

Ascorbate, sodium ascorbate
Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that is found in many fresh fruits and vegetables. It is an essential vitamin that is not synthesized in humans and deficiency has been linked to scurvy. Vitamin C is also necessary for a variety of physiologic functions that include formation of collagen, catecholamines, and carnitine in addition to tyrosine metabolism, and peptide synthesis (1). Vitamin C is also one of the commonly used dietary supplements for immune stimulation, for wound healing, as an antioxidant, and for cancer prevention.
Vitamin C is believed to promote cardiovascular health but findings from the recent Physicians' Health Study II indicate no such benefit for preventing cardiovascular disease (2). Furthermore, supplementation with vitamins C and E increased risk of mortality alnd nonfatal myocardial infarction in patients with coronary artery disease (3). It is not clear if vitamin C helps reduce blood pressure as data are conflicting (4) (5). Vitamin C may reduce the severity and duration of respiratory infections in otherwise healthy patients, although no prophylactic benefit has been demonstrated. The addition of vitamin C to a medication regimen has also been shown to increase the eradication rate of H. pylori infection (6). It may also offer protection against Alzheimer's disease (7) (8); however, conflicting data from another study do not support the utility of antioxidants (vitamin E, vitamin C, lipoid acid, and Coenzyme Q) (31).
The role of vitamin C in cancer treatment and prevention is unclear. Results from in vitro and animal studies showed that cancer cells preferentially uptake vitamin C (9) (10). But supplementation with vitamins C, E, and beta carotene was not beneficial in preventing cancer incidence or affecting cancer mortality (11). Further, supplementation with vitamin C along with vitamins A E, and beta-carotene did not prevent gastrointestinal cancer (12), did not lower the risk of prostate cancer (13), and may actually increase overall mortality (12). A study done in end-stage cancer patients showed no benefit from high-dose vitamin C (14). However, one study did find an association between the intake of vitamins A, C, or E and a reduced risk for cervical cancer (15). Vitamin C was also found to normalize thiobarbituric acid (an indicator of lipid peroxidation and oxidative stress) and antioxidant enzyme levels in breast cancer patients receiving tamoxifen treatment (16). Use of intravenous vitamin C has been examined in cancer patients and clinical trials are underway to assess its efficacy (18) (17) (30).
Vitamin C can render many chemotherapy drugs less effective (10). However, inadequate amounts of antioxidants including vitamin C were associated with increased adverse effects due to chemotherapy in children with acute lymphoblastic leukemia (19). Other potential adverse effects are gastrointestinal in nature, although hypoglycemia and hypotension are documented with doses higher than one gram per day. Patients with history of oxalate kidney stones, renal insufficiency, G6PDH deficiency, hematochromatosis, or those undergoing chemotherapy should consult their physicians before taking vitamin C supplements.
Citrus fruits, cruciferous vegetables, berries, peppers, melons, tomatoes, potatoes (20)
A water-soluble antioxidant, vitamin C reacts directly with superoxide, hydroxyl radicals, and singlet oxygen molecules. One study indicated that the reported preferential cytotoxic affect of ascorbic acid against cancer cells may be due to a redox reaction with copper, which has been observed to be present at elevated levels in various malignancies. This reaction may overwhelm the cancer cells antioxidant capacity, leading to irreversible damage and apoptosis (21). Ascorbic acid promotes wound healing by serving as a reductant in the pathway for the formation and polymerization of collagen. Vitamin C deficiency thus results in impaired wound healing and scurvy (1). Vitamin C is important for the synthesis of catecholamines and carnitine, in addition to the conversion of folic acid to folinic acid. It is also involved with tyrosine metabolism and peptide synthesis. During a state of infection, vitamin C may reduce inflammation caused by oxidizing chemicals released by phagocytic leukocytes following activation (22). Vitamin C also may inhibit free radical inactivation of nitric oxide, thereby improving endothelium-dependent vasodilation (23). Dehydroascorbic acid, the oxidized form of vitamin C, may have cytoprotective effect by preserving mitochondrial membrane potential (10).
Absorption:
Intestinal absorption occurs through a sodium-dependent active transport process that is saturable and dose-dependent. Approximately 70-90 percent of the usual dietary intake of ascorbic acid (30-180 mg/day) is absorbed, although absorption falls to 50 percent or less with increasing doses above 1 g/day. The bioavailability of vitamin C from food or supplements is not significantly different.
Distribution:
Dehydroascorbic acid is the form of the primarily crosses the membranes of cells, after which it is reduced intracellularly to ascorbic acid. High levels of the vitamin are maintained in the pituitary and adrenal glands, leukocytes, eye tissue and humors, and the brain, while relatively low levels are found in plasma and saliva.
Metabolism / Excretion:
Due to homeostatic regulation, the biological half-life varies widely from 8 to 40 days and is inversely related to body pools. Ascorbic acid is also metabolized into oxalic acid (29). Renal excretion increases proportionally with higher intakes . With large intakes of the vitamin, unabsorbed ascorbate is degraded in the intestine, a process that may account for the diarrhea and intestinal discomfort occasionally reported by people ingesting large doses.
(24)
Common: Nausea, diarrhea, stomach cramps and possible hypoglycemia and hypotension with doses greater than 1 gram.
Reported (oral): In patients with a history of kidney stones, increased oxalate kidney stone formation occurs with possible nephrolithiasis, acute renal failure, or renal insufficiency (25).
In patients with G6PDH deficiency, hemolytic anemia may occur at high doses (1).
Reported (oral): Severe cyanide poisoning following ingestion of 3 grams of amygdalin with concurrent use of 4800 mg of vitamin C per day (26).
Toxicity: Excessive use of chewable tablets may break down tooth enamel, increasing the risk of dental caries (27)
Iron: Ascorbic acid increases iron absorption and modulates transport and storage in the body. Significant in patients with hematochromatosis.
(24) (27)
Chemotherapy Drugs: Vitamin C can reduce the effectiveness of many antineoplastic agents, include vincristine, doxorubicin, methotrexate, cisplatin, and imatinib. (10)
High dose ascorbic acid supplementation may alter results of urine glucose testing strips, and may cause a false negative guaiac (occult blood) test (28).
Kim J, et al. Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: a case-control study in Korea. Nutr Cancer. 2010;62(2):181-9.
This study investigated the influence of antioxidant supplements in 144 cervical cancer patients and 288 age-matched, hospital-based controls. All subjects filled out a questionnaire regarding lifestyle and dietary and supplement intake. Study results indicated that patients with cervical cancer reported a statistically lower mean dietary intake for beta-carotene (p=0.004), vitamin A (p = 0.002),and vitamin C (p<0.001), than control subjects. Total dietary and supplement intake of Vitamin A (p=0.003) and E (p=0.001) were also found to be significantly lower in the cancer patients. Subjects in the highest quartiles were also found to have a statistically significant lower risk for cervical cancer compared to those in the lower quartiles for vitamin A (p<0.001), beta-carotene (p = 0.006), and vitamin C (p=0.001) intake. The authors concluded that total intakes of, vitamins A, C, or E were strongly correlated with a reduced risk for cervical cancer However, they advised that these correlations should be studied in large prospective studies with long- term follow-ups.
Muralikrishnan G, et al. Effects of vitamin C on lipid peroxidation and antioxidant status in tamoxifen-treated breast cancer patients. Chemotherapy. 2010;56(4):298-302.
This study enrolled 60 post-menopausal women with resectable breast cancer to determine the antioxidant effects of Vitamin C. Fifteen normal, healthy women were also enrolled as a control group. The women with breast cancer were divided into 4 groups of 15 who were: not treated with tamoxifen; treated with tamoxifen; treated with vitamin C after 45 days of tamoxifen treatment; or treated with vitamin C after 90 days of tamoxifen treatment. Levels of thiobarbituric acid (TBA) substances (an indicator of lipid peroxidation and oxidative stress) and antioxidant enzymes (catalase,superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase) were determined in plasma and red blood cell hemolysates. The level of TBA reacting substances was significantly elevated and the levels of antioxidant enzyme were significantly reduced in the untreated and tamoxifen-treated breast cancer patients. However, the authors found that in the groups receiving vitamin C supplementation wiith tamoxifen, the antioxidant enzyme levels had normalized. The authors concluded that the added antioxidant effect observed with coadministration of Vitamin C may benefit in breast cancer patients receiving tamoxifen treatment.
Sesso, HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men. The Physicians' health study II Randomized Controlled Trial. JAMA. 2008;300(18):2123-2133.
This long-term study sought to evaluate the role of vitamin C or E supplementation in reducing the risk of cardiovascular disease, and involved over 14,000 men aged 50 or older. The participants were randomized to 400 IU of vitamin E every other day or its placebo and 500 mg of vitamin C daily or its placebo. The primary outcome of the study was onset of major cardiovascular events including, nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular disease.
At the 8-year follow-up, researchers observed the same number of cases in both the vitamin and the placebo groups, with increased risk of hemorrhagic stroke in the vitamin E group. These findings suggest no significant effects of vitamins in lowering the risk of cardiovascular disease as widely believed.
It should be noted that both the vitamins used in the study were synthetic and at much higher levels than those achieved via dietary intake, which may have led to the effects observed. More studies at different doses and involving other populations are warranted to fully assess the role of vitamin supplementation for cardiovascular health.
Slatore CG, Littman AJ, Au DH, et al. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am J Respir Crit Care Med. 2008;177(5):524-30.
A prospective study of 77,221 men and women (50-76 years) was conducted to determine the association between vitamin use and lung cancer. A total of 521 cases of lung cancer were identified. The findings were based on 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. Researchers conclude that vitamin supplementation does not decrease risk of lung cancer. Furthermore, vitamin E use was associated with a slight increase in risk of lung cancer.
Bjelokovic G, Nikolova G, Simonetti RG, et al. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev 2004;(4):CD004183.
This is a systematic review of 14 randomized clinical trials. Participants of the studies did not have gastrointestinal diseases but were at high risk of developing gastrointestinal cancer. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. According to the findings of this study, supplementation with beta-carotene, vitamin A, vitamin C, and vitamin E, when taken alone or in combination do not affect incidence of gastrointestinal cancers. Further, they may increase the overall mortality. The effects of Selenium supplementation need confirmation in future randomized trials.
Patients should consult their physicians before initiating vitamin supplementation, especially during and after chemotherapy.
Engelhart MJ, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-9.
A population-based, prospective cohort study evaluating antioxidant intake and risk of developing Alzheimer disease. Subjects (n=5393) were at least 55 years old, free of dementia, noninstitutionalized, and had reliable dietary assessment at baseline. Dietary intake was assessed by self-reported checklist and interview with dietitian using the semiquantitative food-frequency questionnaire (SFFQ). After mean follow-up of 6 years, 146 patients developed Alzheimer disease. After adjustments for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of supplements, high intake of vitamin C and vitamin E were correlated with lower risk of Alzheimer disease. However, the apparent association may be caused by the influence of a preclinical illness on diet or diet recall/reporting, since the SFFQ itself may indirectly assess cognitive functioning. Furthermore, the multiple comparisons made suggests that some associations may be due to chance and that the critical P value should be set lower than .05.
Bottom Line: Vitamin C is important for maintaining general health but it may reduce the effectiveness of chemotherapy drugs.
Vitamin C is a known antioxidant that protects the body against oxidative stress. This means that it reacts with and neutralizes free radicals in the body that can cause cellular and DNA damage. It is also important for the production of many essential molecules in the body, including proteins. Vitamin C plays an important role in the formation of collagen, which is the main structural protein in the skin. Therefore, vitamin C helps promote wound healing. Since the body cannot synthesize vitamin C, it must be gained from outside sources. In addition, scientists think that vitamin C might help reduce inflammation. However, vitamin C can make many chemotherapy drugs less effective. Patients should speak with their doctor before using vitamin C.
Cancer treatment
A study of 144 cervical cancer patients and 288 age-matched control subjects was done to find out the effects of antioxidant supplements. All subjects filled out a questionnaire regarding lifestyle and dietary and supplement intake. The results showed that patients with cervical cancer reported lower dietary intake for beta-carotene, vitamin A, and vitamin C compared to control subjects. The association should however be studied in larger trials.
Another study included 60 post-menopausal women with resectable breast cancer (can be removed with surgery) to find out the effects of Vitamin C. Fifteen normal, healthy women were enrolled as a control group. The women with breast cancer were divided into 4 groups of 15: treated with tamoxifen; treated with tamoxifen; treated with vitamin C after 45 days of tamoxifen treatment; or treated with vitamin C after 90 days of tamoxifen treatment. The level of TBA reacting substances (an indicator of lipid peroxidation and oxidative stress) was much higher and the levels of antioxidant enzyme were greatly reduced in the untreated and tamoxifen-treated breast cancer patients. Women who received vitamin C with tamoxifen had normalized leves of antioxidant enzyme.
A study of 77,221 men and women (50-76 years) was done to find out the association between vitamin use and lung cancer. A total of 521 cases of lung cancer were identified. The findings were based on 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. Vitamin supplementation may not decrease risk of lung cancer. In addition, those who took vitamin E had a slight increase in risk of lung cancer.
A review of 14 clinical trials showed that supplementation with antioxidants B-carotene, vitamins A, C, and E does not seem to prevent gastrointestinal cancer and may increase overall mortality.
Cardiovascular disease
A long-term study involving over 14,000 men aged 50 or older was done to determine the role of vitamin C or E supplementation in reducing the risk of cardiovascular disease. The participants were randomized to receive 400 IU of vitamin E every other day or placebo and 500 mg of vitamin C daily or placebo. At the 8-year follow-up, the number of cases of cardiovascular disease in both vitamin and placebo groups were the same. Those in the vitamin E group also had an increased risk of hemorrhagic stroke. Vitamin supplements may not lower risk of cardiovascular disease.
Alzheimer's disease
A population study in the Netherlands followed 5393 people aged 55+ for six years to compare their dietary antioxidant intake (vitamins C and E, flavonoids, and beta-carotene) to their risk of developing Alzheimer's disease. After statistical analysis that took into account risk factors such as age, alcohol intake, and smoking, people who had a high dietary intake of vitamins C and E were found to have a lower risk of Alzheimer's disease. However, it is likely that some of these associations may be due to chance alone. In addition, Alzheimer's disease develops over a course of 15+ years, indicating that following patients for only six years is not long enough. Most of the 146 patients probably had already begun developing the disease before the study even began, which in turn could adversely affect their diet.
Recent laboratory experiments and animals studies suggest that cancer cells preferentially uptake vitamin C. This raises the possibility that high-dose vitamin C may be detrimental to cancer patients undergoing radiation or chemotherapy.
It is controversial whether antioxidants like vitamin C can lessen or negate the effects of chemotherapy and radiation therapy. Because these therapies work by creating free radicals that kill cancer cells, some physicians have suggested that high levels of antioxidants can neutralize these free radicals and thereby protect cancer cells from these therapies. So what protects healthy cells may protect cancer cells as well. This question is still not fully understood and patients who are interested in taking more than the RDA of any antioxidant should consult with their doctor.