other fruit or vegetable each day. Lists categorizing the fruits and vegetables were given to the subjects, and subjects kept a daily fruit and vegetable journal throughout the experimental period. Subjects met with a nutritionist weekly to turn in the food journals and discuss diet compliance.

All subjects ingested a multivitamin and mineral pill (Centrum®, Whitehall-Robins Healthcare, Madison, NJ) daily during the 10-week experimental period. Beginning at week 3, subjects ingested a vitamin C (n = 8) or placebo (n = 2) capsule in addition to the Centrum®. These capsules were identical in appearance and taste. The content of the vitamin C capsule (Twinlab, Ronkonkoma, NY) increased every two weeks (from 250 mg at week 3–4, to 500 mg, 1000 mg, and 2000 mg at weeks 5–6, 7–8, and 9–10, respectively). For weeks 7–8 and 9–10, the vitamin C and placebo were taken as divided dosages in the morning and evening. At the end of each two-week period, subjects reported to the test site in the early morning and a fasting blood sample was collected.

Analyses
Plasma extracted from EDTA coagulated blood was deproteinized in equal volumes of 10% TCA and frozen at -45°C for later vitamin C analysis using the 2,4-dinitrophenylhy-drazine method of Omaye et al. [10]. In a separate aliquot of plasma, lipids and proteins extracted by the use of a phosphotungstic acid-sulfuric acid system were analyzed for total lipid hydroperoxides, expressed in terms of malondialdehyde, utilizing a fluorometric method [11]. Heinz body formation in packed erythrocytes incubated 24 hours at 37° in open tubes was assessed in red cells ex vivo by standard procedures [12]. Data are reported as the mean ± SE. Differences between means across time and by group (vitamin C supplemented versus placebo) were evaluated using a non-parametric analysis of variance (ANOVA). Multiple analysis of variance for repeated measures and independent t tests were used to identify specific differences between means following a significant ANOVA. The level of significance was set at p < 0.05. The Statistical Package for the Social Sciences (SPSS Base 7.5 for Window, Chicago, IL) was used for all statistical calculations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Based on the food journals maintained daily by the subjects, total fruit and vegetable intake averaged 2.3 servings daily (vitamin C-rich fruits and vegetables represented 1/5 of this total), and the vitamin C content of diet was estimated at about 15 mg/day. The multivitamin and mineral pill provided 60 mg/day; hence, the vitamin C intake for subjects ingesting placebo averaged 75 mg/day throughout the entire study. Subjects consuming vitamin C capsules averaged 325 mg, 575 mg, 1075 mg and 2075 mg daily for weeks 3–4, 5–6, 7–8, and 9–10, respectively. One subject consuming the vitamin C capsules reported diarrhea and abdominal pain at the initiation of the 1000 mg dosage. This subject was advised to consume the capsules with a meal, and the symptoms resolved.

The initial, pre-study plasma vitamin C concentrations of subjects ranged from 19.8 to 54.0 µM (mean, 38.1 ± 4.4 µM). After two weeks on the diet restriction and consuming the multivitamin and mineral pill, plasma vitamin C concentrations ranged from 23.2 to 47.3 µM (mean, 31.8 ± 2.5 µM). Plasma vitamin C concentrations rose steadily from weeks 2–3 to weeks 9–10 in subjects supplementing vitamin C (Fig. 1a). Plasma vitamin C did not differ significantly at the 1075 mg and 2075 mg dosages (55.3 ± 1.6 and 59.3 ± 1.2 µM, respectively), but these levels were significantly greater than those noted at the 75 mg, 325 mg or 575 mg dosages (33.8 ± 2.6, 40.1 ± 2.8 and 48.0 ± 1.4 µM, respectively). Plasma vitamin C concentrations in the supplemented group were significantly greater than that for placebo at weeks 5–6, 7–8 and 9–10.



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  		Fig. 1. Plasma indices in subjects ingesting graded doses of vitamin C (...) or placebo (—) in addition to a multi-vitamin and mineral supplement (Centrum®). Data points represent the Mean ± SE. Means with different letters differ significantly (p < 0.05). The asterisk denotes a significant difference from the placebo mean.

 
After the initial two-week baseline period, plasma lipid hydroperoxides averaged 8.1 ± 0.6 nmol/mL (range, 4.2–10.8 nmol/mL; reported normal range, 1–10 nmol/mL [13]). Plasma lipid hydroperoxide concentrations fell significantly in vitamin C-supplemented subjects when the vitamin C dosage was increased to 325 mg/day (3.6 ± 0.3 nmol/mL, Fig. 1b). Over this same time period, plasma lipid hydroperoxides also fell in placebo subjects, and the mean hydroperoxide concentrations between placebo and vitamin C-supplemented subjects did not differ significantly at weeks 3–4. These data indicate an antioxidant benefit associated with the multi-vitamin and mineral supplement. High-dose vitamin C supplementation, up to 2075 mg/day, did not further reduce lipid hydroperoxide levels beyond the level noted at the 325 mg/day dosage; however, plasma hydroperoxide concentrations were significantly less in vitamin C-supplemented subjects versus placebo subjects at weeks 5–6, 7–8, and 9–10 (Fig. 1b). Individual lipid peroxide concentrations at vitamin C dosages >= 325 mg/day (weeks 3–10) ranged from 2.3–5.9 nmol/mL. The range observed in the placebo controls for this same time period was 3.95–6.46 nmol/mL.

Heinz body formation was 69.1 ± 7.8% after the initial two-week baseline period. The 325 mg vitamin C dosage did not significantly reduce Heinz body formation in subjects, but Heinz body formation following the 575 mg vitamin C dosage (25.5 ± 10.5%) was significantly lower than baseline values as well as placebo values (Fig. 1c). Higher dosages of vitamin C, 1075 and 2075 mg/day did not offer any further protection against oxidative stress to red cells.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The recently revised RDA for vitamin C, 75–90 mg/day, is intended to promote near maximal neutrophil vitamin C concentrations with minimal urinary loss. Although functional indicators of vitamin C status were not considered, this criterion is believed to provide for adequate in vivo antioxidant protection to body tissues [6]. Our results suggest that high intakes of vitamin C, 500–1000 mg/day, as compared to 75 mg/day, may provide added antioxidant protection. The 2000 mg dosage, however, did not confer any further antioxidant protection.

Oxidative damage to tissues occurs when the rate of free radical production in vivo exceeds the rate of their disposal. Vitamin C is one of numerous antioxidant factors that serve to keep free radicals in check. Some of these factors are derived from diet (notably the antioxidant vitamins and phytochemicals), and others, including superoxide dismutase, catalase, uric acid and glutathione, are synthesized endogenously. If antioxidant levels are inadequate, natural defenses are compromised, and free radicals will aggressively attack and modify many biologically important molecules [14]. This oxidative damage to biomolecules is implicated in the pathogenesis of many chronic diseases [15,16]. Furthermore, excessive exposure to environmental stressors, particularly ultraviolet (UV) radiation and environmental pollutants (e.g., ozone, particulate matter from diesel exhaust, and cigarette smoke), increases oxidative stress and is related to tissue damage and pathological conditions [17–18].

Case-control data indicate that antioxidant status is inversely related to oxidative stress and disease pathology for numerous conditions including neurological disorders, diabetes, heart disease and cancer [19–23]. Supplemental antioxidants, particularly vitamins C and E, may reduce the development of age-related lens opacities [24], interfere with the precancerous process in individuals at high risk of gastric carcinoma [25], slow functional deterioration in Alzheimer’s patients [26], normalize erythrocyte glutathione and reduce HbA1c in type 1 diabetes [27] and reduce oxidative stress and viral load in HIV-infected subjects [28]. Although there is accumulating evidence that antioxidant supplementation in healthy individuals reduces markers of oxidative stress [29,30], the issue is very much a matter of debate [31,32].

Most investigative trials use daily supplemental dosages of vitamin C from 500 to 1000 mg, and the data reported herein defend the use of these higher dosage levels. Our data indicate that dosages at the recommended dietary level, 75–90 mg, and even up to 325 mg/day, may not provide the same degree of antioxidant protection as the higher dosages, particularly if oxidative stress is present. Lipid peroxide concentrations indicate the level of endogenous oxidative stress, whereas the degree of Heinz body formation in incubated erythrocytes assesses the ability of tissues to protect themselves from oxidative insult [33]. Both of these markers were lowered significantly once mean plasma vitamin C concentrations approached 50 µM, a level that corresponded to supplemental intakes over 500 mg/day. Our subjects were free-living and consumed self-selected diets containing about 2.3 servings of fruits and vegetables and a commercially available vitamin C supplement. Hence, these results can likely be generalized to similar populations, i.e., young, healthy, non-smoking adults.

It is not yet clear, however, whether long-term vitamin C supplementation will reduce the risk for chronic disease in healthy adults. Data from several randomized clinical trials to date do not support an association between vitamin C supplementation and cardiovascular disease mortality (OR 1.01; 95% CI 0.94–1.10); however, in the Linxian trials, there were favorable results for total cancer mortality in participants <55 years (RR 0.85) [34,35]. Yet supplemental vitamin C consumption in these trials was from 120 to 200 mg/day, levels too low, perhaps, for a vitamin C-related antioxidant benefit. Two large randomized, double-blind, placebo-controlled trials examining the efficacy of antioxidant supplementation, the Physicians’ Health Study II (n = 15,000) and the Women’s Antioxidant and Cardiovascular Study (n = 8,000) [36,37], are underway, and both trials are utilizing a vitamin C dosage of 500 mg/day. Hence, in the near future, importantly relevant information regarding the health benefits, or risks, of large-dose antioxidant supplementation will be available.

High dosages of vitamin C, up to 2000–4000 mg, are considered relatively non-toxic [38], and the Tolerable Upper Intake Level (UL) for vitamin C is 2000 mg/day [6]. Our data indicate that maximal antioxidant protection by vitamin C supplementation was evident at dosages from 500–1000 mg/day, and that the 2000 mg dosage maintained, but did not exceed, this level of protection. Moreover, we have shown previously that vitamin C supplementation at 500 mg/day significantly raised red blood cell glutathione (+47%), and no further benefit was noted when the dosage level was raised to 2000 mg/day [39]. Hence, it appears that the antioxidant protection afforded by vitamin C supplementation is maximal at the 500–1000 mg dosage range.


   ACKNOWLEDGMENTS
 
This research was funded by the Lloyd S. Hubbard Nutrition Research Fund of the Arizona State University Foundation at Arizona State University.

Received June 4, 2001. Accepted August 28, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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