Vitamin E and its role in the prevention of atherosclerosis and carcinogenesis: a review

Epidemiological and experimental studies suggest that antioxidants like vitamin E (alpha-tocopherol) may play an important role in prevention of chronic disease. Several observational surveys have linked populations with a large intake of vitamin E with reduced incidence of heart disease. These observations have been strengthened by the demonstration of strong antioxidant activity by vitamin E in cellular, molecular and animal experiments. These results have highlighted a potential role for vitamin E supplementation in the prevention of chronic disease in humans. Interestingly however, large-scale clinical trials of vitamin E and other antioxidants in preventing specific disease processes (e.g., coronary artery disease) have generated conflicting and mixed outcomes. In this review, the role of vitamin E in the prevention of atherosclerosis and carcinogenesis has been carefully examined with particular emphasis on salient human studies (clinical trials) and their limitations. In addition, pertinent biochemical, physiological and metabolic features of vitamin E have also been incorporated. A list of common natural food sources of vitamin E has been provided. Important in vitro and animal studies related to the antiatherosclerotic and anticarcinogenic actions of vitamin E have been discussed in detail. Finally, the direction of future investigations in primary and secondary prevention of chronic diseases by vitamin E supplementation has been outlined.     

Plasma and Dietary Antioxidant Status as Cardiovascular Disease Risk Factors: A Review of Human Studies

Extensive evidence has demonstrated that many antioxidants such as vitamin C, vitamin E, carotenoids and polyphenols have protective effects in preventing cardiovascular disease (CVD), a chronic disease that is mediated by oxidative stress and inflammation. This review focuses on evidence from prospective cohort studies and clinical trials in regard to the associations between plasma/dietary antioxidants and cardiovascular events. Long-term, large-scale, population-based cohort studies have found that higher levels of serum albumin, bilirubin, glutathione, vitamin E, vitamin C, and carotenoids were associated with a lower risk of CVD. Evidence from the cohort studies in regard to dietary antioxidants also supported the protective effects of dietary vitamin E, vitamin C, carotenoids, and polyphenols on CVD risk. However, results from large randomized controlled trials did not support long-term use of single antioxidant supplements for CVD prevention due to their null or even adverse effects on major cardiovascular events or cancer. Diet quality indexes that consider overall diet quality rather than single nutrients have been drawing increasing attention. Cohort studies and intervention studies that focused on diet patterns such as high total antioxidant capacity have documented protective effects on CVD risk. This review provides a perspective for future studies that investigate antioxidant intake and risk of CVD.     

High doses of vitamin E in the treatment of disorders of the central nervous system in the aged.

Oxidative stress is a putative factor in the pathogenesis of many human disorders of the central nervous system. Therefore, antioxidants such as vitamin E have become attractive as therapeutic agents in the treatment of several diseases. In addition, vitamin E seems to play a specific role in the nervous system. As a result, vitamin E has been used in pharmacologic doses in the treatment of disorders such as Parkinson disease, Alzheimer disease, and tardive dyskinesia. One investigation showed that the use of 2000 IU all-rac-alpha-tocopheryl acetate is beneficial in the treatment of Alzheimer disease. Similar doses of vitamin E, however, were not beneficial for delaying the progression of Parkinson disease. In other studies, dosages >/=400 IU vitamin E/d were found to be beneficial in the treatment of tardive dyskinesia, although this finding was not confirmed in a larger cooperative study conducted by the Veterans Administration. Even though the efficacy of vitamin E in the management of cardiovascular disease has been shown, the potential role of vitamin E in the treatment of cerebrovascular disease remains essentially unknown. The experience from 2 large clinical trials involving the oral intake of 2000 IU vitamin E/d suggests that vitamin E is relatively safe at this dosage for periods <2 y. However, the safety and efficacy of supplemental vitamin E over periods of many years in the prevention of neurologic diseases has not been adequately explored.     

Antioxidants and cardiovascular disease: Still a topic of interest

Cardiovascular disease constitutes a major public health concern in industrialised nations. Over recent decades, a large body of evidence has accumulated indicating that free radicals play a critical role in cellular processes implicated in atherosclerosis. Herein, we present a mechanism of oxidative stress, focusing mainly on the development of an oxidised low density lipoprotein, and the results of a clinical trial of antioxidant therapy and epidemiological studies on the relationships between nutrient antioxidants, such as vitamin E, vitamin C, β-carotene, coenzyme Q, flavonoids and L-arginine, and coronary events. These studies indicated that a diet high in antioxidants is associated with a reduced risk of cardiovascular disease, but did not confirm a strong causality link. With regard to vitamin E, observational studies suggested that the daily use of at least 400 International Units of vitamin E is associated with beneficial effects on coronary events. However, it is apparently too early to define the clinical benefits of vitamin E for cardiovascular disease. From the results of several randomised interventional trials, it appears that no single antioxidant given to subjects at high doses has substantial benefits, and the question of whether nutrient antioxidants truly protect against cardiovascular disease remains open. This article provides an overview of the epidemiological and clinical studies related to antioxidants and cardiovascular disease.     

Vitamin E and cancer prevention: recent advances and future potentials.

Many animal and in vitro experiments have shown that the supplementation of diet with vitamin E within a certain dose range reduced the risk of chemical- and radiation-induced cancers. In vitro studies revealed that alpha-tocopheryl succinate (TS) induced differentiation and growth-inhibition in certain animal and human tumor cells in culture, whereas alpha-tocopherol (alpha-T), alpha-tocopheryl acetate (alpha-TA) and alpha-tocopheryl nicotinate (alpha-TN) were ineffective, alpha-TS also reduced basal and ligand-stimulated adenylate cyclase activity, and expression of c-myc and H-ras oncogenes in certain tumor cells in culture. The relative efficacy of various forms of vitamin E in cancer prevention in animal or human models has not been evaluated. Human epidemiologic studies utilizing retrospective and prospective case-control experimental designs are not suitable for evaluating the role of vitamin E in cancer prevention due to several inherent problems associated with these methodologies. Intervention trials utilizing vitamin E with appropriate biological and statistical rationales are most suitable for testing the role of vitamin E in cancer prevention in humans. Some human trials utilizing vitamin E alone or in combination with other nutrients are in progress.     

Micronutrients and the risk of type 1 diabetes: vitamin D, vitamin E, and nicotinamide

Evidence from animal experiments and human observational studies suggests that some dietary micronutrients may protect against the development of type 1 diabetes. The most promising data so far have been obtained for a beneficial role of vitamin D. Beneficial effects of vitamin E (or other antioxidants) in diabetes development remain hypothetical. Despite plausible theoretical background evidence from animal experiments and supportive data from pilot studies, randomized, controlled trials using nicotinamide have not provided any evidence for a beneficial effect.     

Können Antioxidanzien Atherosklerose verhindern?

In vitro studies have shown that antioxidants (e. g. beta-carotene, vitamin C and vitamin E) can interfere with some pathomechanisms of atherosclerosis and therefore might have a protective effect. From the investigated antioxidants vitamin E showed the best effect. Some animal and epidemiological studies confirmed such a protective effect in vivo especially after administration of high doses of vitamin E. However, most of the placebo-controlled studies for primary or secondary prevention failed to show a protective effect even after administration of high doses. In addition, other studies demonstrated a risk for adverse effects due to antioxidant supplementation (beta-carotene and vitamin E). Our review summarises the principle of antioxidant supplementation and a number of relevant epidemiological and clinical studies for prevention of atherosclerosis. The obtained results suggest that supplementation of antioxidants cannot be recommended for the normal population.     

Effects of Diets Containing Fish Oil and Vitamin E on Rheumatoid Arthritis

Animal, tissue culture, and human studies have evaluated the effects of fish oil supplementation in patients with rheumatoid arthritis (RA) over the last two decades. These studies have clearly shown potentially beneficial changes in cytokine and eicosanoid metabolism. The overall clinical improvement, however, has been only moderate. European clinical trials have shown significant pain reduction in patients with RA treated with vitamin E. A recent animal study in RA-prone mice evaluated the effects of vitamin E in addition to omega-3 and omega-6 fatty acids on cytokine and eicosanoid production. The authors suggest that vitamin E might have an additional positive effect on autoimmune disease by decreasing proinflammatory cytokines and lipid mediators. Is this information ultimately important in terms of dietary advice for patients with RA? Are further clinical trials indicated? The following article will present a brief critical review.     

Alpha-tocopherol and alpha-lipoic acid. An antioxidant synergy with potential for preventive medicine

Reactive oxygen species (ROS) have been involved in the induction and progression of damage of many human disorders, such as: heart infarction, cerebral ischemia, diabetic neuropathy, Alzheimer's disease, etc. In several studies, the synergism between alpha-lipoic acid and vitamin E has been described and potent antioxidant effects can be obtained when both antioxidants are simultaneously used. This review highlights recent findings showing that the combination of alpha-lipoic acid plus vitamin E effectively reduces oxidative damage in brain and cardiac ischemia as well as in other pathological events related to ROS increasing. These antioxidants are present in a broad variety of foods, are also available in several dietary supplements and their side effects are very rare. Therefore, alpha-lipoic acid and vitamin E may play an important role in clinical preventive medicine and human nutrition.     

Vitamin E and the prevention of atherosclerosis

Successful strategy for the prevention of coronary heart disease (CHD) in particular of atherosclerosis, require a detailed understanding of the underlying mechanism. It is now being recognised that dietary antioxidants, in particular vitamin E, will play an important role in designing future strategies. Although more and more beneficial effects of vitamin E on atherosclerosis are being described, the biochemical and cell biological mechanism underlying these benefits are not yet fully understood, preventing the use of vitamin E as therapeutic agent. Recent new findings have shed new light on the physiological role of vitamin E and suggest that it has a much broader array of biological activities than originally expected. In addition to its well described role as an antioxidant, it is becoming evident that vitamin E also can modulate the immune system, suppress local and chronic inflammation, reduce blood coagulation and thrombus formation, and enhance cell function and survival. This review summarises new findings from in vitro studies and discusses their potential relevance in human atherosclerosis.     

Tocotrienol research: past into present

The vitamin E family consists of eight isomers known as alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. Numerous studies focused on the health benefits of these isomers have been performed since the discovery of vitamin E in 1922. Recent discoveries on the potential therapeutic applications of tocotrienols have revolutionized vitamin E research. Nevertheless, despite the abundance of literature, only 1% of vitamin E research has been conducted on tocotrienols. Many new advances suggest that the use of tocotrienols for health improvement or therapeutic purposes is promising. Although the mechanisms of action of tocotrienols in certain disease conditions have been explored, more detailed investigations into the fundamentals of the health-promoting effects of these molecules must be elucidated before they can be recommended for health improvement or for the treatment or prevention of disease. Furthermore, many of the studies on the effects of tocotrienols have been carried out using cell lines and animal models. The effects in humans must be well established before tocotrienols are used as therapeutic agents in various disease conditions, hence the need for more evidence-based human clinical trials.     

The use of selected nutrition supplements and complementary and alternative medicine in liver disease.

Almost all patients with liver disease, especially advanced liver disease, have some evidence of malnutrition, including mineral/vitamin deficiency. A major health trend in the United States has been the significant growth in the use of complementary and alternative medicine (CAM), including nutrition supplements and herbal agents. In the 1990s, the United States government created the National Center for Complementary and Alternative Medicine (NCCAM), as well as the Office on Dietary Supplements, to extend our knowledge in these areas. CAM users are often highly educated and frequently use CAM therapy for chronic diseases, including chronic liver disease. Indeed, most studies suggest that patients with chronic liver disease frequently use nutrition supplements and CAM agents in addition to their traditional medicines. The purpose of this review is to provide an update on the role of nutrition supplements and herbals in liver disease. This article will focus mainly on 7 selected agents (vitamin E, zinc, magnesium, S-adenosylmethionine, betaine, silymarin, and glycyrrhizin), for which there have been not only in vitro and animal studies but also human clinical trials, and we will review both potential efficacy and safety issues.     

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.     

Update on the Biological Characteristics of the Antioxidant Micronutrients: Vitamin C, Vitamin E, and the Carotenoids

Under normal circumstances, free radicals that are produced through biological processes and in response to exogenous stimuli are controlled by various enzymes and antioxidants in the body. Laboratory evidence suggests that oxidative stress, which occurs when free radical formation exceeds the ability to protect against them, may form the biological basis of several acute medical problems, such as tissue injury after trauma, and chronic conditions, such as atherosclerosis and cancer. A potential role for the antioxidant micronutrients (vitamin C, vitamin E, and the carotenoids) in modifying the risk for conditions that may result from oxidative stress has stimulated intense research efforts, increased interest in micronutrient supplements, and heightened consumer interest in these compounds. Much remains to be learned, however, about the bioavailability, tissue uptake, metabolism, and biological activities of these micronutrients. These biological characteristics will ultimately determine their clinical usefulness in modulating oxidative stress. Also, whether the antioxidant mechanism explains their relationship with risk for acute and chronic disease in epidemiologic studies remains to be determined. Increased knowledge in this area of nutrition science will have an impact on both clinical dietetics practice and public health nutrition guidelines. J Am Diet Assoc. 1996; 96:693–702.     

Antioxidant strategies for Alzheimer's disease

Oxidative damage is present within the brains of patients with Alzheimer's disease (AD), and is observed within every class of biomolecule, including nucleic acids, proteins, lipids and carbohydrates. Oxidative injury may develop secondary to excessive oxidative stress resulting from beta-amyloid-induced free radicals, mitochondrial abnormalities, inadequate energy supply, inflammation or altered antioxidant defences. Treatment with antioxidants is a promising approach for slowing disease progression to the extent that oxidative damage may be responsible for the cognitive and functional decline observed in AD. Although not a uniformly consistent observation, a number of epidemiological studies have found a link between antioxidant intake and a reduced incidence of dementia, AD and cognitive decline in elderly populations. In AD clinical trials molecules with antioxidant properties such as vitamin E and Ginkgo biloba extract have shown modest benefit. A clinical trial with vitamin E is currently ongoing to determine if it can delay progression to AD in individuals with mild cognitive impairment. Combinations of antioxidants might be of even greater potential benefit for AD, especially if the agents worked in different cellular compartments or had complementary activity (e.g. vitamins E, C and ubiquinone). Naturally-occurring compounds with antioxidant capacity are available and widely marketed (e.g. vitamin C, ubiquinone, lipoic acid, beta-carotene, creatine, melatonin, curcumin) and synthetic compounds are under development by industry. Nevertheless, the clinical value of these agents for AD prevention and treatment is ambiguous, and will remain so until properly designed human trials have been performed.     

Efficacy of vitamin E,phosphatidyl choline and pyruvate on Abeta neurotoxicity in culture

Oxidative stress is a pivotal factor in neuronal degeneration including that induced by exposure to amyloid-beta (Abeta). Treatment with antioxidants such as vitamin E can alleviate Abeta neurotoxicity. However, vitamin E was only marginally effective in clinical trials in Alzheimer's disease. Recent studies indicate that treatment with vitamin E (as a-tocopherol), sodium pyruvate and phosphatidyl choline (PC) is more effective than vitamin E alone against neuronal oxidative stress. We demonstrate herein that treatment of cultured murine cortical neurons with these 3 agents is also more effective than vitamin E alone against Abeta neurotoxicity as assayed by generation of reactive oxygen species and increased levels of phospho-isoforms of the microtubule-associated protein tau. These data underscore the potential efficacy of a combinatorial neuroprotective formulation against Abeta neurotoxicity.     

Does vitamin E supplementation prevent cardiovascular events?

In recent years, vitamin E has been investigated as a cardioprotective agent. Experimental studies have identified potential mechanisms by which vitamin E may inhibit the development of atherosclerosis, and observational studies of individuals without coronary disease suggest that vitamin E intake may prevent future cardiovascular events. Secondary prevention trials to date have demonstrated little benefit from vitamin E supplementation. It remains possible, however, that supplementation may be useful among certain high-risk groups, including those with nutritional deficiencies. Limited data from completed primary prevention trials also indicate minimal cardioprotection from vitamin E, but large-scale trials now in progress may yet show benefit. Results from ongoing trials will contribute powerfully to the totality of evidence on which to formulate both appropriate clinical recommendations for individual patients and a rational public health policy for the population as a whole. At this time, there is insufficient evidence for issuing a public health recommendation to use vitamin E supplements to prevent cardiovascular disease (CVD). Rather, increased intake of fruits, vegetables, and other antioxidant-rich foods should be promoted as part of a healthy diet because they provide nutritional benefits beyond any potential antioxidant effect. Moreover, even if found to reduce CVD risk, vitamin supplement use should be considered an adjunct, not an alternative, to established cardioprotective measures, such as smoking abstention, avoidance of obesity, adequate physical activity, and control of high blood pressure and hyperlipidemia.     

The antioxidants--vitamin C,vitamin E, selenium, and carotenoids

This is the second in a series of articles reviewing the recent revisions of the Recommended Dietary Allowances (RDA) and the resulting Dietary Reference Intakes (DRI). In April of 2000, the Food and Nutrition Board of the National Academy of Sciences released Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. The central premise of the report did not perpetuate the prevailing popular thought that large doses of antioxidants will prevent chronic diseases. Instead the panel concluded that at this time, insufficient scientific evidence exists to sustain claims that ingesting megadoses of dietary antioxidants can prevent certain chronic illnesses such as cardiovascular disease or cancer. In some instances recommended nutrient levels were reduced from the previous report in 1989; e.g., for the first time upper tolerable levels of ingestion (UL) were established to prevent the harmful effects of over consumption of essential nutrients, such as vitamin C, vitamin E, and selenium. Although dietary recommendations do exist for vitamin A, the panel did not set recommendations for beta-carotene or the other carotenoids due to lack of sufficient research to support recommended intakes or upper tolerable levels of intake. However, the panel advises the public to avoid intakes of provitamin A compounds, such as the numerous carotenoids, beyond the levels required to prevent vitamin A deficiency. Changes were also made with regard to estimating the amount of provitamin A carotenoids required to make a unit of retinal. The revised estimate suggests a twofold higher conversion rate than previously believed. Although this comprehensive report on the dietary reference intakes for vitamin C, vitamin E, selenium, and the carotenoids did not decisively confirm the role of antioxidants for the prevention of chronic diseases in humans, many research studies have generated new data to support this concept. Additional research is needed to define the attributes of antioxidants as studies progress from in vitro and animal studies to human nutrition.     

Diet and asthma: nutrition implications from prevention to treatment

Asthma is characterized by lung airway inflammation initiated and perpetuated by an inappropriate immune response, increased airway responsiveness, and variable airflow obstruction. In Western countries there has been a marked increase in asthma prevalence such that it has become a public health concern. It has been hypothesized that the increase may be due to changing antioxidant intake, increasing dietary ratio of n-6:n-3 polyunsaturated fatty acids (PUFA), and vitamin D deficiency (and supplementation). Observational studies have reported associations between asthma and dietary antioxidants (vitamin E, vitamin C, carotenoids, selenium, polyphenols, and fruit), PUFA, and vitamin D. However, supplementing the diets of adults with asthma with antioxidants and n-3 PUFA has minimal, if any, clinical benefit. Currently there is insufficient evidence to support the use of nutrient supplements to complement conventional treatment; however, results of ongoing studies are awaited, and additional research is required, particularly in children. Interest in the potential of dietary intervention during pregnancy to reduce the likelihood of childhood asthma has increased. A small number of cohort studies have highlighted associations between childhood asthma and reduced maternal intake of some nutrients (vitamin E, vitamin D, selenium, zinc, and PUFA) during pregnancy. Although vitamin D intervention studies during pregnancy are ongoing and two intervention studies suggest that dietary PUFA manipulation during pregnancy may be advantageous, further trials are needed to establish if modification of maternal nutrient intake during pregnancy can be used as a healthy, low cost, public health measure to reduce the prevalence of childhood asthma.     

Prebiotics and synbiotics in clinical medicine.

Pharmaceutical medicine has thus far been unable to stop the increasing global morbidity and mortality both in acute and chronic diseases. Typically, medical practice has focused on reducing the aggressor with treatments such as antibiotics; little interest has been given to efforts to increase the individual's resistance to disease. The increased morbidity has occurred in parallel to a deviation from a large consumption of fresh fruits, vegetables, and tubers rich in live lactic acid bacteria (LAB), plant fibers, and natural antioxidants to an industry-produced diet rich in fat and refined sugar but containing little fiber, antioxidants, and LAB. Plant fiber/prebiotics, plant-derived antioxidants, and LAB/probiotics are known to have the potential to reinforce the immune system of the body and increase resistance to disease. However, this depends on the type of fiber, antioxidant, and strain or combination of strain used. At this stage, only about 10% of the LAB studied have proven strong immunosupportive effects. Similarly, only a few plants contain what has been called superantioxidants, antioxidants 10 or more times stronger than vitamin C and E. Increasing evidence suggests that combining several probiotic bacteria into multistrain probiotics will achieve stronger effects than single-strain probiotics. And combining probiotics and prebiotics into "synbiotics" will further enhance the immunosupportive effects. There is little evidence that a single-strain-based "superprobiotic"/magic LAB will ever be found. Instead, combining several specific and defined probiotics and several key plant fibers into multistrain/multifiber synbiotics appears to be the most promising alternative. Some edge-cutting effects from using multistrain and multifiber compositions are reported both from animal and controlled clinical studies.