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Ideal vitamin C intake

Authors:
BioFactors 15 (2001) 71–74 71
IOS Press
Ideal vitamin C intake
Mark Levine, Yaohui Wang, Arie Katz, Peter Eck, Oran Kwon, Shenglin Chen,
Je-Hyuk Lee and Sebastian J. Padayatty
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, Building 10 Room 4D52, MSC
1372, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892-1372, USA
1. Introduction
To determine ideal vitamin C intake, it is necessary to know the relationship between vitamin C doses
and resulting concentrations in plasma and tissues. Biochemical outcomes can be predicted based on
functions of the vitamin within the concentration ranges measured in subjects at different doses. Clinical
outcomes can be characterized in relation to the measured vitamin concentrations. Recommendations
for ideal vitamin C intake can be guided by these specific criteria [1]:
Biochemical function in relation to concentration
Dietary availability
Dose and steady-state concentrations for plasma
Dose and steady-state concentrations for tissues
Bioavailability
Urine excretion: threshold, fractional excretion
Adverse effects and toxicity
Beneficial effects, observations in populations
Prevention of deficiency
Here we summarize dose concentration data for plasma in healthy young male subjects [2].
2. Methods
Study design and details were previously described [2–4]. Briefly, seven healthy male subjects ages
19–26 were hospitalized for 4–6months on a metabolic ward. Throughout hospitalization theyconsumed
a diet containing less than 5 mg of vitamin C daily [3]. Deficiencies of other nutrients were prevented
by supplementation. When plasma vitamin C concentrations achieved nadir <10 µM, vitamin C was
administered at 15 mg orally in the fasted state twice daily (30 mg total) until steady state for the dose
Corresponding author: Dr. Mark Levine MD, Building 10 Room 4D52 MSC 1372, National Institutes of Health, Bethesda
MD 20892-1372, USA. Tel.: +1 301 402 5588; Fax: +1 301 402 6436; E-mail: MarkL@intra.niddk.nih.gov.
0951-6433/01/$8.00 2001 – IOS Press. All rights reserved
72 M. Levine et al. / Ideal vitamin C intake
was achieved. The following procedures were performed at steady-state: bioavailability sampling; urine
collections for vitamin C, oxalate, urate, creatinine; isolation of circulating neutrophils; apheresis for
isolation of lymphocytes and monocytes; semen collection. When these procedures were complete,
vitamin C dose was increased to 30 mg twice daily (60 mg total) until steady state was achieved, when
the procedures were repeated. In this way subjects received the following doses in mg/day: 30, 60,
100, 200, 400, 1000, and 2500. Vitamin C was measured by HPLC with coulometric electrochemical
detection.
3. Results
Plasma data for all 7 subjects at all doses are shown in Fig. 1. These data reveal several aspects of
the relationships between vitamin C doses and resulting concentration. For the depletion phase (0 mg),
the rate of depletion varied several fold. For the first repletion dose (30 mg daily), the mean plasma
concentration at steady state was 8.7+/1.7µM [2]. At 60 mg daily, the plasma concentration for 6
subjects at steady state was approximately 19.2+/3.2µM. One subject had a much higher steady
state concentration, 58.8+/3.1µM. By steady state at 200 mg daily, there was approximately 80%
saturation of plasma for vitamin C. The data show that there was a sigmoidal relationship between dose
and concentration for doses 30–100 mg daily [2]. Data for neutrophils, monocytes, and lymphocytes
indicate that these cell types are saturated at 100–200 mg daily [2]. At doses above 200 mg daily, the
absorbed dose is nearly completely excreted in urine [2].
4. Discussion
Dose concentration data for healthy men reveal that vitamin C concentrations are tightly controlled in
plasma and tissues [2]. At oral doses less than 100 mg daily, small changes in dose produce large changes
in plasma concentrations. Once plasma concentrations of approximately 60–70 µM are achieved, at oral
doses of approximately 200 mg daily, plasma concentrations are kept within a narrow range. Further
dose increases produce little change in resulting steady state concentrations. Vitamin C plasma and
tissue concentrations are tightly controlled as a consequence of absorption, tissue accumulation and
distribution, and renal excretion [2,4]. Why tight control of vitamin C occurs in humans is not currently
known and is worthy of investigation.
Variations between subjects in two aspects were noteworthy: differences in depletion rates, and
difference in repletion at 60 mg daily. Although the reasons for these findings are uncertain, possible
explanations include variations in vitamin C transport, recycling, distribution, utilization, or degradation.
Possible enzymatic explanations include differences in the following: vitamin C sodium dependent
transport by the transporters SVCT1 or SVCT2; dehydroascorbic acid transport by GLUT transporters
GLUT1, GLUT3, or GLUT4; dehydroascorbic acid reduction by glutaredoxin, thioredoxin reductase, or
dehydroascorbic acid reductase; or reduction of glutathione and/or NADPH via glutathione reductase,
6-phosphogluconate dehydrogenase, or other proteins in the pentose shunt.
It was proposed 15 years ago that ideal vitamin intake is best determined based on biochemical,
functional, and/or clinical outcome in relation to vitamin concentration [5]. The data here and in
related publications [2,4] define the concentration ranges of vitamin C found in healthy young men in
plasma and tissues at a wide range of vitamin C doses. Data describing similar dose-concentration
relationships are needed in women, smokers, elderly subjects, and in patients with chronic diseases.
M. Levine et al. / Ideal vitamin C intake 73
Plasma vitamin C (µM)
AM fasting
0
20
40
60
80
100
120
30 32 56 35 14 9 10 8
Duration of each phase (Days)
0 mg 30 mg 60 mg 100 mg 200 mg 400
mg
1000
mg
2500
mg
0 5 10 15 20 25 30
Scale: Days
Maximum duration of each phase is indicated
Fig. 1. Seven subjects were hospitalized 4–6 months as described in the text [2]. The duration in days for each subject for the
depletion phase (0 mg) and for receipt of 7 different vitamin C doses is shown on the X axis. The maximum duration of each
phase is indicated numerically on the X axis. Fasting vitamin C concentrations for all phases of the study are shown on the Y
axis. Vitamin C doses for each phase are indicated at the top of the figure. Each subject is indicated by a different symbol.
There was variation between subjects in the time taken to reach nadir and in the number of days required to reach steady state
for each dose.
Such information is essential for characterizing biochemical, functional, and/or clinical outcomes in
relationship to vitamin C concentrations in healthy and ill people. Functional and clinical outcomes are
difficult measures in humans, but perhaps provide the most meaningful justification for ideal vitamin
intake. Sound recommendations for nutrient intake are ideally made on the basis of clinical outcomes
such as improvement in the quality of life, or reduction in morbidity or mortality. In the absence of such
information, surrogate markers and dose concentration relationships can be used to deduce ideal intake.
Every effort should be made to use surrogate markers that are known to influence or determine clinical
outcome.
To date, the only clear clinical benefit of vitamin C ingestion is to prevent scurvy. Direct beneficial
effects of vitamin C in populations are controversial for many diseases including cancer, cataract, and
heart disease. However, ingestion of five servings of fruits and vegetables daily is strongly associated
with protection against cancers of the GI andrespiratory tracts, with potential benefit in preventing heart
disease. Five servingsof fruits and vegetables provide 210–280 mg of vitamin C daily. Taken together,
the available data suggest that ideal vitamin C intake is 200 mg daily, from a variety of fresh fruits and
vegetables [1].
References
[1] M. Levine, S.C. Rumsey, R.C. Daruwala, J.B. Park and Y. Wang, Criteria and recommendations for vitamin C intake,
J.A.M.A. 281 (1999), 1415–1423.
74 M. Levine et al. / Ideal vitamin C intake
[2] M. Levine, C. Conry-Cantilena and Y. Wang et al., Vitamin C pharmacokinetics in healthy volunteers: evidence for a
Recommended Dietary Allowance, Proc. Natl. Acad. Sci. USA 93 (1996), 3704–3709.
[3] J. King, Y. Wang, R.W. Welch, K.R. Dhariwal, C. Conry-Cantilena and M. Levine, Use of a new vitamin C-deficient diet
in a depletion/repletion clinical trial, Am. J. Clin. Nutr. 65 (1997), 1434–1440.
[4] J.F. Graumlich, T.M. Ludden, C. Conry-Cantilena, L.R. Jr. Cantilena LR, Y. Wang and M. Levine, Pharmacokinetic
model of ascorbic acid in healthy male volunteers during depletion and repletion, Pharmaceutical Research 14 (1997),
1133–1139.
[5] M. Levine, New concepts in the biology and biochemistry of ascorbic acid, N. Engl. J. Med. 314 (1986), 892–902.
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