Vitamin C, also known as ascorbate and ascorbic acid (Fig. 1), is synthesized by all animals except humans, monkeys, guinea pigs, bats, and several bird species. The chief biologic function of vitamin C is as a water-soluble reducing agent (ie, electron donor). Vitamin C has the potential to reduce cytochromes a and c of the electron transport chain, as well as molecular oxygen itself. Arguably the most important reaction requiring ascorbic acid as a cofactor involves the hydroxylation of proline residues in collagen (Table 1). As such, vitamin C is required for the maintenance of normal connective tissue and wound healing. Vitamin C also is needed for the remodeling of bone, because of the presence of collagen in the organic matrix. A number of other metabolic reactions require vitamin C to act as a cofactor; notable among those are the synthesis of epinephrine from tyrosine, and the synthesis of the bile acids. Also, vitamin C is suspected to have involvement in the process of adrenal steroidogenesis. Other putative biochemical uses of vitamin C include a role in antioxidant protection, thyroxin synthesis, amino acid metabolism, strengthening resistance to infection, and aiding in the absorption of iron . The work of Nobel Prize laureate Linus Pauling stimulated public interest in megadoses of this vitamin to prevent infection with the viruses responsible for the common cold; research on this topic over the past 20 years has offered conflicting results . The classic vitamin C deficiency disease is scurvy, due to the role of the vitamin in the post-translational modification of collagens. Vitamin C deficiency symptoms include small cell-type anemia, atherosclerotic plaques, and pinpoint hemorrhages; bone fragility and joint pain; poor wound healing and frequent infections; bleeding gums and loosened teeth; muscle degeneration and pain, hysteria and depression; and rough skin and blotchy bruises . An excessive intake of vitamin C (eg, gram doses) may cause diarrhea, abdominal bloating, overabsorption of iron, hyperoxalemia (in dialysis patients), and hemolysis (in patients with glucose-6-phosphate dehydrogenase deficiency). A tolerable upper intake level for vitamin C was set at 2000 mg/d by the Food and Nutrition Board in 2000 . The current RDA is 90 mg for men, and 75 mg for women (with an additional 35 mg added for smokers), and at these doses, vitamin C bioavailability is close to 100%. Significant food sources include citrus fruits, cabbage-type vegetables, dark green vegetables, cantaloupe, lettuce, tomatoes, potatoes, papayas, and mangoes. Despite its abundance in foods, it is important to note that vitamin C is easily destroyed by light, heat, and oxygen .
Limited Vitamins A and C and Calcium in Pantries
Although food pantries serve over 19 million Americans, primarily those in low-income households, according to Akobundu et al.  little is known about the nutritional quality of foods distributed in pantry bags. Consequently, Akobundu et al.  calculated the nutrient and food group content of foods in bags from 133 clients from 19 pantry sites. Foods distributed were of adequate or high nutrient density for protein, fiber, iron, and folate, but were of low nutrient density for vitamin C, calcium, and vitamin A. The researchers concluded that pantries should undertake efforts to procure, store, and distribute additional fruit, dairy products, and other sources of vitamins C and A, and calcium.
Vitamin C and Diabetes
Many diabetic complications are the result of glycosylated protein, or more specifically advanced glycosylation end products (AGE). Likewise, oxidative stress may play a role in the pathogenesis of diabetes. Because antioxidants block the production of AGE and help counter oxidative stress, several studies have examined the impact of vitamin C on diabetic complications.
Vitamin C and diabetic retinopathy
In a study of 1353 subjects with type 2 diabetes, Millen et al.  examined the association between prevalent diabetic retinopathy and intake of vitamins C and E. Although there was no association of retinopathy with intake of vitamin C or E from food alone or from food and supplements combined, there was a significant (P < 0.05) interaction of the observed relations with serum glucose concentration. Additionally, a decreased likelihood of retinopathy was found among users of vitamin C or E supplements, or multisupplements, compared with those who reported use of no supplements.
Vitamin C and cardiovascular disease in diabetes
Although vitamin C is generally thought to function as an antioxidant, in vitro experiments have shown it can also have pro-oxidant effects . These observations led Lee et al.  to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis. Subsequently, Lee et al.  examined the relation between vitamin C intake and mortality from cardiovascular disease in postmenopausal diabetic women. The results led the researchers to conclude that a high vitamin C intake from supplements is indeed associated with an increased risk of cardiovascular disease mortality in postmenopausal women with diabetes, but not in nondiabetic subjects.
Contrary to the results of Lee et al. , Vega-Lopez et al.  presented data indicating that vitamin C supplementation (as well as vitamin E and alpha-lipoic acid) has beneficial effects on oxidative stress (decrease) and the management of diabetic cardiovascular disease. Likewise, Evans et al.  found that vitamin C therapy (1 g/d) augmented the vascular benefits of insulin in type 2 diabetics through additional effects on oxidative stress (reduced) and endothelial function (improved).
The conflicting results between the research by Lee et al.  and that of Vega-Lopez et al.  and Evans et al.  may be explained, at least in part, by two other studies. It is fairly well accepted that low-density lipoprotein (LDL) oxidation plays a major role in atherosclerosis, and that free or extracellular hemoglobin acts as a trigger for LDL oxidation. Because of its ability to bind hemoglobin, haptoglobin (Hp) serves as an antioxidant. According to Levy et al. , antioxidant therapy reduces LDL oxidizability in haptoglobin 1 allele homozygotes (Hp 1-1), but not in individuals with the haptoglobin 2 allele (Hp 2-1 or Hp 2-2). Therefore, Levy et al.  investigated whether haptoglobin type would be predictive of the effect of vitamin C and E therapy on coronary atherosclerosis as assessed by angiography in diabetic and nondiabetic postmenopausal women. Results indicated a significant benefit on the change in minimum luminal diameter (MLD) with vitamin therapy as compared with placebo in Hp 1-1 subjects (P = 0.049), which was more marked in diabetic subjects (P = 0.021). However, there was a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (P = 0.027). Hence, the relative benefit or harm of vitamin therapy on the progression of coronary artery stenoses in women was dependent on haptoglobin type; and this influence seemed to be stronger in women with diabetes.
Further, Carroll and Schade  demonstrated that the timing of antioxidant vitamin ingestion has an effect on altering postprandial proatherogenic serum markers in type 2 diabetics. Either presupper or prebreakfast vitamins E (800 IU) and C (1 g) prevented a meal-induced rise in C-reactive protein (CRP), although taking vitamins at both timepoints was the most effective strategy. However, only prebreakfast vitamins prevented the meal-induced rise in plasminogen activator inhibitor-1 (P = 0.006).
Vitamin C and Cardiovascular Disease
Through its role as an antioxidant and an agent for decreasing CRP, vitamin C may have a favorable influence on the progression of cardiovascular disease in some individuals.
Vitamin C and coronary heart disease risk
In a cohort study pooling nine prospective studies, Knekt et al.  studied the relationship between the intake of antioxidant vitamins C and E, and coronary heart disease (CHD) risk. The results of a 10-year follow up indicated that dietary intake of antioxidant vitamins was only weakly related to a reduced CHD risk. However, a reduced incidence of major CHD events was seen with high supplemental vitamin C intakes (> 700 mg/d). By comparison, the risk reductions with high vitamin E or carotenoid intakes appeared to be small.
Vitamin C and CRP
Because CRP may directly affect the progression of atherosclerosis, Block et al. [13•] examined whether antioxidant supplementation reduces plasma CRP in active and passive smokers. Participants were randomized to receive a placebo or vitamin C (515 mg/d) or antioxidant mixture including vitamin C, alpha- and gamma-tocopherols, mixed tocotrienols, and alpha lipoic acid. The results indicated that vitamin C supplementation yielded a 24% reduction (P < 0.036) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction.
Antioxidants, Asthma, and Allergy
As referenced by Higdon , large doses of vitamin C have been shown to have an antihistamine effect. This may contribute to the fact that a number of patients with asthma and allergies have been attracted to nontraditional therapies (eg, complementary and alternative medicine), including vitamin C therapy .
Vitamins C and E, beta-carotene, selenium, and asthma
Rubin et al.  investigated the relationship between serum vitamin E, beta-carotene, vitamin C, and selenium with asthma in 7505 youth (4–16 years old) in the Third National Health and Nutrition Examination Survey. Separate antioxidant models found that blood levels of vitamin E had little or no association with asthma. However, a standard deviation increase in beta-carotene was associated with a 10% reduction in asthma prevalence in those not exposed to smoke and a 40% reduction in young persons who had passive smoke exposure. The pattern for vitamin C was similar to beta-carotene results. An increase in selenium was associated with a 10% to 20% decrease in asthma prevalence, and a 50% decrease in asthma prevalence in youth with passive smoke exposure.
Vitamin C in pregnancy and wheezing in children
In contrast to the results of Rubin et al. , Martindale et al.  reported that mothers consuming high levels of dietary vitamin C during late pregnancy were more than twice as likely to report wheezing in their children in their second year. This was unexpected because many previous studies of dietary vitamin C, fruit, asthma, and respiratory symptoms have reported beneficial associations. In fact, Martindale et al.  acknowledged that dietary vitamin C and fruit intake have been negatively associated with wheezing symptoms in adults and children and with adult asthma in previous research. An important limitation of the study by Martindale et al.  is the reliance on postal questionnaires and parental reports during the follow-up period, rather than direct pediatric assessment of symptoms.
Vitamin C in breast milk and atopy in infants
Hoppu et al.  investigated the effects of maternal dietary and supplemental intake of vitamins C and E on breast milk antioxidant composition and their protective potential against the development of atopy in infants. The authors concluded that a maternal diet rich in natural sources of vitamin C during breastfeeding could reduce the risk of atopic dermatitis in high-risk infants.
Vitamin C and Cancer
Studies conducted by Cameron and Pauling  in the 1970s suggested that very large doses of vitamin C were helpful in increasing the survival time and improving quality of life of terminal cancer patients. Subsequent studies at the Mayo Clinic did not find similar results , although the route of administration (intravenous [IV] versus oral) may explain the discrepant results. Padayatty et al. [20••] recently examined three well-documented cases of advanced cancers in which patients had unexpectedly long survival times after receiving high-dose IV vitamin C. They concluded that vitamin C therapy may have antitumor effects in certain cancers and that further safety and efficacy studies are warranted.
Low antioxidant intake and childhood leukemia
As noted by Kennedy et al. [21••], chemotherapy leads to an increase in reactive oxygen species, which stresses the antioxidant defense system. Kennedy et al. [21••] conducted a recent study to investigate the effect of therapy on antioxidant intakes in children with acute lymphoblastic leukemia, the relation between dietary antioxidant intakes and plasma antioxidant concentrations, and the relation between the incidence of side effects due to treatment and antioxidant intake. The results indicated that greater vitamin C intakes at 6 months were associated with fewer therapy delays, less toxicity, and fewer days spent in the hospital.
Vitamin C, fruit, lycopene, and stomach cancer
The team from the US National Cancer Institute and National Public Health Institute of Finland assessed the association between fruit and vegetable consumption and the risk of stomach cancer in approximately 29,000 male smoker participants of the Alpha-Tocopherol, Beta Carotene cancer prevention study in Finland. Presenting their findings at the Frontiers in Cancer Prevention Research conference , researchers indicated they had found fruit and vitamin C intake, but not vegetable consumption, reduced risk of noncardiac cancer (the major form of stomach cancer in most parts of the world) approximately 45%. Lycopene also appeared to lower risk of stomach cancer by 34%.
Vitamin C and Exercise
As noted in a recent study by Bell et al. , vitamin C supplementation does not appear to improve exercise performance. Researchers gave vitamin C initially via infusion, followed by 30-day oral administration, to a group of 12 young and 10 older (61 years old) adults just before exhaustive exercise on a treadmill. This administration regimen of vitamin C did not affect maximal aerobic capacity or maximal cardiac output in either group of subjects. Interestingly, researchers did note a decrease in oxidized LDL cholesterol in both groups after acute IV administration of vitamin C.
Vitamin C and fat loss
The incidence of vitamin C deficiency in the United States is increasing . Because vitamin C is required for the biosynthesis of carnitine, the molecule responsible for transporting long-chain fatty acids into the mitochondria for oxidation, Johnston  recently completed several studies examining the effect of vitamin C status on fat oxidation. In an unpublished trial, subjects with poor vitamin C status (defined as plasma vitamin C < 34 μmol/L) oxidized less fat than subjects with adequate vitamin C status (plasma concentration ≥ 34 μmol/L) during a submaximal walking test. In addition, plasma carnitine was inversely associated with fatigue (r = −0.61; P = 0.009) as measured with the Profile of Moods States questionnaire. In another study by Johnston et al. , subjects who first underwent 3 weeks of vitamin C depletion, followed by 2 weeks of vitamin C repletion (500 mg/d), were able to perform 10% more work during a 90-minute walk at 50% of their maximal aerobic capacity. Although preliminary, these findings are intriguing, and ongoing studies are continuing to examine the potential link between vitamin C, body composition, and performance.
Vitamin C is indispensable for the development, normal growth, and functioning of the human body. Epidemiologic evidence generally supports the relationship between a diet replete with sufficient vitamin C and the maintenance of overall health and wellness. Given their high nutrient content, and the possibility that they contain yet-to-be-identified micronutrients, the most prudent recommendation for consuming vitamin C is to consume copious quantities of fruits and vegetables daily. In this regard, supplementation with vitamin C, if necessary, to achieve the level of the RDA is strongly recommended. Supplementation above the RDA (200–500 mg) may be prudent during periods of extreme physical stress to mitigate respiratory infections. Until further studies are completed, megadoses of vitamin C (>2000 mg/d) should only be done under the auspices of a knowledgeable physician or other qualified healthcare provider.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
1. Whitney EN Cataldo CB Rolfes SR: Understanding Normal and Clinical Nutrition. Belmont, CA: Wadsworth/Thompson Learning; 2002:335–341.
2. Higdon J: An Evidence-Based Approach to Vitamins and Minerals. New York: Thieme; 2003:65–72.
3. Johnston CS: Vitamin C. In Present Knowledge in Nutrition, edn 8. Edited by Bowman BA Russell RM. Washington, DC: ISLI Press; 2001:175–183.
4. Akobundu UO, Cohen NL, Laus MJ, et al.
: Vitamins A and C, calcium, fruit and dairy products are limited in food pantries.JADA
5. Millen AE, Klein R, Folsom AR, et al.
: Relation between intake of vitamins C and E and risk of diabetic retinopathy in the Atherosclerosis Risk in Communities Study.Am J Clin Nutr
6. Lee KW, Mossine V, Ortwerth BJ: The relative ability of glucose and ascorbate to glycate and crosslink lens proteins in vitro.Exp Eye Res
7. Lee D-K, Folsom AR, Harnack L, et al.
: Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes?Am J Clin Nutr
8. Vega-Lopez S, Devaraj S, Jialal I: Oxidative stress and antioxidant-supplementation in the management of diabetic cardiovascular disease.J Invest Med
9. Evans M, Anderson RA, Smith JC, et al.
: Effects of insulin lispro and chronic vitamin C therapy on postprandial lipaemia, oxidative stress and endothelial function in patients with type 2 diabetes mellitus.Eur J Clin Invest
10. Levy AP, Friedenberg P, Lotan R, et al.
: The effect of vitamin therapy on the progression of corona artery atherosclerosis varies by haptoglobin type in postmenopausal women.Diabetes Care
11. Carroll MF, Schade DS: Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers.Circulation
12. Knekt P, Ritz J, Pereira MA, et al.
: Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts.Am J Clin Nutr
13.• Block G, Jensen C, Dietrich M, et al.
: Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation.J Am Coll Nutr
Randomized, double-blind, placebo-controlled parallel group trial demonstrated that vitamin C supplementation yielded a 24.0% reduction (P < 0.036 compared with control) in plasma CRP.
14. Steurer-Stey C, Russi EW, Steurer J: Complementary and alternative medicine in asthma: do they work?Swiss Med Wkly
15. Rubin RN, Navon L, Cassano PA: Relationship of serum antioxidants to asthma prevalence in youth.Am J Respir Crit Care Med
16. Martindale S, McNeill G, Devereux G, et al.
: Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life.Am J Respir Crit Care Med
17. Hoppu U, Rinne M, Salo-Väänänen P, et al.
: Vitamin C in breast milk may reduce the risk of atopy in the infant.Eur J Clin Nutr
18. Cameron E, Pauling L: Supplemental ascorbate in supportive treatment of cancer: prolongation of survival times in terminal human cancer.Proc Natl Acad Sci U S A
19. Moertel CG, Fleming TR, Creagan ET, et al.
: High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: a randomized double-blind comparison.N Engl J Med
20.•• Padayatty SJ, Riordan HD, Hewitt SM, et al.
: Intravenously administered vitamin C therapy: three cases.CMAJ
An assessment of three patients with well-documented advanced cancers with poor prognoses that instead had long clinical remissions. All patients were treated with high-dose IV vitamin C (along with other alternative medicine therapies), and researchers speculated that ascorbic acid selectively kills some cancer cells but no normal cells by generating extravascular hydrogen peroxide.
21.•• Kennedy DD, Tucker KL, Ladas ED, et al.
: Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia.Am J Clin Nutr
A 6-month observational study of 103 children with acute lymphoblastic leukemia indicated that greater vitamin C intakes were associated with fewer therapy delays, less toxicity, and fewer days spent in the hospital; greater vitamin E intakes were associated with a lower incidence of infection; and greater beta-carotene intakes at 6 months were associated with a decreased risk of toxicity.
22. Nouraie M, Pietinen P, Kamangar F, et al.
: Fruits, vegetables, and antioxidants, and risk of gastric cancer.Frontiers in Cancer Prevention Research
2004; Poster Session #C69
23. Bell C, Carson JM, Motte NW, Seals DR: Ascorbic acid does not affect the age-associated reduction in maximal cardiac output and oxygen consumption in healthy adults.J Appl Physiol
24. Hampi JS, Taylor CA, Johnston CS: Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey.Am J Pub Health
25. Johnston CS: Strategies for healthy weight loss: from vitamin C to the glycemic response.J Am Coll Nutr
26. Johnston CS, Swan PD, Corte C: Substrate utilization and work efficiency during submaximal exercise in vitamin C depleted-repleted adults.Int J Vit Nutr Res