High-Dose Vitamin C Supplementation as a Legitimate Anti-SARS-CoV-2 Prophylaxis in Healthy Subjects—Yes or No?

Vitamin C has a number of acitvities that could contribute to its immune-modulating effects. The only question is whether we should provide ourselves with only the right level of it, or do we need much more during a pandemic? The possibility of reducing the incidence of viral diseases in a well-nourished population through the use of dietary supplements based on vitamin C is not supported in the literature. Despite this, the belief that an extra intake of vitamin C can increase the efficacy of the immune system is still popular and vitamin C is advertised as a remedy to prevent infectious disease. This article refers to the justification of the use of vitamin C in high doses as an anti-SARS-CoV-2 prophylaxis in healthy subjects. Does it make sense or not? As it turns out, any effects of vitamin C supplementation may be more prominent when the baseline vitamin C level is low, for example in physically active persons. People with hypovitaminosis C are more likely to respond to vitamin C administration. No studies regarding prevention of COVID-19 with high-dose vitamin C supplementation in healthy subjects were found.     

Vitamin D Deficiency in Older Patients—Problems of Sarcopenia,Drug Interactions,Management in Deficiency

Vitamin D deficiency frequently occurs in older people, especially in individuals with comorbidity and polypharmacotherapy. In this group, low vitamin D plasma concentration is related to osteoporosis, osteomalacia, sarcopenia and myalgia. Vitamin D levels in humans is an effect of the joint interaction of all vitamin D metabolic pathways. Therefore, all factors interfering with individual metabolic stages may affect 25-hydroxyvitamin D plasma concentration. The known factors affecting vitamin D metabolism interfere with cytochrome CYP3A4 activity. There is another group of factors that impairs intestinal vitamin D absorption. The phenomenon of drugs and vitamin D interactions is observed first and foremost in patients with comorbidity. This is a typical situation, where the absence of “hard evidence” is not synonymous with the possible lack of adverse effects. Osteoporosis and sarcopenia (generalized and progressive decrease of skeletal muscle mass and strength) are some of the musculoskeletal consequences of hypovitaminosis D. These consequences are related to an increased risk of adverse outcomes, including bone fractures, physical disabilities, and a lower quality of life. This can lead not only to an increased risk of falls and fractures but is also one of the main causes of frailty syndrome in the aging population. Generally, Vitamin D plasma concentration is significantly lower in subjects with osteoporosis and muscle deterioration. In some observational and uncontrolled treatment studies, vitamin D supplementation resulted in a reduction of proximal myopathy and muscle pain. The most conclusive results were found in subjects with severe vitamin D deficiency and in patients avoiding large doses of vitamin D. However, the role of vitamin D in muscle pathologies is not clear and research has provided conflicting results. This is plausibly due to the heterogeneity of the subjects, vitamin D doses and environmental factors. This report presents data on some problems with vitamin D deficiency in the elderly population and the management of vitamin D deficiency D in successful or unsuccessful aging.     

Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate

There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed.     

Reduction of dehydroerythorbic acid in vitamin C-deficient guinea pigs.

A reduction of dehydroerythorbic acid (DERA) to erythorbic acid (ERA) in vitamin C-deficient guinea pigs was evaluated and compared with that of dehydroascorbic acid (DASA). Thirty-six guinea pigs were fed with vitamin C-deficient diets for 18 days. On day 19, the guinea pigs were divided into four groups for the administration of 100 mg of DERA, ERA, ascorbic acid (ASA), or DASA every day. After 12 days of oral administration, the concentration of DERA, ERA, ASA, and DASA in the liver, adrenal, spleen, kidney, and plasma of guinea pigs was determined by HPLC. A recovery from scurvy was measured in terms of weight gain and serum alkaline phosphatase activity. All four groups showed similar recovery, indicating that the oral administration of relatively high concentrations of DERA reversed the effects of scurvy in vitamin C-deficient guinea pigs. In spite of DERA or DASA administration, ERA or ASA was mainly detected in the tissues. The reduction ratios of DEAR and DASA were similar (approximately 80%) in all tissues except spleen. These results suggest that both DASA and DERA are taken up and reduced to ASA or ERA in vivo.     

Interactions between drugs and vitamins at advanced age.

Drug consumption increases at advanced age due to increased morbidity. At the same time the state of repletion is reduced for several vitamins. Physiological and kinetic alterations in the elderly are reviewed in order to analyse possible interrelations between these two phenomena. At high age the status of all vitamins is compromised by reduced food intake. Decreased active intestinal transport and an increased propensity for atrophic gastritis may reduce the absorption of vitamins A, B1, folate and B12. Decreased exposure to sunlight and reduced cutaneous synthesis impair the vitamin D status. Studies on the state of vitamin repletion in hospital patients indicate a specific response of vitamins A, B1, B6 and C to drug administration at advanced age. Reduced food intake in the elderly is further compromised by drugs that impair appetite and absorption. Anticonvulsives and other drugs that induce hepatic microsomal enzymes accelerate vitamin D metabolism and aggravate post-menopausal osteoporosis. Acid inhibiting agents increase achlorhydria and reduce vitamin B12 absorption. Renal clearance of acidic drugs such as acetylsalicylic acid and barbituric acid, which is impaired at high age, is further reduced by high doses of vitamin C. Vitamin B6 reduces the therapeutic effect of L-dopa. When recognised, the negative effects of drug-vitamin interactions can be compensated by adequate vitamin supplementation and by adaptation of drug dosing.     

Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults.

The purpose of this study was to determine whether carnitine metabolism or histamine degradation would be useful parameters for investigating the optimal requirement for vitamin C.

Twenty-two non-scorbutic subjects with subnormal vitamin C status (plasma vitamin C < 28 mumol/L) were placed on a metabolic diet low in vitamin C for 3 weeks and repleted with graded doses of vitamin C: 10, 30 and 60 mg vitamin C daily (group 1) or 10,125 and 250 mg vitamin C daily (group 2) for weeks 1, 2 and 3, respectively. Fasting blood samples were collected weekly and analyzed for plasma vitamin C, plasma free carnitine and blood histamine.

Group 1 subjects remained in a subnormal vitamin C state throughout the 3-week study, and blood histamine and plasma free carnitine were not impacted by the experimental treatment. Plasma vitamin C in group 2 subjects rose significantly during the study, and these subjects finished the study with an ample vitamin C status indicative of vitamin C intakes above the recommended dietary allowance. Both blood histamine and plasma free carnitine were inversely related to vitamin C status in group 2 subjects.

These data indicate that blood histamine and plasma free carnitine are altered in individuals with subnormal, non-scorbutic vitamin C status and provide evidence that metabolic changes independent of collagen metabolism occur prior to the manifestation of scurvy. Thus utilizing scurvy as an end-point to determine vitamin C requirements may not provide adequate vitamin C to promote optimal health and well-being.     

Recommended dietary intakes (RDI) of vitamin C in humans

Vitamin C is unevenly distributed throughout all body cells and fluids. A total-body pool of 900 mg (5.11 mmol) in an adult male meets the following criteria of a satisfactory vitamin C status: it is threefold higher than one that prevents scurvy, no known health advantages accrue at higher pool sizes, absorption efficiency is high and urinary loss low at appropriate intakes, and a 1-mo reserve allows for periods of low intake or stress. To maintain a suitable body pool in healthy 76-kg men and 62-kg women requires daily intakes (RDI) of 40 mg (227 mumol) and 30 mg (170 mumol), respectively. Reasons for not increasing RDI values to enhance iron absorption and to prevent nitrosamine formation are given. The specific association of normal intakes of dietary vitamin C with cancer is very weak and not quantifiable. Advisable intakes for children, pregnant and lactating women, and the elderly are considered. The present recommendations are in better accord with current information than are the 1980 RDA values.     

Intestinal, hepatic, and circulating vitamin K levels at low and high intakes of vitamin K in rats

The aim of the present study was to assess how high doses of dietary vitamin K influence the intestinal profile of K-vitamins in vitamin K-deficient rats, and whether the induced changes are reflected in the hepatic vitamin K store. Vitamin K-deficient rats were fed for 10 d on diets containing different forms of vitamin K, and it was determined how these diets affected the vitamin K concentration at various sites of the instestine, serum, and the liver. It was found that the absorption of phylloquinone from standard food is not more than 10%, while the absorption of pharmacological doses of oil-solubilized phylloquinone and menaquinone-4 was also far from complete (18 and 55% respectively). High intakes of phylloquinone suppress the colonic production of all higher menaquinones. High menaquinone-4 intake induces very high menaquinone-8 concentrations, both in the colonic contents as well as in the liver. These data suggest that menaquinone-4 may be converted into menaquinone-8 (but not into other menaquinones) via a metabolic pathway which has not been reported previously.     

Vitamins, selenium, iron, and coronary heart disease risk in Indians, Malays, and Chinese in Singapore

STUDY OBJECTIVE: To examine the hypothesis that the higher rates of coronary heart disease (CHD) in Indians (South Asians) compared with Malays and Chinese is partly because of differences in antioxidants (vitamins A, C, and E, and selenium) and pro-oxidants (iron). DESIGN: Cross sectional study of the general population. SETTING: Singapore. PARTICIPANTS: Random sample of 941 persons aged 30 to 69 years. MAIN RESULTS: There were moderate correlations between vitamin A and vitamin E, and between these vitamins and selenium. Mean plasma vitamins A and E were similar by ethnic group. Vitamin A concentration for Indians were (men 0.66 and women 0.51 mg/l), Malays (men 0.67 and women 0.54 mg/l), and Chinese (men 0.68 and women 0.52 mg/l). Vitamin E concentrations for Indians were (men 12.9 and women 12.8 mg/l), Malays (men 13.6 and women 13.3 mg/l), and Chinese (men 12.6 and women 12.6 mg/l). In contrast, mean plasma vitamin C concentrations were lower in Indians (men 5.7 and women 6.9 mg/l) and Malays (men 5.1 and women 6.4 mg/l) than Chinese (men 6.3 and women 8.4 mg/l). Mean serum selenium was lower in Indians (men 117 and women 115 micrograms/l) than Malays (men 122 and women 122 micrograms/l) and Chinese (men 126 and women 119 micrograms/l). Mean serum ferritin was much lower in Indians (men 132 and women 50 micrograms/l) than Malays (men 175 and women 85 micrograms/l) and Chinese (men 236 and women 92 micrograms/l). MAIN CONCLUSIONS: Lower vitamin C and selenium in Indians, particularly in combination, could play a part in their increased risk of CHD. Vitamins A and E, and ferritin (iron) have no such role. Lower vitamin C in Indians and Malays is probably because of its destruction by more prolonged cooking. In Indians, lower selenium is probably because of a lower dietary intake and the much lower ferritin to a lower dietary intake of iron and its binding by phytates.

 

     

Parenteral ascorbic acid in haemodialysis patients

PURPOSE OF REVIEW: Parenteral ascorbic acid has been frequently used to overcome problems of vitamin C deficiency in haemodialysis patients. The benefits of vitamin C supplementation in clinical studies have been controversial and did not consider toxicological aspects. The review summarizes recent findings of the effects of parenteral ascorbic acid and discusses toxicological effects. RECENT FINDINGS: Vitamin C deficiency in haemodialysis patients, which has been frequently described, cannot be improved with oral supplementation due to limited absorption of high dosages. To avoid consequences of vitamin C deficiency, parenteral vitamin C solutions should be administered because this intervention is the only way to guarantee a sufficient supply to the cells. A beneficial consequence of parenteral vitamin C on the recombinant human erythropoietin resistance is an additional therapeutic effect, which contributes to the prevention of iron deficiency anaemia in haemodialysis patients. Thus, large amount of supplemental vitamin C are required for extended periods of time (up to 500 mg 3 times a week). To avoid hyperoxaluria, plasma oxalate levels should be monitored on a regular basis, for example, once a week. SUMMARY: Parenteral administration of ascorbic acid may be an approach that can overcome problems of vitamin C deficiency in haemodialysis patients - in particular problems of iron overload, erythropoetin resistance, and chronic inflammation.     

Vitamin C as an antioxidant: evaluation of its role in disease prevention

Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues. Oxidation of lipids, proteins and DNA results in specific oxidation products that can be measured in the laboratory. While these biomarkers of oxidation have been measured in humans, such assays have not yet been validated or standardized, and the relationship of oxidant markers to human disease conditions is not clear. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.     

Vitamin C Transporters and Their Implications in Carcinogenesis

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe²⁺ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer therapy has been a controversial and disputed issue. Vitamin C is transferred to the cells with sodium dependent transporters (SVCTs) and glucose transporters (GLUT). However, it is unknown whether the impaired function of these transporters may lead to carcinogenesis and tumor progression. Notably, previous studies have identified SVCTs’ polymorphisms or their altered expression in some types of cancer. This review discusses the potential effects of vitamin C and the impaired SVCT function in cancers. The variations in vitamin C transporter genes may regulate the active transport of vitamin C, and therefore have an impact on cancer risk, but further studies are needed to thoroughly elucidate their involvement in cancer biology.     

B-vitamins, homocysteine metabolism and CVD

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6 and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12 and, to a lesser extent, vitamin B6 are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.     

Disposition kinetics and dosage regimen of vitamin E administered intramuscularly to sheep

Three experiments were conducted to estimate the effects of single intramuscular (IM) administrations of vitamin E on blood plasma and tissue concentrations of alpha-tocopherol in sheep. In Expt 1, plasma kinetics of alpha-tocopherol in sheep (n 30) were investigated following IM administration of three doses (ten sheep/dose) of DL-alpha-tocopheryl acetate, (20, 40 and 60 mg/kg live weight). Plasma profiles of alpha-tocopherol consisted of a lag phase followed by an apparent first-order absorption and elimination phase. The rate of absorption and elimination, as well as the lag phase, were independent of the dose, but the extent of absorption was directly proportional to dose. In Expt 2 (eighteen experimental and five control sheep), the animals were injected as in Expt 1 and were killed at 0, 80 and 176 h. Increases in alpha-tocopherol levels in organs were much higher than in plasma. Some tissues such as liver, spleen, lung and adrenal appeared to exhibit rapid absorption and elimination phases. The amount absorbed was proportional to the dose administered. Other organs such as heart, kidney and pancreas had a slow elimination rate. In Expt 3, D-alpha-tocopherol was injected IM into ten sheep at either 604 mg or 1208 mg. The mean hepatic alpha-tocopherol concentrations in both groups rose rapidly and after 4 weeks of dosing its concentrations were higher than the predosing levels. The increase in hepatic tocopherol concentrations were higher following 1208 mg dosing than 604 mg D-alpha-tocopherol. No simple relationship existed between plasma and hepatic alpha-tocopherol concentrations. This suggests a difference in body mechanisms controlling vitamin E in blood and liver.     

Vitamin C—An Adjunctive Therapy for Respiratory Infection,Sepsis and COVID-19

There are limited proven therapies for COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2–8 g/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6–24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients’ vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.     

Vitamin C and bone markers: investigations in a Gambian population

Vitamin C is an essential micronutrient. Absence from the diet will result in the deficiency disease scurvy, typically characterised by weakening of collagenous structures. High intakes of vitamin C have been associated with decreased incidence or severity of a number of diseases, including cancer and cardiovascular disease. These beneficial effects may be attributed to its antioxidant properties, although the exact mechanisms of action remain elusive. It is also unclear what intake levels are required for optimal health benefits. The task of defining optimal intakes is hindered by the lack of a reliable functional marker of tissue vitamin C status in man. Many different pathways have been investigated, but none of them have measurable outcome variables relating directly to scorbutic changes. The bone-collagen formation pathway has the potential to provide a functional index of tissue vitamin C adequacy. Vitamin C acts as a cofactor for the enzyme lysyl hydroxylase, which is required for the hydroxylation of lysine residues in procollagen chains. Pyridinoline is a mature collagen cross-link formed from three hydroxylysine residues, deoxypyridinoline is formed from two hydroxylysine and one lysine residue. Guinea-pig studies have shown an alteration in the pyridinium cross-link ratios in response to graded vitamin C intakes (Tsuchiya & Bates, 1998). In order to investigate whether these changes can be seen in a human population group, a study was carried out in rural Gambia, where there is a marked seasonal variation in dietary vitamin C. The present review discusses the rationale behind the study and presents some preliminary results.     

Genetic Aspects of Scurvy and the European Famine of 1845–1848

The view of scurvy being exclusively a nutritional disorder needs to be updated. Genetic polymorphisms of HFE and haptoglobin (Hp) may explain the geographic variability of mortality caused by the European famine of the mid-19th century. In this period, potatoes had fallen victim to the potato blight and Ireland was more severely hit than continental Europe. Hereditary hemochromatosis is a genetic disorder with mutations in the HFE gene, characterized by iron overload (with a reduced vitamin C stability) and with a predominance of affected men. The Irish have the world’s highest frequency of the C282Y mutation and the particular iron metabolism of the Irish helps to understand the size of the catastrophe and the observed overrepresentation of male skeletons showing scurvy. Hp is a plasma α₂-glycoprotein characterized by 3 common phenotypes (Hp 1-1, Hp 2-1 and Hp 2-2). When the antioxidant capacity of Hp is insufficient, its role is taken over by hemopexin and vitamin C. The relative number of scurvy victims corresponds with the Hp 2-2 frequency, which is associated with iron conservation and has an impact on vitamin C stability. As iron is more abundant in males, males are overrepresented in the group of skeletons showing scurvy signs.     

Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries

A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 μmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always <250 μmol/L and frequently <150 μmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25-30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H(2)O(2)) formation, which can lead to extracellular fluid at concentrations as high as 200 μmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H(2)O(2).     

Vitamin E: absorption, plasma transport and cell uptake

PURPOSE OF REVIEW: Large-scale clinical trials have failed to demonstrate a benefit for vitamin E supplementation in cardiovascular prevention. This contrasts with previous epidemiological studies indicating that individuals with high vitamin E status benefit from protection against chronic illnesses, including cardiovascular diseases. These conflicting results suggest that the metabolism of supplemental versus naturally delivered vitamin E and their potential roles, other than a potent antioxidant action, are not fully understood. The purpose of this review is to provide an update on current knowledge on the intestinal absorption of vitamin E, its plasma transport and its supply to cells. The review will also discuss the intravascular metabolism of intravenously delivered vitamin E. RECENT FINDINGS: Although the luminal digestion of vitamin E is fairly well understood, several pathways regulating net vitamin E absorption remain to be elucidated. In several cell types, cholesterol and vitamin E share common mechanisms for cellular uptake (scavenger receptor B type I and LDL receptors) and efflux (ABCA1 transporters). The role of specific binding proteins in alpha-tocopherol intracellular trafficking is increasingly being understood, leading to new insights into the non-antioxidant functions of vitamin E. SUMMARY: Substantial progress has been made in characterizing the plasma transport of vitamin E and its delivery to cells. Mechanisms regulating the balance between the cellular uptake and efflux of vitamin E are under investigation. Vitamin E is not only an antioxidant but may also modulate pathways of cell signalling and gene expression. The translation of this new knowledge into clinical studies will help define future indications for vitamin E supplementation.