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Vitamin E

Nutrient Name: Vitamin E.
Synonyms: Vitamin E; d-alpha-tocopherol.
Related Compounds: d-beta-tocopherol, d-gamma-tocopherol, d-delta-tocopherol; tocopheryl acetate, tocopheryl succinate.
Trade Names: Aqua Gem E, Aquasol E, E-Gems, Key-E, Key-E Kaps.

Summary Table
nutrient description

Chemistry and Forms

Alpha-tocopherol is either d-alpha (RRR) or dl- (all-racemic) alpha tocopherol.

Naturallly ocurring forms of vitamin E include tocopherols (d-alpha-tocopherol, d-beta-tocopherol, d-gamma-tocopherol, d-delta-tocopherol) and tocotrienols (alpha-tocotrienol, d-beta-tocotrienol, d-gamma-tocotrienol, d-delta-tocotrienol).

Physiology and Function

Vitamin E was discovered in the 1920s, but our comprehension of the full implications of this nutrient in health, dysfunction, and disease is only beginning to emerge. Alpha-tocopherol is the only recognized form of the lipid-soluble vitamin E in animal tissues and plasma. However, vitamin E antioxidants are a group of eight tocopherol and tocotrienol compounds, including four tocopherols and four additional tocotrienol (alpha, beta, gamma, delta), which occur naturally in foods. Research over the past decade has focused on this nutrient's role in antioxidant functions, but important discoveries have also emerged concerning the direct role of vitamin E in control of cell division, inflammatory processes, xenobiotic detoxification, blood cell regulation, and connective tissue growth.

Vitamin E absorption depends on the presence of bile and decreases as dosage increases. At normal levels of intake, about 50% of dietary vitamin E is absorbed. A diet high in unsaturated fat increases vitamin E requirements. Vitamin E is distributed to all body tissues but has a particular affinity for adipose tissue. Adipose tissue slowly accumulates vitamin E and then in time slowly releases it while the liver just briefly stores vitamin E, and does so continuously. Alpha-tocopherol transfer protein (TTP), present in the liver and cerebellum, is the lipophilic vitamin-binding protein responsible for the incorporation of alpha-tocopherol into lipoproteins and for the transport of alpha-tocopherol between membranes. Dietary intake of vitamin E is metabolized in the liver to CEHCs, which are then glucuronidated and excreted via the urine.

Vitamin E's principal physiological role is to act as an antioxidant to prevent free-radical damage (lipid peroxidation) and protect the stability and integrity of cellular tissues and membranes. Vitamin E's role in stabilizing cell membranes is especially important in the lungs and red blood cells (RBCs), which are particularly susceptible to oxidative damage because of their high oxygen tension. As a fat-soluble nutrient, this antioxidant activity occurs particularly in lipid media and protects fatty acids against oxidative damage caused by various pollutants, peroxides, and free radicals formed during metabolic processes. It also reduces formation of lipofuscin, an oxidized fat that has been implicated in the aging process. If insufficient vitamin E is present, polyunsaturated fatty acids (PUFAs) may become oxidized in the body, creating toxins that may lead to chromosomal damage and carcinogenesis. Alpha-tocopherol has been shown to inhibit platelet aggregation, enhance vasodilation, affect the expression and activity of immune and inflammatory cells, and inhibit the activity of protein kinase C, an important cell-signaling molecule. Researchers have recently determined that vitamin E, especially as d-alpha-tocopherol, can act as a ligand for, and thereby increase the metabolic activity of, pregnane X receptor (PXR), which regulates a constellation of genes involved in detoxification of xenobiotics. 1 Vitamin E also plays an important role in preventing neurological abnormalities such as peripheral neuropathies.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Research into the role of vitamin E in health and disease has yet to mature and remains the subject of controversy and discovery. Within the conventional perspective on nutrition, the metabolic function of vitamin E is usually considered as still unidentified, although its major function as a nonspecific chain-breaking antioxidant is acknowledged and emphasized. In contrast, since the 1940s, health care professionals practicing nutritional therapeutics have often presented vitamin E as a primary component of health optimization, disease prevention, and therapeutic intervention. Although conventional medicine usually disclaims the value of antioxidant therapy via nutritional supplements in the primary prevention of cardiovascular disease and cancer, the lack of cohesive understanding of the role of vitamin E and other antioxidants in secondary prevention is also acknowledged. Clinical trials have typically investigated individual antioxidants, such as vitamin E, without considering that most health care professionals practicing nutritional therapeutics employ antioxidant formulations aimed at achieving synergistic action from multiple ingredients. Such factors may account for many of the recent inconsistencies and disappointments in outcomes of studies examining the efficacy of vitamin E supplementation for heart disease and other conditions. Further, research employing vitamin E, as with most other studies involving nutritional supplements, have often been designed without regard to the particular form of the nutrient(s) employed, dosage levels typical of informed clinical practice, or the underlying pathophysiological mechanisms.

This subject exemplifies the need for well-designed clinical trials focused on clearly defined health care goals and informed by an integrative approach utilizing the knowledge and experience of clinicians and researchers from a diverse range of perspectives. Furthermore, the conclusions of reviews and meta-analyses of vitamin E studies require a careful parsing of trial data based on form of the nutrient involved, design and time frame, concomitant therapies, and patient population characteristics if they are to be accurate and clinically useful. Fortunately, in the meantime, a broad consensus supports the primary value of a balanced and diverse diet rich in antioxidants as the foundation of health optimization and disease prevention.

Possible Uses

Acne, allergies, Alzheimer's disease, amyotrophic lateral sclerosis (risk reduction), anemia (sickle cell anemia and other types of hemolytic anemia), angina, anti-inflammatory, antioxidant, ataxia with isolated vitamin E deficiency (AVED), atherosclerosis, bronchitis, burns, cardiovascular effects, cataracts, cold sores, cystic fibrosis, dermatitis herpetiformis, diabetes mellitus, diabetic retinopathy (prevention), Down syndrome, Dupuytren's contracture, dysmenorrhea, epilepsy (pediatric), fibrocystic breast disease, fibromyalgia, hemolytic anemia (deficiency), hepatitis, herpetic lesions and postherpetic neuralgia, high-altitude exercise performance, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, hypercholesterolemia, mild hypertension, hypoglycemia, immune support (especially for elderly), infertility, inflammatory thrombophlebitis, intermittent claudication, leukoplakia, lung cancer (risk reduction), macular degeneration, menopause (including hot flashes and atrophic vaginitis), menorrhagia (heavy menstruation), muscular dystrophy, myocardial infarction, nocturnal cramping, Osgood-Schlatter disease, osteoarthritis, pancreatic insufficiency, peripheral neuropathy (due to deficiency), photosensitivity, preeclampsia (risk reduction), premature infants, premenstrual syndrome, prostate cancer (risk reduction), psoriasis, Raynaud's syndrome, restless legs syndrome, retinopathy, retrolental fibroplasia, rheumatoid arthritis, scar tissue, seborrheic dermatitis, scleroderma, skin ulcers, spinocerebellar ataxia (due to deficiency), spontaneous abortion, sudden infant death syndrome (SIDS), sunburn, systemic lupus erythematosus (SLE), tardive dyskinesia, vaginal atrophy, vaginitis, wound healing, yellow nail syndrome.

Deficiency Symptoms

Frank vitamin E deficiency is rare in humans, but dietary intake in developed countries is often compromised by heavy reliance on processed foods. Very little vitamin E is transferred across the placenta, so premature infants, who are not breast-fed or supplemented, are susceptible to deficiency and subsequent damage of the retina (retrolental fibroplasia) if exposed to high oxygen tension from oxygen supplementation. Individuals with a genetic defect in alpha-tocopherol transfer protein (TTP) have an especially significant susceptibility to a severe vitamin E deficiency, characterized by low blood and tissue levels of vitamin E and progressive nerve abnormalities. Deficiency of vitamin E can cause a peripheral neuropathy, in which sensory neurons are particularly affected, such that the large-caliber axons die, ultimately resulting in a spinocerebellar ataxia.

Possible signs and symptoms of vitamin E deficiency include decreased integrity of RBC membranes, hemolytic anemia (with consequent elevated indirect bilirubin), peripheral neuropathy, spinocerebellar ataxia, elevated heavy metal levels, cataracts, cystic fibrosis, cholestatic liver disease, various lipid malabsorption syndromes, atrophy of reproductive organs, infertility, premenstrual syndrome, hot flashes, fibrocystic disease, benign prostatic hypertrophy, dry skin, eczema, psoriasis, poor wound healing, atrophy and weakness in skeletal and smooth muscles, and Osgood-Schlatter disease (also associated with selenium deficiency), as well as increased risk of cancer, atherosclerosis, rheumatoid arthritis, major depression, and preeclampsia. Sickle cell anemia and beta-thalassemia predispose to vitamin E insufficiency.

Dietary Sources

Unrefined, cold-pressed vegetable oils, particularly wheat germ oil, sunflower seed oil, and olive oil and all whole, raw, or sprouted seeds, nuts, and grains (especially whole wheat) are considered the best dietary sources of vitamin E. Asparagus, avocados, brussels sprouts, egg yolks, legumes, shrimp, spinach, sweet potatoes, and leafy green vegetables, generally, can be good sources. Although wheat germ can be an excellent source, it must be absolutely fresh (less than a week old) because the oil oxidizes rapidly, and rancid wheat germ does not contain active vitamin E.

Food sources can provide the recommended dietary allowance (RDA) level of 15 mg alpha-tocopherol per day, an appropriate intake for many conditions, while offering a rich diversity of gamma-tocopherol and other tocopherols. However, clinical research indicates that the maintenance dosage levels and especially the higher range of therapeutic dosage levels, typically hundreds of units per day, required for some conditions may be difficult to obtain through diet alone. This is particularly true for individuals who reduce their intake of dietary fats, because vitamin E tends be more abundant in diets richer in fats. Moreover, recent research on vitamin E bioavailability shows that absorption of vitamin E is higher if it is part of or closely associated with the digestion of a food that contains fat. For example, grain cereal fortified with vitamin E raised plasma levels of new vitamin E more consistently and to higher levels proportionately than did vitamin E as a supplement only, with liquids on an empty stomach, or even taken with milk. 2 On a broader level, there is a growing body of evidence that large doses of vitamin E, especially if used without an accompanying diverse antioxidant network, may be deleterious for some individuals.

Tocopherols are oily yellow liquids that are water insoluble, heat and acid stable, and deteriorate with exposure to alkali, light, oxygen, iron, or lead. Frying of foods as well as freezing also decreases the potency of vitamin E. In contrast, tocopheryl esters, which are most often found in fortified foods (particularly breakfast cereals), tend to be fairly resistant to both frying and freezing (as well as highly bioavailable).

Nutrient Preparations Available

Although alpha-tocopherol has long been the standard of vitamin E supplementation, research is evolving to a greater understanding of the importance of naturally occurring forms and the advantages of mixed tocopherols. RRR-alpha-tocopherol, more commonly known as d-alpha-tocopherol, is the only form of alpha-tocopherol that occurs naturally in foods, whereas synthetic dl-alpha-tocopherol (all-racemic alpha-tocopherol) is composed of equal amounts of all stereoisomers. The establishment of d-alpha as the “active” isomer was based on the rat fetus resorption assay developed in the 1940s, in which only the d-alpha isomer is active; in pregnant rats made vitamin E deficient, the fetuses die and are resorbed, which is prevented only by d-alpha-tocopherol. The other isomers may have superior in vivo biological antioxidant activity, and gamma appears to have greater prostate cancer–preventive activity than alpha. The tocotrienols are much superior in cellular membrane protection because of a greater ability to move within membrane structures. Naturally occurring d-alpha-tocopherol is significantly more bioavailable, perhaps 200%, and exerts greater physiological activity than synthetic dl–alpha-tocopherol. 3 Some clinicians have reported that water-soluble forms of vitamin E can be better absorbed and more effective with individuals experiencing fat malabsorption problems, especially middle-age and menopausal women. Vitamin E is sold in both esterified and nonesterified forms but is usually manufactured as acetate or succinate esters because pure vitamin E compounds are easily oxidized. A tocopherol form is appropriate in topical use; tocopheryl forms require an enzyme to split the vitamin E from the acid moiety to which it is attached by an ester linkage.

Dosage Forms Available

Capsule, gel capsule; emulsified liquid drops, mycelized liquid drops; injection; liquid; ointment; powder; solution, oral drops; spray; suppository; tablet; topical.

Equivalencies:

  • 1 mg d-alpha-tocopheryl acetate=1.49 IU
  • 1 IU all-racemic alpha-tocopherol=0.45 mg

The current RDA is given in milligrams of alpha-tocopherol.

Dosage Range

Adult

  • Dietary:   RDA based on RRR-alpha-tocopherol (d-alpha-tocopherol):
  • Adults, 19 years and older: 15 mg (22.5 IU)/day
  • Pregnancy (all ages): 15 mg (22.5 IU)/day
  • Breastfeeding (all ages): 19 mg (28.5 IU)/day

Supplemental/Maintenance: 15 mg/day, higher doses may not be more efficacious. 4,5

Pharmacologic/Therapeutic: 400 to 2500 IU/day (excluding pregnant or lactating women) in clinical practice; 100 to 1000 IU/day in the scientific literature.

Toxic: The safe upper intake level (UL) of vitamin E for adults as d-alpha-tocopheryl acetate is 1500 IU/day (1000 mg), or 1100 IU/day dl-alpha.

Pediatric (<18 years)

Dietary: RDA based on RRR-alpha-tocopherol (d-alpha-tocopherol)

  • Infants, birth to 6 months: 4 mg (6 IU)/day
  • Infants, 7 to 12 months: 5 mg (7.5 IU)/day
  • Children, 1 to 3 years: 6 mg (9 IU)/day
  • Children, 4 to 8 years: 7 mg (10.5 IU)/day
  • Children, 9 to 13 years: 11 mg (16.5 IU)/day
  • Adolescents, 14 to 18 years: 15 mg (22.5 IU)/day
Supplemental/Maintenance: Not established.

Laboratory Values

Plasma vitamin E: Less than 11.6 μmol/L indicates deficiency.

Plasma alpha-tocopherol (μmol/L)/plasma cholesterol (mmol/L): Ratio less than 2.2 indicates deficiency. Accurate measurement of vitamin E status inherently includes the ratio of vitamin E/total cholesterol because vitamin E level in the blood is directly correlated with the blood lipid level.

Plasma tocopherol: Less than 10 μmol/L generally indicates deficiency.

Note: Alpha-tocopherol normally constitutes more than 90% of total plasma vitamin E.

There is no correlation between plasma levels and vitamin E stores. A serum peroxide value can give an indirect status.

safety profile

Overview

Vitamin E supplements are widely considered to be safe and unlikely to cause adverse side effects in most individuals at typical dosage levels. At common therapeutic doses intended for long-term use, 800 IU per day, vitamin E, in its various forms, is considered nontoxic in most individuals. Daily doses of 2000 to 3500 IU have been used in clinical setting for extended periods without adverse effects. Nevertheless, there has been a recent trend in the scientific literature suggesting potential adverse effects of dosages significantly higher than the recently revised RDA. Warnings against use of dosage levels greater than 200 IU/day usually derive from trials using vitamin E as an isolated antioxidant, synthetic dl-alpha-tocopherol, and patients with pathologies, behaviors, diet, or other factors characterized by high oxidative stress. Meta-analyses and reviews encompassing such studies are limited by their failure to emphasize the clinical implications of such study factors and attendant mixing of findings from trials employing essentially different substances (e.g., natural vs. synthetic forms, multiple vs. single nutrient). Thus, a potentially dangerous pro-oxidant effect can be created when one or two antioxidants, especially in synthetic forms, are given in high dosages to individuals who are chronically antioxidant deficient and under increased oxidative stress. Even so, “higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.” 6 Unfortunately, the mainstream of scientific research and medical practice has yet to consider, let alone investigate this concept.

Nutrient Adverse Effects

General Adverse Effects

The rare occasions of adverse effects from supplemental forms of vitamin E, typically in high dosages for extended durations, have been characterized by fatigue, headache, hemorrhage, double vision, nausea, flatulence, diarrhea, gastrointestinal distress, and muscular weakness. One study, published in 2005 and widely publicized in the popular press when initially released online in late 2004, was a meta-analysis suggesting that high dosages of vitamin E were associated with a small increase in risk for all-cause mortality at doses above 400 IU daily among individuals being treated for various health conditions, and this dose-dependent increase began to be seen above doses of 150 IU/day. These researchers also found that the meta-analysis of the vitamin E studies involving low doses (i.e., <200 IU/day) indicated a small decrease in all-cause mortality, although it did not reach statistical significance. These conclusions were based on meta-analysis from 19 randomized, placebo-controlled trials involving d-alpha-tocopherol and dl-alpha-tocopherol (synthetic form) in diverse populations, including high proportions of the elderly and high-risk individuals with chronic pathologies. 7 None of these studies included any of the other naturally occurring tocopherol or tocotrienol isomers of the vitamin E complex.

Pregnancy and Nursing

Note: With pregnant women, monitor plasma tocopherol concentrations (normal range, 6-14 μg/mL).

In one randomized, placebo-controlled trial involving 722 pregnant women at risk for preeclampsia, researchers observed a slightly elevated incidence of small-for-gestational-age neonates among women administered vitamin C (1000 mg) and vitamin E (RRR-alpha-tocopherol, 400 IU) versus placebo. 8

Infants and Children

Reports of infant deaths from vasculocentric hepatotoxicity in 1983 due to parenteral administration of vitamin E were found to be related to the solubilizing agent polysorbate instead of vitamin E. 9 This compound, E-Ferol, was subsequently banned. In a 1989 review article, Mino 10 summarized a cautious perspective: “In the course of therapy with elevated dosages of vitamin E, administered either orally, intramuscularly, or intravenously, many problems arose in the infants, such as unexpected death, increased frequency of necrotizing enterocolitis (NEC) and sepsis, and the development of unusual symptoms including hepatic injuries.”

Toxicity: Vitamin E toxicity is generally considered to be very rare. Increased risk of hemorrhage may result from vitamin E toxicity. A dose of 1800 IU/day has been shown to cause a prolonged bleeding time (an in vivo test of platelet function).

Contraindications

  • Chronic rheumatic heart disease: Avoid initial use of high doses; increase gradually.
  • Hypertension.
  • Congestive heart failure (CHF): Large doses of a single antioxidant supplement, such as vitamin E, in patients likely to be under oxidative stress who do not consume a diet rich in antioxidants, may contribute to further oxidative stress.

Precautions and Warnings

Hypersensitivity to vitamin E, source material, or any component of the formulation; intravenous (IV) route.

interactions review

Strategic Considerations

Vitamin E deficiency resulting from inadequate dietary intake is relatively uncommon in the developed world, but it may occur within certain populations, such as elderly persons and institutionalized individuals. Further, a wide range of common drugs deplete key nutrients, including vitamin E and other antioxidants, and the risk of drug-induced deficiency of vitamin E and consequent adverse effects is considered to be substantial.

Conversely, supplementation with naturally occurring forms of vitamin E may prevent or reverse adverse effects of many medications. However, controversy continues as to whether coadministration of vitamin E with drugs that deplete it offers superior therapeutic outcomes, or whether such polypharmacy simply obscures the outcome or even interferes with intended drug actions.

The role of vitamin E in conventional medicine has undergone many sharp turns, particularly at the start of the twenty-first century, as a number of interventional clinical trials, as well as several meta-analysis studies, were published. Perhaps most importantly, the issue of single versus multiple isomers of vitamin E, as well as natural versus synthetic sources, reveals deep divisions within the medical and scientific community as to nutritional therapeutics and underlying assumptions. This pivotal factor in clinical practice, research design, and scientific discourse was further exacerbated by the recent redefinition of “vitamin E” away from the previous functional definition based on physiological action to a narrower, more pharmaceutic definition exclusively specifying d-alpha-tocopherol.

Any discussion of “vitamin E” first requires a common understanding of meaning and context and should begin with questions as to forms and sources being applied. Thus, studies referring to “vitamin E” could indicate alpha-tocopherol more exactly (although often failing to differentiate isomer and source), supplements containing multiple tocopherol isomers, supplements containing multiple forms of naturally occurring vitamin E (i.e., mixed tocopherols and tocotrienols), or food sources. Many controversies and much confusion would be rapidly resolved if discourse was founded on such clear communication and consistent nomenclature. The clinical significance of such discriminations becomes apparent in the treatment of conditions such as congestive heart failure, in which the interaction between different forms of “vitamin E” may constitute one of the more significant physiological factors. The exclusive reliance on alpha-tocopherol in almost all clinical trials of vitamin E fails to acknowledge the inherent balance and synergistic interplay among alpha-, beta-, gamma-, and delta-tocopherol and thus limits both the immediate applicability of any resultant findings and their extrapolation.

Over the past 40 years the role of vitamin E in preventing heart disease has been the subject of often acrimonious debate and collegial miscommunication. The ongoing controversy regarding the role of vitamin E in the prevention and treatment of cardiovascular disease reveals a deep schism in the often opposing world views of the linear reductionistic philosophy that permeates much of conventional medicine, and the more holistic empirical approaches of “natural” medicine. This dynamic suggests an emerging paradigm that might offer novel approaches to research, prevention, and therapeutics that can transcend and yet be inclusive of previously conflicting viewpoints. Oxidative stress plays a central role in the physiopathology underlying many chronic degenerative diseases, particularly cardiovascular disease, but its clinical implications are not understood in a consistent and comprehensive way. The underlying assumption in the field was that if the antioxidant effect of vitamin E conclusively proved to be clinically significant, vitamin E would logically be confirmed as playing an integral role in the prevention and treatment of heart disease. The role of antioxidant nutrients has evolved through a cycle of ill-founded enthusiasm and premature expectations that verge on regarding them as a panacea, into a body of research using single antioxidants in high doses (and often synthetic forms), with mostly negative results, and toward an emerging reconceptualization of nutrients’ physiological nature and function, clinical uses, and effects. The interactions between antioxidants and statin drugs provide an important illustration of this dialogue and suggest ways in which both research and clinical practice can mature.

Thus, over the past two decades, the attitude toward vitamin E has gone from acceptance and often enthusiasm in some quarters, especially in relation to heart disease, to near-condemnation in more recent papers. However, the limitations of the research thus far clearly point to the need for further research into the differences between pharmaceutical and food sources of vitamin E, the physiological functions of and interplay among the various forms of naturally occurring tocopherol isomers, and the implications of such findings in formulating preparations for research and clinical practice. Furthermore, the emerging knowledge of physiological detoxification systems, such as hepatic phase I, II, and III enzyme systems, and the operative mechanisms of nuclear receptors, such as pregnane X receptor (PXR), offers significant prospects for understanding the clinical significance of drug metabolism and its stimulation by vitamin E and other nutrients. Further research, education, and communication will also be necessary to clarify the importance of using naturally occurring forms of vitamin E, preferably mixed tocopherols and tocotrienols, within the context of a comprehensive antioxidant strategy and with a respect for the particular needs and vulnerabilities of specific patient populations.

Some aspects of this controversy may derive from differences in the research questions being asked, trial design, observational studies versus randomized controlled clinical trials versus meta-analyses, characteristics of subject populations, nutrient forms and dosages, dietary sources versus supplemental intake, concomitant dietary and lifestyle factors, polypharmacy, and outcome measures. From early research into the possible beneficial nature of the interaction between the two, the ground shifted dramatically to claims that antioxidants diminish the effectiveness of statins, and finally to frank warnings that key antioxidants such as beta-carotene and alpha-tocopherol might actually increase risk of coronary artery disease and heart failure. 11,12Conversely, the unresolved concerns regarding the safety and ultimate efficacy of statin drugs increasingly suggest that the dominant paradigm of scientific knowledge of their nature and action (i.e., lowering of cholesterol) may provide an inadequate explanation of their preventive and therapeutic effects as observed in a wide range of conditions. Ultimately the key to resolving such apparent conflicts may reside in greater individualization of care, with reference to the emerging tools of pharmaco-/nutrigenomics, through titration of drug doses to effect and/or blood levels and close monitoring within a flexible, responsive, and evolving integrative approach.

Many of the issues that arise in clinical research regarding vitamin E reflect clinical experience with vitamin E in particular and nutritional therapies in general, and the role such interventions play in defining clinical options and shaping therapeutic strategy. For example, the HATS study published in fall 2001 (discussed later) was widely interpreted as a negative interaction between antioxidants and statins, but on closer analysis more likely shows a blunting effect of the antioxidants on the rise of high-density lipoprotein (HDL) cholesterol, more associated with niacin, rather than a direct effect on the statin therapy. Most statins have minimal if any positive effects on HDL, and often actually reduce HDL, along with low-density lipoprotein (LDL), which is why the statin-niacin combination has become widely used since that study. Even so, the accepted fact that simvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) may be a potentially significant observation given the findings of a single in vitro experiment showing that alpha-tocopherol could theoretically stimulate drug metabolism, particularly through its effect on PXR, with subsequent increased expression of the CYP3A4 enzyme. Nevertheless, failure to include coenzyme Q10 and methyl donors in the nutrient mix may also have represented a significant limitation in the trial design. Such modification would have addressed underlying mechanisms at issue: the inhibitory activity of statins on endogenous synthesis of coenzyme Q10 and niacin's depletion of methyl donors, particularly in the liver. Correction of these two drug-nutrient interactions with supplementation might have led to a very different outcome.

Lastly, an important aspect of antioxidant function rarely factored into the design of clinical trials is a recognition of the pro-oxidant potential of antioxidants. One or two antioxidants, especially synthetic ones (e.g., all- trans beta carotene), given in high doses to individuals under high oxidative stress, who consume diets low in antioxidants (e.g., male Finnish smokers, alcohol/tobacco users), can create a situation in which the antioxidants are forced to act as pro-oxidants. The resultant deficit in the antioxidant network causes the carotene and/or tocopherol and/or ascorbate radicals to persist without being quenched, and thereby increase free-radical damage. The increased incidence of heart failure among high-risk individuals taking 400 mg/day of vitamin E (with ramipril), observed in the HOPE study, appears to reveal such an adverse effect of increased oxidative stress when a comprehensive antioxidant network is not available. 13 Subsequent meta-analyses will be limited by their indiscriminate inclusion of trials using varied agents in isolation with diverse populations. Similarly, the related findings of HOPE and HOPE-TOO trials emphasized the limitations and potential adverse response to use of vitamin E as a single antioxidant in individuals characterized by a state of oxidative stress. These researchers reported that natural-source vitamin E (400 IU alpha-tocopherol daily) failed to significantly reduce risk of cancer or cardiovascular events, the primary focus of the study, and appeared to be associated with an increased risk of heart failure. It is noteworthy that the subject group comprised older patients (average age, >70 years) with a history of heart disease, stroke, or diabetes, most of whom demonstrated very strong risk factors and were taking numerous medications. Furthermore, the authors of this study, as well as most commentators, do not appear to have considered the established relationship between alpha-tocopherol and gamma-tocopherol and its implications in such a patient population. High doses of alpha-tocopherol are known to deplete gamma-tocopherol, not only disrupting the natural balance among the various forms, but particularly influencing the production of natriuretic hormone, which plays a central role in regulating fluid and salt balance and for which gamma-tocopherol is a precursor. Any gamma-tocopherol deficiency induced by alpha-tocopherol could further stress the heart in this already-compromised population and thus contributed to an increased risk of heart failure. The authors conceded that the “unexpected” results “cannot be confirmed at this time by other trials” and “could be due to chance.” 11 Such findings reveal an emerging pattern, approaching consensus, confirming the lack of efficacy of an exclusively pharmacological approach to vitamin E therapeutics, narrowly defined as alpha-tocopherol, in achieving the successes attributed to “vitamin E,” particularly in individuals with heart disease, diabetes, or similarly compromised conditions. The findings point strongly toward the appropriate use of nutrient-rich food sources, or at least their closest approximation in the form of supplements, providing coordinated, multiple antioxidants, particularly mixed tocopherols and tocotrienols (which are up to 50 times more potent antioxidants than the tocopherols).

As knowledge of interactive complexity at molecular and cellular levels unfolds, so do prospects for more appropriately designed clinical trials. The French SuViMax study, which coadministered five antioxidants, showed a cancer prevention effect in likely dietarily antioxidant-deficient males. This exemplifies the hypothesis that the larger the number of antioxidant nutrients combined, that act in both aqueous and lipidic compartments, the better the clinical results should be. As collective knowledge of the mechanisms and nuances of integrative therapeutics matures, so do prospects for increasingly relevant, large-scale, well-designed clinical trials focusing on clinical outcomes. In the meantime, the role of vitamin E as a key antioxidant is undergoing a reassessment as clinicians and researchers obtain greater knowledge and deeper insight into antioxidant networks, the influences of dietary and supplemental sources, and their roles in health promotion, disease prevention, and therapeutic intervention.

nutrient-drug interactions
Acetylsalicylic Acid (ASA, aspirin)
Anthralin
Bile Acid Sequestrants
Chemotherapy (Various Agents)
Interaction Type and Significance
Interaction Type and Significance
Cisplatin and Oxaliplatin
Cyclosporine
Dapsone
Doxorubicin and Related Anthracycline Chemotherapy
Gemfibrozil
Glyburide
Haloperidol
HMG-CoA Reductase Inhibitors (Statins)
Omeprazole
Orlistat
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Amiodarone
Benzamycin and Benzoyl Peroxide
Cationic Amphiphilic Drugs
Clofibrate
Cyclophosphamide
Cytochrome P450 3A4 Substrates
Fenofibrate
Gentamicin
Griseofulvin
Hormone Replacement Therapy (HRT): Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
Insulin
Isoniazid
Isotretinoin and Related Retinoids
Lindane
Mineral Oil
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Paclitaxel
Pentoxifylline
Phenobarbital, Phenytoin, Valproic Acid, and Related Anticonvulsant Medications
Ramipril and Other Angiotensin-Converting Enzyme (ACE) Inhibitors
Rifampicin

Rifampicin (Rifadin, Rifadin IV); combination drugs: isoniazid and rifampicin (Rifamate, Rimactane); isoniazid, pyrazinamide, and rifampicin (Rifater).

In an in vitro experiment, both vitamin E and rifampicin activated PXR, an orphan nuclear receptor central to xenobiotic metabolism. Production of vitamin E metabolites increased when hepatocytes were incubated with rifampicin and vitamin E (all-racemic alpha-tocopherol). This observation suggests that a CYP3A-type cytochrome initiates tocopherol metabolism by omega oxidation. 166 The clinical implications of this potential interaction are unknown at this time.

Risperidone
Verapamil
Zidovudine (AZT)
nutrient-nutrient interactions
Antioxidants
Chitosan
Iron
Polyunsaturated Fatty Acids; Omega-3 and Omega-6 Fatty Acids
Selenium
Vitamin A
Vitamin C
Vitamin K
Citations and Reference Literature
  • 1.Traber MG. Vitamin E, nuclear receptors and xenobiotic metabolism. Arch Biochem Biophys 2004;423(1):6-11. (Review.)View Abstract
  • 2.Leonard SW, Good CK, Gugger ET, Traber MG. Vitamin E bioavailability from fortified breakfast cereal is greater than that from encapsulated supplements. Am J Clin Nutr 2004;79:86-92.View Abstract
  • 3.Acuff RV, Thedford SS, Hidiroglou NN et al. Relative bioavailability of RRR- and all-rac-alpha-tocopheryl acetate in humans: studies using deuterated compounds. Am J Clin Nutr 1994;60:397-402.View Abstract
  • 4.Rimm E. Micronutrients, coronary heart disease and cancer: should we all be on supplements? 60th Annual Biology Colloquium. Oregon State University, Corvallis; 1999.
  • 5.Panel on Dietary Antioxidants and Related Compounds, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press: Institute of Medicine, National Academy of Sciences; 2000:249-259.
  • 6.Wright ME, Lawson KA, Weinstein SJ et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 2006;84:1200-1207.View Abstract
  • 7.Miller ER 3rd, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2004;142(1):37-46.View Abstract
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