Vitamin C stimulates procollagen formation, enhances collagen synthesis, and stimulates alkaline phosphatase activity, a marker for osteoblast formation.9
Vitamin C is essential for collagen synthesis because it acts as a reducing agent in a number of hydroxylation reactions in the body including proline 4-hydroxylase.
Vitamin C is a water-soluble antioxidant and can quench both reactive oxygen species and reactive nitrogen species. This antioxidant activity diminishes lipid peroxidation, oxidative DNA damage, and oxidative protein damage. Oxidation of low density lipoprotein (LDL) has been suggested to be a factor leading to atherosclerosis. Vitamin C prevents LDL oxidation. Vitamin C may also increase high density lipoprotein (HDL) cholesterol concentrations, possibly resulting in decreased risk of atherosclerosis.
Vitamin C can prevent the formation of carcinogens (e.g. nitrosamines) in foods and in the gastrointestinal tract.
Vitamin C is required for enzyme reactions that produce the neurotransmitters serotonin and norepinephrine.
Vitamin C is essential for the synthesis of carnitine which is required for the transport of fat to the mitochondria for production of energy. 32
Vitamin C is involved in the metabolism of cholesterol to bile acids which may contribute to healthy blood cholesterol levels or prevent formation of gall stones. 33
Severe vitamin C deficiency results in scurvy, an acute or chronic disease characterized by hemorrhagic manifestations and abnormal osteoid and dentin formation. Scurvy is rare in the United States.
In adults, scurvy remains latent for 3 to 12 months following onset of severe vitamin C deficiency.
Symptoms are weakness, irritability, weight loss, and vague myalgias and sometimes appearance of a crescent near the distal end of the nail.
The gums become swollen, purple, spongy, and readily bleed.
In secondary infection, gangrene occurs, accompanied by loosening of the teeth and gum changes. Also, old scars break down, new wounds fail to heal, and spontaneous hemorrhages may occur in any part of the body.
Other symptoms and signs of scurvy include: bulbar conjunctival hemorrhage, femoral neuropathy, oliguria, edema of the lower extremities, impaired vascular reactivity, and arthritis resembling rheumatoid arthritis.
Massive doses of vitamin C increase the amount of oxalate excreted, although the amount usually remains within a normal and safe range. Only persons predisposed to urolithiasis are likely to be troubled by oxalate stones.
Large doses of ascorbic acid (4 g) will increase the amount of uric acid excreted in the urine, which may cause urate crystals. Lower doses of vitamin C may reduce serum concentrations of uric acid and reduce risk for development of gout. [~37~]
Ascorbic acid when ingested with sources of non-heme iron increases iron absorption. Chronic high doses may be unsafe for individuals with hemochromatosis, thalassemia, and sideroblastic anemia.
Excessive doses of vitamin C can cause diarrhea. Ascorbate in the feces and urine can interfere with a variety of clinical laboratory tests.
High intake of vitamin C (more than 1500 mg) may decrease the absorption of copper in the intestine.
Safety of Vitamins E and C
A review article published in the 2005 Journal of Clinical Nutrition evaluated over 45 published clinical trials and several meta-analyses on the safety of vitamin E, vitamin C, or the combination of the two. The data consistently shows the safety of both these vitamins, alone or combined. More than 20 published clinical trials involving 80,000 subjects or more have documented the safety of vitamin E supplements. Three meta-analyses that combined the results of randomized controlled trials designed to evaluate the efficacy of vitamin E supplements for the prevention or treatment of cardiovascular disease (CVD) found no evidence that E supplementation up to 800 IU/day significantly increased or decreased CVD mortality or all-cause mortality. In addition, few reports have cited any adverse effects, such as bleeding, for vitamin E. Regarding vitamin C, the authors include over 20 published clinical trials with doses ranging from 60 mg to 10 grams. No pattern of evidence supports concerns about safety of vitamin C other than the occasional gastrointestinal upset or mild diarrhea. Both AREDS and MRC/BHF Heart Protection Study support the safety of vitamin E and C in combination. The Food and Nutrition Board of the Institute of Medicine established upper limits for vitamin E at 1000 mg (1600 IU), and 2000 mg for vitamin C. These recommendations support the consensus of published studies that vitamin E doses up to 1000 mg/day and vitamin C doses up to 2000 mg/day are safe for use by the general population.181920
Almost 90% of dietary vitamin C comes from foods of plant origin. Vitamin C can be found in fruits (especially citrus) and vegetables, including green and red peppers, tomatoes, potatoes, and green, leafy varieties (e.g. spinach and collard greens). Cooking and food preparation can diminish the amount of vitamin C in foods.
• Increased urinary loss of vitamin C may occur when aspirin is taken concurrently with ascorbic acid. Patients taking high doses of aspirin who have signs or symptoms of ascorbic acid deficiency should be evaluated for deficiency. Routine administration of vitamin C supplements may be recommended.
Vitamin C may interfere with the anticoagulant effects of warfarin (Coumadin). It is advisable to consult a physician or pharmacist during drug therapy.
The concurrent administration of vitamin C and fluphenazine (Prolixin), an antipsychotic agent, results in decreased fluphenazine plasma concentrations. It is advisable to consult a physician or pharmacist during drug therapy.
Vitamin C concentrations are decreased by use of estrogen or estrogen-containing oral contraceptives. The clinical significance is unclear. It is advisable to take the vitamin 1 to 2 hours before or 3 to 4 hours after the administration of the contraceptives to maximize absorption.
A large dose of vitamin C (more than 500 mg) may cause false-negative urine glucose determinations. No exogenous vitamin C should be ingested for 48 to 72 hours before amine-dependent stool occult blood tests.
Three grams of vitamin C with acetaminophen (Tylenol), an analgesic agent, was shown to prolong the amount of time acetaminophen stays in the body. People who take the drug should consult with a physician or pharmacist before adjusting the dose.
Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.
Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative
The relationship between antioxidant consumption and bone mineral density (BMD) was investigated as a part of the Women’s Health Initiative. A total of 11,068 women aged 50 to 79 years participated in the study. Antioxidant consumption from the diet was estimated from a food-frequency questionnaire; supplement use was determined from a separate, investigator conducted questionnaire. After adjustment for low BMD risk factors, antioxidant consumption was not related to BMD. A beneficial interaction was detected for women on hormone therapy with high total intake of vitamin C (P < 0.01 for top quarter compared to lower three-quarters). The beneficial effect of hormone therapy on femoral neck BMD was greater in women with higher concentrations of total vitamin C; the interaction was significant for total-body (P < 0.045), spine (P = 0.03), and total-hip BMDs (P = 0.029). These results did not find a beneficial effect of antioxidants alone but did find a possible beneficial interaction between vitamin C levels and hormone therapy for BMD in women. 28
Vitamin C and hyperglycemia in the European Prospective Investigation into Cancer-Norfolk (EPIGNorfolk) Study.
A large population based study examined the association between plasma vitamin C concentrations and glucose tolerance. Findings in this study confirm the observation that subjects with diabetes have lower plasma vitamin C concentrations than subjects without diabetes. Therefore, dietary measures to increase plasma vitamin C concentrations may be an important public health strategy for reducing the prevalence of diabetes. 10
Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes?
A prospective study investigated the relationship between vitamin C intake and cardiovascular disease risk in women with diabetes. A total of 1923 postmenopausal women with self-reported diabetes participated in the study. Subjects were given a food-frequency questionnaire at the beginning of the study and were followed for 15 years. All subjects were initially free of cardiovascular diseases. At the end of the trial, 281 total cases of cardiovascular disease mortality, 175 cases of coronary artery disease mortality, and 57 mortality from strokes were reported. After adjustment for a variety of risk factors, medications, and other vitamins and minerals, relative risks for cardiovascular disease mortality across increasing quintiles of total vitamin C intake from food and supplements were 1.0, 0.97, 1.11, 1.47, and 1.84 (P for trend < 0.01). For coronary artery disease, relative risks across the same quintiles of vitamin C intake were 1.0, 0.81, 0.99, 1.26, and 1.91 (P for trend = 0.01). For stroke, relative risks across the quintiles of vitamin C intake were 1.0, 0.52, 1.23, 2.22, and 2.57 (P for trend < 0.01). When examined independently, dietary vitamin C did not show these trends but supplemental vitamin C increased risk for total cardiovascular disease mortality, coronary artery disease mortality, and stroke mortality.25
The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.
The effect of haptoglobin type on response to vitamin therapy was investigated in the Women’s Angiographic Vitamin and Estrogen (WAVE) trial. Haptoglobin is an antioxidant protein. Two classes of functionally distinct alleles, denoted 1 and 2, exist for the haptoglobin gene in man. It has been suggested that this polymorphism might explain the discrepancy between animal and human trials with vitamin therapy and cardiovascular diseases. In humans, haptoglobin type can be homozygous for type 1 (Hb1-1), heterozygous (Hb2-1), or homozygous for type 2 (Hb2-2). The response to vitamin therapy in these three groups was investigated with reference to coronary artery atherosclerosis. A total of 299 women completed the study. Haptoglobin type was identified for each participant and an angiogram was completed at baseline and after a median time of 2.8 years. For this study, women who consumed the vitamin supplement (400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily) were compared to women who consumed the placebo during the trial. A significant benefit from vitamin supplementation on median luminal diameter (MLD) was found for Hb1-1 women (0.079 ± 0.040 mm, P = 0.049). This benefit was more marked in Hb1-1 women with diabetes (0.149 ± 0.064 mm, P = 0.021). However, for Hb2-2 women a trend toward decreased MLD was found; this trend was more marked for women with diabetes. (0.128 ± 0.057 mm, P = 0.027).26
Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes.
A randomized, double-blind, placebo-controlled clinical trial investigated the affects of vitamin, mineral, vitamin plus mineral, or a placebo on glomerular and tubular dysfunction in people with type 2 diabetes. A total of 69 people participated in the three month study. Participants were randomly assigned to one of four groups: Group M (200 mg Mg and 30 mg Zn, n=16), Group V (200 mg vitamin C and 100 IU vitamin E, n=18), Group MV (minerals plus vitamins, n=17), or Group P (placebo, n=18). After three months, urinary excretion of albumin was significantly decreased in both Group V and Group MV (P = 0.034 and P = 0.005, respectively). In Group MV, significant reductions in systolic, diastolic, and mean blood pressure were noted (P = 0.008, P = 0.017, and P = 0.009, respectively). Group MV also demonstrated significantly decreased fasting serum glucose (P = 0.035) and malondialdehyde concentrations (P = 0.004). HDL cholesterol concentrations and apolipoprotein A1 levels were significantly improved in Group MV (P = 0.019). These changes indicate that the combination of vitamins and minerals examined here may improve glomerular but not tubular renal function for people with type 2 diabetes. 27
Association of vitamin E and C supplement use with cognitive function and dementia in elderly men.
The Honolulu-Asian Aging Study of Japanese-American men examined the association of vitamin E and C supplement use with cognitive function and dementia. The study included 3,385 men, aged 71 to 93 years, who were surveyed on their supplement use in 1988 and cognitive functions between 1991 and 1993. The Cognitive Abilities Screening Instrument was used for dementia analysis. A significant protective effect was found for vascular dementia for men who reported taking both vitamin C and vitamin E in 1988 (odds ratio (OR), 0.12; 95% CI, 0.02 to 0.88). A protective effect was also found for mixed or other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). For those without dementia (n=2,999), those who reported use of either vitamin E or C supplements alone in 1988 demonstrated significantly better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50). The use of both vitamin E and C together by those without dementia had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39) with regard to cognitive test performance. No protective effect was seen for Alzheimer’s disease. These results suggest that taking both vitamins C and E may protect against vascular dementia and mixed or other dementia, but not against Alzheimer's dementia. 12
Ascorbic acid status and subsequent diastolic and systolic blood pressure.
To investigate the relationship between vitamin C status and blood pressure, a controlled-diet study enrolling 68 men aged 30 to 59 years was conducted. Participants consumed a planned diet consisting of approximately 50% of energy from carbohydrates, 14% from protein, and 36% from fat. For a one month period, vitamin C intake was restricted to approximately 9 mg/d (depletion), followed by a one month repletion period which provided 117 mg/d. The entire depletion-repletion cycle was then repeated. After one month of vitamin C depletion, plasma vitamin C concentration was inversely associated with diastolic blood pressure (correlation -0.48, P<0.0001). Men in the bottom quarter of plasma vitamin C concentrations had more than 7 mmHg higher diastolic blood pressure than those in the top quarter. Plasma vitamin C concentration was also associated with systolic blood pressure. Even after adjustment of confounding factors such as BMI and nutrient intake, the inverse relation was significant, suggesting that vitamin C intake and plasma vitamin C concentrations contribute to maintaining healthy blood pressures.13
Serum vitamin C concentration is low in peripheral artery disease and is associated with inflammation and severity of atherosclerosis.
To determine the relationships between vitamin C concentrations, inflammation, and severity of peripheral arterial disease (PAD), vitamin C status was measured in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum ascorbic acid concentrations were significantly lower in PAD patients (median, 27.8 micromol/L; P<0.0001), regardless of smoking and dietary intake. Fourteen percent of PAD patients were found to have subclinical vitamin C deficiency (<11.4 micromol/L); subclinical deficiency was not found in the other groups. PAD patients had higher concentrations of serum C-reactive protein (CRP, a marker of inflammation; P<0.0001). CRP was inversely correlated with low ascorbic acid concentrations (r=-0.742, P<0.0001). Thus, low vitamin C concentration in PAD patients was associated with, in order, high CRP level (P=0.0001), smoking (P=0.0009), and shorter absolute claudication distance on a standardized graded treadmill test (P=0.029). These results suggest that low vitamin C levels in PAD may contribute to inflammation and severity of disease. 14
Decrease in vitamin C concentration in human lenses during cataract progression.
Although pathogenesis of cataract is multi-factorial, maintenance of sufficient vitamin C in the blood is required to prevent oxidative damage to the lens. Vitamin C concentration in cataractous lenses was assessed in a study. Concentrations of vitamin C, dehydroascorbic acid, and furosine were determined in 48 cataractous lens nuclei. Lens vitamin C concentrations significantly decreased with increasing cataract severity. The most severe depletion of vitamin C was detected in severe brown cataracts (around 88 mumol/100 g lens in mild cataracts, and 50 mumol/100 g in dark brown lenses). Concentrations of dehydroascorbic acid and furosine were low and stable regardless of cataract severity. Cataract formation is believed to result from an oxidative insult that decreases antioxidant defense of the lens, particularly vitamin C concentration. Upon oxidation, vitamin C contributes with glucose to protein glycation. Overall, vitamin C content appears to be a good indicator of cataract severity and oxidation may take part in cataract progression. 15
Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes.
effects of smoking on plasma antioxidant status, concentrations of vitamin C, vitamin E, beta-carotene, and lycopene were measured before and after participants took a vitamin supplement for three months. Thirty-seven smokers and 38 non-smokers participated in the study. Supplements contained 272 mg of vitamin C, 31 mg of tocopheryl acetate and 400 mcg of folic acid. Only plasma vitamin C was depleted by smoking (P<0.01). After 3 months of supplementation, plasma vitamin C concentrations were normalized (P<0.001). The results of this study indicate that vitamin C is depleted by smoking and that moderate supplementation can return plasma concentrations to normal. 16
Serum ascorbic acid and cardiovascular disease prevalence in U.S. adults.
Data from the second National Health and Nutrition Examination Survey (NHANES II) was used to investigate the relationship between cardiovascular disease (CVD) and vitamin C levels. The study included 6,624 men and women in the united states who were surveyed. Serum vitamin C concentration was independently associated with coronary heart disease (CHD) and stroke. A 0.5 mg/dl increase in vitamin C was associated with an 11% decrease in CHD and stroke. A 27% decreased prevalence of CHD (95% confidence interval = 10-41%) and a 26% decreased prevalence of stroke (95% confidence interval = 3-44%) was found when comparing those with low to marginally low serum vitamin C levels to participants in the highest serum vitamin C category. The findings showed that women had higher serum ascorbic acid concentrations than men and non-smokers had higher concentrations than smokers. The authors concluded that higher vitamin C may reduce risk for cardiovascular disease. 17
Cardiovascular disease-risk factors in middle-aged osteopaenic women treated with calcium alone or combined to three nutrients essential to artery and bone collagen.
A one-year placebo-controlled trial investigated the impact of supplements on cardiovascular disease risk factors for women with normal or low bone mineral density (BMD). Sixty women participated in the study; twenty participants had normal BMD while forty participants had low BMD. Women consumed a daily placebo (n=20), a calcium supplement (n=20), or the calcium supplement plus vitamin C (500 mg), vitamin B6 (75 mg), and proline (n=20). No changes were detected in the placebo or calcium group. The calcium plus vitamins C and B6 group had significant reductions in total cholesterol (4%), LDL cholesterol (7%), and triglycerides (25%). The calcium plus vitamins C and B6 group also had a 14% increase in HDL cholesterol concentration and a trend toward lower homocysteine. These results suggest that this combination of vitamins and minerals may improve cardiovascular disease risk factors. 21
Antioxidant vitamins intake and the risk of coronary heart disease: meta-analysis of cohort studies.
A meta-analysis of fifteen cohort studies evaluated the relationship between antioxidant vitamin intake and risk for coronary heart disease. A total of 374,488 participants were included in the study with a total of 7,415 cases of coronary heart disease. The median follow-up for vitamin C was 10 years, for vitamin E was 8.5 years, and for beta-carotene was 15 years. For each nutrient, a comparison of individuals in the top third were compared with those in the bottom third of baseline values. For vitamin C this comparison yielded a combined relative risk of 0.84 (95% CI, 0.73-0.95). For vitamin E the comparison yielded a combined relative risk of 0.76 (95% CI, 0.63-0.89). For beta-carotene the comparison yielded a combined relative risk of 0.78 (95% CI, 0.53-1.04). Subgroup analyses investigated the differing effects of dietary versus supplemental vitamins C and E. Dietary intake of vitamins C and E and supplement use of vitamin E were inversely associated with CHD risk. However, supplement use of vitamin C had no significant association with CHD risk. The results of this study indicate that an increase in dietary intake of antioxidants may reduce risk for coronary heart disease. 22
Vitamin C and risk of coronary heart disease in women.
A prospective study investigated the association between vitamin C and coronary heart disease in women. A total of 85,118 women participated in the study. After 16 years of follow-up, 1,356 cases of coronary heart disease were identified. A significant inverse association between total intake of vitamin C and coronary heart disease was revealed (relative risk (RR) = 0.73; 95% CI 0.57 to 0.94). Among women who did not take vitamin C supplements, the inverse association with coronary heart disease was non-significant and weak. After adjusting for age, smoking, and other coronary risk factors, vitamin C supplement use remained associated with a significantly lower risk of CHD (RR = 0.72; 95% CI 0.61 to 0.86). These results indicate the use of vitamin C supplements may reduce risk of CHD for women. 23
Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts.
The relationship between antioxidant vitamin uptake and coronary heart disease risk was investigated in a cohort study pooling data from nine prospective studies. A total of 293,172 subjects free of coronary heart disease at baseline were included in the study. After 10 years of follow-up, 4,647 major incidents of coronary heart disease occurred. Only a weak correlation was found between dietary intake of vitamin C and E and coronary heart disease was found. Subjects in the highest intake quintiles for vitamins E and C had relative risks of coronary heart disease incidence of 0.84 (95% CI: 0.71, 1.00; P=0.17) and 1.23 (1.04, 1.45; P=0.07), respectively, compared with subjects in the lowest dietary intake quintiles. The relative risks for subjects in the highest intake quintiles for the carotenoids varied from 0.90 to 0.99. Overall, those who consumed supplemental vitamin C had lower risk for coronary heart disease than those who did not. Compared with non-users of supplemental vitamin C, supplement users consuming more than 700 mg vitamin C daily had a relative risk of coronary heart disease incidence of 0.75 (0.60, 0.93; P for trend <0.001). These results indicate that supplemental vitamin C may help to reduce risk of coronary heart disease. 24
Decrease in oxidative stress through supplementation of vitamins C and E is associated with a reduction in blood pressure in patients with essential hypertension.
A randomized, double-blind, placebo-controlled clinical trial investigated the efficacy of vitamin C and vitamin E supplementation for essential hypertension. One-hundred-ten men with essential hypertension aged 35 to 60 years enrolled in the eight week study; 110 normotensive adult males were also studied as normal controls. Among those with essential hypertension, participants were randomly assigned to receive either a supplement of vitamins C and E (1 g/d vitamin C and 400 IU/d vitamin E) or a daily placebo. At the beginning of the trial, participants with essential hypertension had 27% lower antioxidant status, as plasma FRAP, 15% lower vitamin C levels, and 15% lower erythrocyte GSH/GSSG ratios (P<0.01). Compared with the normotensive control participants, the activity of CAT was 24% lower, Cu-Zn SOD was 21% lower, and GSH-Px was 10% lower in erythrocytes of patients with essential hypertension (P<0.01). Participants with EH also had increased plasma 8-isoprostane levels (37%) and erythrocyte MDA or lipid peroxidation levels (23%) relative to the controls (P<0.001). After eight weeks of supplementation, participants in the vitamins C+E group had significantly lower plasma and erythrocytes lipid peroxidation compared to either the placebo group or the baseline values. Use of the vitamins C+E supplement increased plasma and erythrocyte antioxidant capacity, GSH/GSSH ratio and plasma vitamin C levels, compared with either the placebo group or with baseline values.31
Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan.
In a controlled, population-based study, the relationship between pancreatic cancer and antioxidant vitamin intake was assessed. A total of 109 people with newly diagnosed pancreatic cancer and controls randomly selected from the population participated in the study. Dietary intake was assessed by interview. A positive trend was found between cholesterol intake and pancreatic cancer (OR, 2.06; 95% CI, 1.11-3.85; Ptrend = 0.02); subjects in the highest tertile experienced a two fold increased risk. For subjects in the highest tertile compared to the lowest tertile, vitamin C intake was negatively associated with pancreatic cancer risk (OR, 0.45; 95% CI, 0.22-0.94; Ptrend = 0.04). The results of this study indicate that high cholesterol intake may increase pancreatic cancer risk and high vitamin C intake may reduce risk for pancreatic cancer. 29
Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.MAX trial.
A subset of the SU.VI.MAX trial investigated the impact of antioxidant vitamin and mineral supplementation on prostate cancer risk. A total of 3,616 men participated in the trial and were randomly assigned to receive either a placebo or nutritional doses of vitamin C, vitamin E, beta-carotene, selenium and zinc daily for 8 years. One-hundred-three prostate cancer cases were identified. A moderate nonsignificant decrease in the rate of prostate cancer was found with the supplement (hazard ratio = 0.88; 95% CI = 0.60-1.29). However, when stratified for PSA levels, significant effects were found. For men with normal PSA at baseline, a significant decrease in prostate cancer risk was found with the supplement compared to placebo (hazard ratio = 0.52; 95% CI = 0.29-0.92). But, for men with elevated PSA levels at baseline, a significant increase in risk for prostate cancer with supplement use was found (hazard ratio = 1.54; 95% CI = 0.87-2.72). The use of supplements by men at risk for prostate cancer should be carefully monitored. For men with normal PSA levels, this study suggests that moderate intake of a vitamin and mineral supplement may reduce risk for prostate cancer. 30
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