Vitamin C

Research Update

Abstract

For more than 50 years, the Food and Nutrition Board of the National Academy of Sciences has been reviewing nutrition research and defining nutrient requirements for healthy people, referred to as the Recommended Dietary Allowances (RDA). As new nutrition research is published, the importance of vitamins as vital nutrients is underscored, and new physiologic roles and applications to human health are examined and considered with regard to updating the RDA. Each year a substantial amount of new research is published on vitamins. This review examines recent research published on the importance of vitamin C with regard to general health.

Introduction

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 [¹]. 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 [²]. 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 [¹]. 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 [²]. 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 [³].

Table 1: Enzymes requiring ascorbic acid as a cofactor or cosubstrate and their function

Figure 1: Ascorbic acid.

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. [⁴] little is known about the nutritional quality of foods distributed in pantry bags. Consequently, Akobundu et al. [⁴] 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. [⁵] 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 [⁶]. These observations led Lee et al. [⁷] to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis. Subsequently, Lee et al. [⁶] 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. [⁶], Vega-Lopez et al. [⁸] 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. [⁹] 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. [⁶] and that of Vega-Lopez et al. [⁸] and Evans et al. [⁹] 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. [¹⁰], 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. [¹⁰] 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 [¹¹] 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. [¹²] 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 [²], 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 [¹⁴].

Vitamins C and E, beta-carotene, selenium, and asthma

Rubin et al. [¹⁵] 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. [¹⁵], Martindale et al. [¹⁶] 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. [¹⁶] 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. [¹⁶] 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. [¹⁷] 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 [¹⁸] 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 [¹⁹], 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 [²²], 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. [²³], 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 [²⁴]. 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 [²⁵] 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. [²⁶], 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.

Conclusions

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.