Effects of Vitamin C on Health: a Review of Evidence

Giuseppe Grosso, Roberto Bei, Antonio Mistretta, Stefano Marventano, Giorgio Calabrese, Laura Masuelli, Maria Gabriella Giganti, Andrea Modesti, Fabio Galvano, Diego Gazzolo

Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. The lack of vitamin C causes scurvy, pathological condition leading to blood vessel fragility and connective tissue damage due to failure in producing collagen, and, finally, to death as result of a general collapse. Vitamin C is potentially involved also in cancer and cardiovascular diseases prevention. In addition, vitamin C effects on the nervous system and chronically ill patients have been also documented.

INTRODUCTION

Vitamin C, or ascorbic acid, is an essential dietary nutrient for a variety of biological functions. Under physiological conditions, it is fundamental in the biosynthesis of collagen through facilitating the hydroxylation of proline and lysine residues, thus allowing proper intracellular folding of pro-collagen for export and deposition as mature collagen. Vitamin C serves in humans also as a cofactor in several important hydroxylation reactions, such as the biosynthesis of catecholamines (through the conversion of dopamine to norepinephrine), L-carnitine, cholesterol, amino acids, and some peptide hormones. The growing understanding of mechanisms of vitamin C on human health led to calls for continuous updated reappraisals regarding the dietary requirements for this nutrient. Given the potential involvement of vitamin C in cancer and cardiovascular diseases (CVD), as well as its effects on nervous system and chronically ill patients, the aim of this review is to address the potential effects of vitamin C at both experimental and clinical stages focusing on recent evidences supporting a potential role for vitamin C in degenerative diseases prevention.

VITAMIN C IN HUMANS:

ADSORPTION, DEFICIENCY, EXCESS

Though most animals are able to endogenously synthesize large quantities of vitamin C, humans do not have the capability to synthesize vitamin C due to a series of mutations of the gene encoding gulonolactone oxidase which catalyses the last enzymatic step in ascorbate synthesis. The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility, connective tissue damage, fatigue, and, finally, death. In addition to poor dietary intake of vitamin C, alcoholism, elderly age, socioeconomic deprivation, mental illness, malabsorption disorders, kidney failure, hemodialysis, and peritoneal dialysis have been identified as risk factors for low vitamin C endogen levels and developing clinical symptoms of scurvy. Intake of 10 mg per day of vitamin C is appropriate to prevent scurvy. However, the current recommended dietary allowance (RDA) for vitamin C for adult men and women, is set at 75 mg/day for women and 90 mg/day for men.

Generally, high doses of vitamin C can be toxic. Excess ascorbate is normally excreted harmlessly in the urine, but the excess formation of oxalate can accumulate in various organs in patients with renal failure or renal insufficiency (such as kidney transplanted patients) and in patients undergoing dialysis. Administration of high doses of vitamin C is contraindicated for patients with oxalate kidney stones or hyperoxaluria (due to the incapacity of eliminating oxalate) and in patients with a deficiency in glucose-6-phosphate dehydrogenase (due to the occurring of intravascular haemolysis).

MECHANISM OF ACTIONS OF VITAMIN C

4.1. Collagen synthesis

Vitamin C is required for collagen synthesis by acting as a cofactor for non-heme iron α-ketoglutarate-dependent dioxygenases such as prolyl 4-hydroxylase. Vitamin C stimulates all types of collagen synthesis by donating electrons required for hydroxylation of proline and lysine in procollagen by specific hydroxylase enzymes. Collagen synthesis is required for maintaining normal vascular function but also for tumor angiogenesis.

4.2. Regulation of hypoxia-inducible factor 1α

Ascorbate has been shown to assist prolyl and lysyl hydroxylases in the hydroxylation of hypoxia-inducible factor 1α (HIF- 1α), a transcription factor responsible for the cellular response to low oxygen conditions through activation of genes controlling several cellular transduction pathways by regulating growth and apoptosis, cell migration, energy metabolism, angiogenesis, vasomotor regulation, extracellular matrix and barrier functions, and transport of metal ions and glucose.

4.3. Antioxidant action

In all of its known functions, vitamin C functions as a potent reducing agent that efficiently quenches potentially damaging free radicals produced by normal metabolic respiration of the body. At physiological concentrations, vitamin C is a potent free radical scavenger in the plasma, protecting cells against oxidative damage caused by ROS. The antioxidant property of ascorbic acid is attributed to its ability to reduce potentially damaging ROS, forming, instead, resonance-stabilized and relatively stable ascorbate free radical (AFR) serving as a one-electron donor.

4.4. Pro-oxidant action

Vitamin C, under certain conditions such as low concentrations and/or in the presence of free transition metals such as copper and iron, may function as a pro-oxidant. Metal ions are indeed reduced by ascorbate and, in turn, may react with hydrogen peroxide leading to the formation of highly reactive and damaging hydroxyl radicals. The pro-oxidant activity of vitamin C leads to the formation of ROS (57) or glycated proteins. On the other hand, in vitro models suggested that certain pro oxidant effects of ascorbate such as the capacity to promote protein thiol oxidation in rat liver microsomes can also be advantageous. We next discuss the effects of vitamin C in preventing or treating chronic and acute pathologic conditions due to all its properties listed above.

ANTI-CARCINOGENIC EFFECTS OF VITAMIN C

Indeed, high-dose of intravenous vitamin C has been found to increase the average survival of advanced cancer patients and for a small group of responders, survival was increased to up to 20 times longer than that of controls. Other researchers reported benefits consisting of increased survival, improved well-being and reduced pain. The anti-inflammatory action of ascorbic acid in cellular ambient is evident in a number of cytoprotective functions under physiological conditions, including prevention of DNA mutation induced by oxidation. Since DNA mutation is likely a major contributor to the age-related development of cancer, attenuation of oxidation-induced mutations by vitamin C may be considered as a potential anticancer mechanism. Vitamin C may also function as cancer cells killer due to its pro-oxidant capacity. The tumor cell-killing action is dependent upon ascorbate incubation time and extracellular ascorbate concentration. Among the possible mechanisms, stimulatory effects on apoptotic pathways, accelerated pro-oxidant damage that cannot be repaired by tumor cells, and increased oxidation of ascorbate to the unstable metabolite DHA, which in turn can be toxic, have been hypothesized. The killing of cancer cells is dependent on extracellular H2O2 formation with the ascorbate radical as an intermediate.

VITAMIN C AND CARDIOVASCULAR DISEASES

Reactive oxygen species (ROS) are highly reactive molecules that derive mainly from the mitochondrial electron transport chain and that are necessary for sever normal cellular functions, ranging from their role as signaling molecules to the more unexpected role in inducing certain cancers. However most studies have linked the excessive generation of ROS, so-called oxidative stress, to disease states, such as cancer, insulin resistance, diabetes mellitus, cardiovascular diseases, atherosclerosis, and aging and superoxide is the most biologically relevant radical in vasculature, as it is naturally produced by most vascular cell. Vitamin C provides collagen synthesis, hence allowing proper folding into the triple helical collagen molecule that is then secreted to form the extracellular matrix, or to form part of the basement membrane with regard to type IV collagen. Vitamin C has been found to prevent apoptosis.

Indeed, vitamin C enhances the NO synthase activity by maintaining tetrahydrobiopterin, an essential cofactor for the enzyme, in its reduced and active form, normally inhibited by ROS that oxidize and thus deplete the cofactor. By increasing NO production, vitamin C may indirectly protect the vascular endothelium due to its actions, namely smooth muscle cell relaxation, downstream vasodilatation, and inhibition the effects of pro-inflammatory cytokines and adhesion molecules important in atherosclerosis.

THE ROLE OF VITAMIN C IN CRITICALLY ILL PATIENTS

Vitamin C concentrations in plasma and leukocytes have been reported to be commonly subnormal in critically ill patients, inversely correlating with multiple organs failure and directly with survival. Since sepsis is associated with increased production of ROS and peroxynitrite that deplete antioxidant molecules and oxidize proteins and lipids, potential therapeutic implication of vitamin C in the treatment of various infections has been studied for a long time. Indeed, enteral administration of vitamin C and other antioxidants in patients with sepsis has been shown to affect faster recovery whereas parenteral administration decreased morbidity and mortality.

A possible mechanism of such effects may depend on the role of ascorbate in both inhibiting apoptosis in endothelial cells and stimulating their proliferation preventing the loss of barrier function in sepsis condition. Moreover, vitamin C improves arteriolar responsiveness to vasoconstrictors (norepinephrine, angiotensin, vasopressin) and prevents inhibition of endothelium- dependent vasodilation responses to acetylcholine in human subjects who have inflammatory disease or have been injected with LPS, thus preventing hypotension in sepsis and, consequently, edema.

VITAMIN C EFFECTS ON NERVOUS SYSTEM

Several effects produced by ascorbate have been explored on the nervous system. Vitamin C can in fact efflux from various types of cells, including neurons, because of its hydrophilic nature and negative charge at physiological pH. Vitamin C appears to be allowed to enter into several brain cell lines, improving neurotransmission and leading to a number of effects on behaviors such as learning, memory and locomotion.

Regarding neurodegenerative diseases, a positive relationship has been shown between ascorbate supplement use and reduced incidence of Alzheimer's disease that is known to be caused by a combination of genetic and lifestyle factors and in part by oxidative stress, although these beneficial results are not universal.

VITAMIN C IN OCULAR DISEASES

The role of Vitamin C in preventing ocular disease has been evaluated, demonstrating that the development of cataract is influenced by ascorbate and that a combination of ascorbate with other antioxidant vitamins and minerals slows down the progression of advanced age-related macular degeneration and loss of visual acuity in people with signs of this disease. The effectiveness of vitamin C as a treatment of diabetic retinopathy has also been examined, but further studies are required to prove that it has a significant impact on its progress.

CONCLUSIONS

This review attempts to summarize recent and well established advances in vitamin C research and its clinical implications. Since vitamin C has the potential to counteract inflammation and subsequent oxidative damage that play a major role in the initiation and progression of several chronic and acute diseases, it represents a practical tool to administer in humans for the early prevention of such pathologic conditions. However, many of such well-known beneficial effects of vitamin C intake are still only understood at the phenomenological level and further research is needed to explore the precise effects of ascorbate in physiological systems and in the pathology of diseases at the molecular level. A better understanding of the mechanisms of its action is of major importance in order to define novel potential therapeutic implications regarding vitamin C.

Reference:

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