The role of vitamin C as a cofactor is also related to its redox potential. By maintaining enzyme-bound metals in their reduced forms, vitamin C assists mixed-function oxidases in the synthesis of several critical biomolecules 1. These enzymes are either monooxygenases or dioxygenases see Table 1.
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Symptoms of vitamin C deficiency, such as poor wound healing and lethargy, likely result from the impairment of these vitamin C-dependent enzymatic reactions leading to the insufficient synthesis of collagen , carnitine , and catecholamines see Deficiency. Moreover, several dioxygenases involved in the regulation of gene expression and the maintenance of genome integrity require vitamin C as a cofactor.
These enzymes contribute to the epigenetic regulation of gene expression by catalyzing reactions involved in the demethylation of DNA and histones. The capacity of vitamin C to influence the methylation status of DNA and histones in mammalian cells supports a role for the vitamin in health and disease beyond what was previously understood, in particular by safeguarding genome integrity 3, 4.
In response to invading microorganisms, phagocytic leukocytes release non-specific toxins, such as superoxide radicals, hypochlorous acid "bleach" , and peroxynitrite; these reactive oxygen species kill pathogens and, in the process, can damage the leukocytes themselves Vitamin C, through its antioxidant functions, has been shown to protect leukocytes from self-inflicted oxidative damage Phagocytic leukocytes also produce and release cytokines , including interferons, which have antiviral activity Additional studies have reported that vitamin C enhances the chemotactic and microbial killing capacities of neutrophils and stimulates the proliferation and differentiation of B- and T-lymphocytes reviewed in It is widely thought by the general public that vitamin C boosts immune function, yet human studies published to date are conflicting.
Disparate results are likely due to study design issues, often linked to a lack of understanding of vitamin C pharmacokinetics and requirements 19, Finally, vitamin C increases the bioavailability of iron from foods by enhancing intestinal absorption of non- heme iron see the article on Iron Depletion-repletion pharmacokinetic experiments demonstrated that plasma vitamin C concentration is tightly controlled by three primary mechanisms: intestinal absorption, tissue transport, and renal reabsorption One hundred percent absorption efficiency is observed when ingesting vitamin C at doses up to mg at a time.
Once plasma vitamin C concentrations reach saturation, additional vitamin C is largely excreted in the urine. Notably, intravenous administration of vitamin C bypasses absorptive control in the intestine such that very high concentrations of vitamin C can be achieved in the plasma; within a few hours, renal excretion restores vitamin C to baseline plasma concentrations see Cancer Treatment While plasma vitamin C concentration reflects recent dietary intake, leukocyte white blood cell vitamin C is thought to be an indicator of body stores.
However, leukocyte vitamin C concentration does not accurately reflect vitamin C in several tissues and may specifically underestimate vitamin C uptake into skeletal muscle There is also some limited evidence suggesting that individuals who carry certain polymorphisms in genes involved in vitamin C transport and detoxification mechanisms may have lower plasma vitamin C concentrations even with high vitamin C intakes see also Vascular complications of diabetes mellitus reviewed in Scientific studies investigating vitamin C efficacy to prevent or treat disease need to assess baseline vitamin C status before embarking on an intervention or statistical analysis 22 , Severe vitamin C deficiency has been known for many centuries as the potentially fatal disease, scurvy.
By the late s, the British navy was aware that scurvy could be cured by eating oranges or lemons, even though vitamin C would not be isolated until the early s. Symptoms of scurvy include subcutaneous bleeding, poor wound closure, and bruising easily, hair and tooth loss, and joint pain and swelling. Such symptoms appear to be related to the weakening of blood vessels, connective tissue, and bone, which all contain collagen. Early symptoms of scurvy like fatigue may result from diminished levels of carnitine , which is needed to derive energy from fat, or from decreased synthesis of the catecholamine norepinephrine see Function.
Could Vitamin C Be the Cure for Deadly Infections?
Scurvy is rare in developed countries because it can be prevented by as little as 10 mg of vitamin C daily However, cases have occurred in children and the elderly on very restricted diets 33, The recommended dietary allowance RDA for vitamin C is based on the amount of vitamin C intake necessary to maintain neutrophil vitamin C concentration with minimal urinary excretion of vitamin C and is proposed to provide sufficient antioxidant protection Table 2 The amount of vitamin C required to help prevent chronic disease is higher than the amount required for prevention of scurvy.
Prospective cohort studies can examine the incidence of a specific disease in relation to vitamin C intake or body status in a cohort of participants who are followed over time. In contrast, trials are intervention studies that can establish a causal relationship between an exposure and an outcome, e. Endothelial dysfunction is considered to be an early step in the development of atherosclerosis.
Alterations in the structure and function of the vascular endothelium that lines the inner surface of all blood vessels are associated with the loss of normal nitric oxide -mediated endothelium-dependent vasodilation. Endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. The measurement of brachial artery flow-mediated dilation FMD is often used as a functional marker of endothelial function; FMD values are inversely correlated with the risk of future cardiovascular events A meta-analysis of 44 randomized controlled trials in subjects with or without chronic diseases summarized the effect of supplemental vitamin C on endothelial function by measuring FMD 19 studies , assessing forearm blood flow 20 studies , or by pulse wave analysis 5 trials Short-term supplementation with vitamin C was found to reduce endothelial dysfunction in subjects with heart failure , atherosclerosis, or diabetes mellitus , but it had no effect in those with hypertension.
Vitamin C also limited endothelial dysfunction that was experimentally induced in healthy volunteers Improved endothelial function was observed with daily vitamin C doses above mg Hypertension is a major risk factor for cardiovascular disease , including coronary heart disease , stroke , and atrial fibrillation. On the other hand, when plasma vitamin C concentration was measured, cross-sectional studies have consistently indicated an inverse relationship between plasma vitamin C concentration and blood pressure in both men and women A year follow-up of about 2, participants in the Coronary Artery Risk Development in Young Adults CARDIA study found that higher plasma vitamin C and a higher diet quality score were independently associated with a reduced risk of developing hypertension Interestingly, there was no relationship between diet score and risk of hypertension in those with the lowest plasma vitamin C, and plasma vitamin C was positively associated with risk of hypertension in those with low diet scores A meta-analysis of 29 small randomized controlled trials of short durations median duration, 8 weeks in 1, participants 10 to subjects per trial; including both normotensive and hypertensive subjects found that daily supplementation with 60 to 4, mg of vitamin C median dose, mg reduced systolic blood pressure by 3.
Good quality long-term trials are needed to examine whether the anti-hypertensive effect of vitamin C is sustained over time and eventually results in a reduced risk of cardiovascular events. It is important for individuals with significantly elevated blood pressure not to rely on vitamin C supplementation alone to reduce their hypertension. They should instead seek or continue treatment with anti-hypertensive medication and make dietary and lifestyle changes in consultation with their health care provider. Coronary heart disease CHD is characterized by the buildup of plaque inside the arteries that supply blood to the heart atherosclerosis.
Over years of buildup and accumulated damage to the coronary arteries , CHD may culminate in a myocardial infarction or heart attack. Many prospective cohort studies have examined the relationship between vitamin C intake from diet and supplements and CHD risk , the results of which have been pooled and analyzed in two separate analyses 46, Conversely, a meta-analysis of 14 cohort studies concluded that dietary, but not supplemental, vitamin C intake was inversely related to CHD risk The most recent large prospective cohort study found an inverse association between dietary vitamin C intake and CHD mortality in Japanese women, but not in men In spite of the variable association depending on source, these analyses indicate an overall inverse association between higher vitamin C intakes and CHD risk.
Limitations inherent to dietary assessment methodology, such as recall bias , measurement error , and residual confounding , may account for some of the inconsistent associations between vitamin C intake and CHD risk. In order to overcome such limitations, some prospective studies measured plasma or serum concentrations of vitamin C as a more reliable index of vitamin C intake and biomarker of body vitamin C status. The European Investigation into Cancer and Nutrition EPIC -Norfolk prospective cohort study investigated the relationship between vitamin C status and incident heart failure in healthy adults 9, men and 11, women, aged After a mean follow-up of This highlights the fact that limitations associated with dietary assessment methods such as food frequency questionnaires may be overcome by using biomarkers of nutrient intake 50, Notably, this study had several limitations 54 , including no measurement of vitamin C status and the recruitment of a well-nourished study population.
There is a need for better quality studies to examine the effect of vitamin C on cardiovascular endpoints in participants with elevated risk of cardiovascular disease. A cerebrovascular event, or stroke , can be classified as hemorrhagic or ischemic. Hemorrhagic stroke occurs when a weakened blood vessel ruptures and bleeds into the surrounding brain tissue. Ischemic stroke occurs when an obstruction within a blood vessel blocks blood flow to the brain. Therefore, as in many studies of vitamin C intake and chronic disease risk, it is difficult to separate the effects of vitamin C from the effects of other components of fruit and vegetables.
Other trials also failed to show any evidence of an effect of vitamin C on the risk of stroke. Additional detail is provided below for those cancer subtypes with substantial scientific information obtained from prospective cohort studies. Randomized , double-blind , placebo -controlled trials that have tested the effect of vitamin C supplementation alone or in combination with other antioxidant nutrients on cancer incidence or mortality have shown no effect Two large prospective studies found dietary vitamin C intake to be inversely associated with breast cancer incidence in certain subgroups.
A number of observational studies have found increased dietary vitamin C intake to be associated with decreased risk of gastric stomach cancer , and laboratory experiments indicate that vitamin C inhibits the formation of carcinogenic N-nitroso compounds in the stomach Infection with the bacteria , Helicobacter pylori H.
Because vitamin C can inactivate urease an enzyme that facilitates H. By pooling data from 13 prospective cohort studies comprising , participants, it was determined that dietary intake of vitamin C was not associated with colon cancer , while total intake of vitamin C i. Each of the cohort studies used self-administered food frequency questionnaires at baseline to assess vitamin C intake.
Action Alert—Now the FDA Is Going After Vitamin C! | The Alliance for Natural Health
Overall, an inverse association between fruit and vegetable intake and risk of NHL was observed. Additionally, dietary, but not supplemental, intake of vitamin C and other antioxidant nutrients carotenoids , proanthocyanidins, and manganese was inversely associated with NHL risk. Supplementation with vitamin C had no effect on the overall risk of cancer or on the risk of prostate , bladder, or pancreatic cancer; there was a marginal reduction in colorectal cancer incidence with vitamin C compared to placebo Additionally, several cross-sectional studies reported inverse associations between circulating vitamin C concentrations and markers of insulin resistance or glucose intolerance , such as glycated hemoglobin HbA1c concentration 50 , 85, Yet, short-term randomized controlled studies have found no effect of vitamin C supplementation on fasting glucose, fasting insulin, and HbA1c concentrations in healthy individuals It is not known whether supplemental vitamin C could improve markers of glycemic control in subjects at risk of diabetes.
A meta-analysis of 29 randomized controlled trials found that administration of vitamin C during pregnancy, alone or in combination with a few other supplements , failed to reduce the risks of stillbirth, perinatal death, intrauterine growth restriction, preterm birth, premature rupture of membranes, and preeclampsia Cigarette smoking during pregnancy causes intrauterine growth restriction and preterm birth, among other pregnancy complications 90, 91 , and is the primary cause of childhood respiratory illness For some still unclear reasons, smoking has been associated with a lower risk of preeclampsia during pregnancy However, antioxidant supplementation resulted in reduced risks of placental abruption and preterm birth in women who smoked during pregnancy but not in non-smokers The Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function [VCSIP] study is an ongoing trial designed to confirm these preliminary observations using more accurate measurements of pulmonary function in a larger sample of women randomized to receive supplemental vitamin C or placebo Lower vitamin C concentrations in the cerebrospinal fluid CSF and brain extracellular matrix of a mouse model of AD were found to increase oxidative stress and accelerate amyloid deposition and disease progression In another AD mouse model that was lacking the ability to synthesize vitamin C, supplementation with a high versus low dose of vitamin C reduced amyloid deposition in the cortex and hippocampus and limited blood-brain barrier impairments and mitochondrial dysfunction The majority of large, population-based studies examining the relationship of vitamin C intake or supplementation with AD incidence have reported null results Few studies have measured vitamin C concentration in the CSF, which more closely reflects the vitamin C status of the brain.
Vitamin C is concentrated in the brain through a combination of active transport into brain tissue and retention via the blood-brain barrier Although CSF vitamin C is maintained at concentrations several-fold higher than plasma vitamin C, the precise function of vitamin C in cognitive function and AD etiology is not yet fully understood In a small, longitudinal biomarker study in 32 individuals with probable AD, a higher CSF-to-plasma vitamin C ratio at baseline was associated with a slower rate of cognitive decline at one year of follow-up The effect of vitamin C supplementation, in combination with other antioxidants , on CSF biomarkers and cognitive function has been examined in only a few trials involving AD patients.
In this latter trial, a greater decline in the Mini Mental State Examination MMSE score was observed in the supplemented group, however, the significance of this observation remains unclear. At this time, avoidance of vitamin C deficiency or insufficiency, rather than supplementation in replete individuals, seems prudent for the promotion of healthy brain aging The lens of the eye focuses light, producing a clear, sharp image on the retina , a layer of tissue on the inside back wall of the eyeball. Age-related changes to the lens thickening, loss of flexibility and oxidative damage contribute to the formation of cataract , i.
Decreased vitamin C concentrations in the lens of the eye have been associated with increased severity of cataracts A meta-analysis of observational studies found that a reduced risk of age-related cataract with higher dietary vitamin C intakes in case-control studies and with higher circulating vitamin C concentrations in cross-sectional studies. Urate crystals may form in joints, resulting in inflammation and pain, as well as in the kidneys and urinary tract, resulting in kidney stones.
The tendency to exhibit elevated blood uric acid concentrations and develop gout is often inherited; however, dietary and lifestyle modification may be helpful in both the prevention and treatment of gout In an observational study that included 1, men, higher intakes of vitamin C were associated with lower serum concentrations of uric acid In a cross-sectional study conducted in 4, African Americans, the odds of having hyperuricemia was associated with dietary intakes high in fructose, low in vitamin C, or with high fructose-to-vitamin C ratios A prospective study that followed a cohort of 46, men for 20 years found that total daily vitamin C intake was inversely associated with incidence of gout, with higher intakes being associated with greater risk reductions The results of this study also indicated that supplemental vitamin C may be helpful in the prevention of gout Such a reduction falls within the range of assay variability and is unlikely to be clinically significant An eight-week, open-label , controlled trial randomized 40 subjects with gout to receive either allopurinol standard-of-care , vitamin C, or both treatments The effect of vitamin C, alone or with allopurinol, decreasing serum uric acid was modest and much less than that of allopurinol alone.
The trial did not examine the effect of vitamin C on other outcomes associated with gout Although observational studies suggested that supplemental vitamin C may be helpful to prevent incident and recurrent gout, this has not been demonstrated by intervention studies undertaken thus far. In addition, there is currently little evidence to support a role for vitamin C in the management of patients with gout Two large prospective cohort studies assessed the relationship between dietary and supplemental vitamin C intakes and mortality.
In the Vitamins and Lifestyle Study, 55, men and women ages years were questioned at baseline on their use of dietary supplements during the previous 10 years After five years of follow-up, vitamin C supplement use was associated with a small decreased risk of total mortality, although no association was found with cardiovascular disease - or cancer -specific mortality. In the second prospective cohort study, the Diet, Cancer and Health Study, 55, Danish adults ages years were questioned at baseline about their lifestyle, diet, and supplement use during the previous 12 months No association between dietary or supplemental intake of vitamin C and mortality was found after approximately 14 years of follow-up.
In contrast, a meta-analysis of 10 prospective cohort studies in 17, women with breast cancer found a lower risk of total and breast cancer-specific mortality with higher supplemental and dietary vitamin C intakes A meta-analysis of 29 trials found no effect of oral vitamin C, given alone or in combination with other antioxidants, on all-cause mortality In parallel to these dietary assessment studies, a strong inverse association between plasma vitamin C and mortality from all-causes, cardiovascular disease, and ischemic heart disease and cancer in men only was observed in the EPIC-Norfolk multicenter, prospective cohort study Periprocedural myocardial injury: Coronary angioplasty also called percutaneous transluminal coronary angioplasty is a nonsurgical procedure for treating obstructive coronary heart disease CHD , including unstable angina pectoris , acute myocardial infarction , and multivessel CHD.
Angioplasty involves temporarily inserting and inflating a tiny balloon into the clogged artery to help restore the blood flow to the heart.
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Periprocedural myocardial injury that occurs in up to one-third of patients undergoing otherwise uncomplicated angioplasty increases the risk of morbidity and mortality at follow-up. One randomized , placebo -controlled trial has examined the effect of intravenous vitamin C administered to patients with stable angina undergoing elective coronary angioplasty Administration of a 1-gram g vitamin C infusion one hour prior to the angioplasty reduced the concentrations of oxidative stress markers and improved microcirculatory perfusion compared to placebo Another trial randomized patients to receive a 3-g vitamin C infusion or a placebo saline solution within six hours prior to coronary angioplasty Vitamin C treatment substantially reduced the incidence of periprocedural myocardial injury, as assessed by a reduction in the concentrations of two markers of myocardial injury, namely creatine kinase and troponin-I A recent randomized controlled trial assessed the effect of vitamin C and vitamin E administration on reperfusion damage in patients who experienced acute myocardial infarction and underwent coronary angioplasty see below Myocardial reperfusion injury: Reperfusion injury refers to tissue damage occurring at the time of blood flow restoration reperfusion following transient ischemia.
The heart muscle may become oxygen-deprived ischemic as the result of myocardial infarction or with aortic clamping during coronary artery bypass graft CABG surgery. Increased generation of reactive oxygen species ROS when the heart muscle's oxygen supply is restored might be an important contributor to myocardial damage occurring at reperfusion Myocardial reperfusion injury leads to complications, such as reperfusion arrhythmias see Atrial fibrillation and myocardial stunning.
A more recent randomized, double-blind , placebo -controlled trial has been designed to examine the effect of vitamin C and vitamin E administration on ischemia-reperfusion damage in 99 patients with acute myocardial infarction undergoing coronary angioplasty Vitamin C infusion sodium ascorbate: 3.
The protocol also limited microvascular dysfunction i. However, no difference in the infarct size between antioxidant vitamin treatment and placebo was seen It is also a common post-cardiac surgery complication, leading to an increased risk of cardiovascular morbidity e. Three meta-analyses of prospective cohort studies and randomized controlled trials have reported an overall reduction in the risk of post-operative atrial fibrillation following administration of primarily oral vitamin C Of note, a subgroup analysis in one of the meta-analyses showed a reduction of post-operative atrial fibrillation with vitamin C in non US-based trials 10 trials but no effect of vitamin C in US-based trials 5 trials Cardiovascular disease CVD is the leading cause of death in individuals with diabetes mellitus.
The role of increased oxidative stress in the occurrence of vascular complications in subjects with diabetes has led to hypothesis that higher intakes of antioxidant nutrients could help lower the risk of CVD in diabetic subjects Yet, most studies were small and of short duration and thus did not assess the consequence of long-term use of antioxidant vitamins on the risk of vascular complications in diabetic patients. Both vitamin C and aspirin reduced fasting blood glucose and HbA1c concentrations and improved blood lipid profile in metformin-treated patients.
Compared to placebo, both treatments were found to be more likely to limit risk factors contributing to diabetes-related complications, as well as to lower the risk of future cardiovascular events over a year period estimated using the Framingham risk score Of note, it is possible that genetic differences among diabetic patients influence the effect of vitamin C supplementation on cardiovascular risk.
In particular, a specific allele of the haptoglobin gene Hp , namely Hp2, appears to be associated with an increased risk of diabetic vascular complications. Carriers of two copies of the Hp2 allele Hp express a Hp protein that has a lower capacity to bind and remove pro-oxidant , free hemoglobin Hb from plasma , compared to Hp proteins coded by the Hp and Hp genotypes. Results from another study by the same investigators suggested that vitamin C could not prevent the oxidation of high-density lipoprotein HDL - cholesterol by glycated Hb-Hp complexes in vitro nor restore impaired HDL function in diabetic mice carrying the Hp genotype Because systemic inflammatory responses involve excessive oxidative stress , it has been suggested that providing antioxidant nutrients like vitamin C may improve the outcome of critically ill patients in intensive care units.
Vitamin C requirements are likely to be increased in this population due to the hypermetabolic response driven by the systemic inflammatory reaction , Intravenous administration of 50 mg or mg of vitamin C per kg per day for 96 hours to patients with sepsis admitted in intensive care unit was found to correct vitamin C deficiency. Vitamin C infusion also lowered the concentration of markers of inflammation and endothelial injury in patients compared to placebo Similar results have been reported in septic patients given intravenous vitamin C 1.
Compared to standard-of-care, this intervention cocktail more than halved the mean duration of vasopressor use Although intravenous vitamin C administration appears to be safe and well tolerated, there is a non-negligible risk of oxalate nephropathy a rare cause of kidney failure in these critically ill patients Controversy surrounding the efficacy of vitamin C in cancer treatment ensued, leading to the recognition that the route of vitamin C administration is critical 22 , Compared to orally administered vitamin C, intravenous vitamin C can result in 30 to fold higher plasma vitamin C concentrations Higher plasma concentrations achieved via intravenous vitamin C administration are comparable to those that are toxic to cancer cells in culture.
The anticancer mechanism of intravenous vitamin C action is under investigation. It may involve the production of high levels of hydrogen peroxide, selectively toxic to cancer cells 22 , , or the deactivation of hypoxia inducible factor, a prosurvival transcription factor that protects cancer cells from various forms of stress , , Vitamin C likely also plays a role in the maintenance of genome integrity and in the protection against cellular transformation through regulating DNA and histone demethylating enzymes see Function Current evidence from controlled clinical trials indicates that intravenous vitamin C is generally safe and well tolerated in cancer patients.
Of note, because intravenous administration of 80 g of vitamin C precipitated hemolytic anemia in two subjects with glucosephosphate dehydrogenase deficiency, patients due to receive high-dose vitamin C infusion are systematically screened for this genetic disorder Four phase I clinical trials in patients with advanced cancer found that intravenous administration of vitamin C at doses up to 1.
A phase I study in nine patients with metastatic pancreatic cancer showed that millimolar concentrations of plasma vitamin C could be reached safely when administered in conjunction with the cancer chemotherapy drugs, gemcitabine and erlotinib Retrospective in vitro colony formation assays revealed that patient leukemic cells displayed variable sensitivity to vitamin C treatment: leukemic cells from seven out of the nine patients who experienced a significant clinical benefit were sensitive to vitamin C in vitro i.
Thus, in vitro vitamin C sensitivity assays may provide predictive value for the clinical response to intravenous vitamin C treatment. The mechanisms underlying differential sensitivity to vitamin C are under investigation. In vitro experiments performed using 11 different cancer cell lines demonstrated that sensitivity to vitamin C correlated with the expression of catalase, an enzyme involved in the decomposition of hydrogen peroxide Approximately one-half of the cell lines tested were resistant to vitamin C cytotoxicity, a response associated with high levels of catalase activity.
Sensitivity to vitamin C may also be determined by the expression of sodium-dependent vitamin C transporter-2 SVCT-2 , which transports vitamin C into cells Higher SVCT-2 levels were associated with enhanced sensitivity to vitamin C in nine different breast cancer cell lines. Moreover, SVCT-2 was significantly expressed in 20 breast cancer tissue samples, but weakly expressed in normal tissues. Finally, mutations in genes coding for vitamin C-dependent TET demethylases, mutations that are common in cancer cells, may also contribute to resistance to vitamin C treatment There is a need for larger, longer-duration phase II clinical trials that test the efficacy of intravenous vitamin C in disease progression and overall survival For information about the use of high-dose intravenous vitamin C as an adjunct in cancer treatment, visit the University of Kansas Medical Center Program in Integrative Medicine website.
In the past 40 years, numerous placebo -controlled trials have examined the effect of vitamin C supplementation on the prevention and treatment of colds. A meta-analysis of 53 placebo-controlled trials evaluated the effect of vitamin C supplementation on the incidence, duration, or severity of the common cold when taken as a continuous daily supplement 43 trials or as therapy upon onset of cold symptoms 10 trials Regarding the incidence of colds, a difference was observed between two groups of participants. Regular supplementation with vitamin C 0.
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