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α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological determinants and its deficiency symptoms in humans. The mechanisms for the preferential α-T tissue enrichment in the human body include the α-T transfer protein (TTPA) and the preferential metabolism of non-α-T forms. Potential new α-T biomarkers, pharmacokinetic data, and whether there are better approaches to evaluate and set the α-T dietary requirement are discussed. Finally, the possible role of α-T supplements in delay of chronic diseases and the evaluation of vitamin E safety are considered., (Copyright © 2021 Elsevier Inc. All rights reserved.)

It has been reported that the degree of anxiety-like behavior differs between inbred strains of mice, and that this phenomenon was linked to the expression levels of the oxidative stress-related genes glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr) in the brain. Therefore, we investigated whether antioxidative activity in the brain affects the Glo1 and Gsr mRNA expressions and strain-dependent anxiety-like behavior using mice fed different amounts of vitamin E. First, we measured brain Glo1 and Gsr mRNA levels and evaluated the anxiety-like behaviors presented by C57BL/6J (B6) and DBA/2C (D2) mice. We demonstrated that D2 mice presented both significantly elevated Glo1 and Gsr mRNA levels as well as more prominent anxiety-like behavior in elevated plus-maze and open field tests. Next, we fed mice from these two strains either a control, vitamin E-free, or vitamin E-supplemented diet for four weeks. Plasma, liver, and brain α-tocopherol concentrations changed in a dose-dependent manner. However, neither brain Glo1 and Gsr mRNA levels nor anxiety-like behavior were affected by dietary vitamin E intake. These results demonstrated that while strain-dependent anxiety-like behavior in mice was related to oxidative stress-related gene expression, the regulatory mechanisms for these genes and anxiety-like behaviors were independent of antioxidative activity in the brain. Strain-dependent differences of the anxiety in mice are probably related to the anxiolytic effects of methylglyoxal, a substrate for Glo1 and Gsr., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Vitamin E refers to a family of eight isomers divided into two subgroups, tocopherols and the therapeutically active tocotrienols (T3). The PEGylated α-tocopherol isomer of vitamin E (vitamin E TPGS) has been extensively investigated for its solubilizing capacity as a nonionic surfactant in various drug delivery systems. Limited information, however, is available about the PEG conjugates of the tocotrienol isomers of vitamin E. In this study two PEGylated γ-T3 variants with mPEG molecular weights of 350 (γ-T3PGS 350) and 1000 (γ-T3PGS 1000) were synthesized by a two-step reaction procedure and characterized by (1)H NMR, HPLC, and mass spectroscopy. The physical properties of their self-assemblies in water were characterized by zeta, CMC, and size analysis. Similar physical properties were found between the PEGylated T3 and vitamin E TPGS. PEGylated T3 were also found to retain the in vitro cytotoxic activity of the free T3 against the MCF-7 and the triple-negative MDA-MB-231 breast cancer cells. PEGylated γ-T3 also increased the oral bioavailability of γ-T3 by threefolds when compared to the bioavailability of γ-T3 formulated into a self-emulsified drug delivery system. No significant differences in biological activity were found between the PEG 350 and 100 conjugates. Results from this study suggest that PEGylation of γ-T3 represents a viable platform for the oral and parenteral delivery of γ-T3 for potential use in the prevention of breast cancer., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Glaucoma patients frequently instill eye drops multiple times each day, which is a cause for reduced compliance. Additionally, eye drops suffer from other limitations including low bioavailability, which can lead to side effects. We propose to develop drug-eluting contact lenses for managing glaucoma with increased bioavailability and improved compliance. Contact lenses are developed for extended simultaneous release of timolol and dorzolamide, both of which are commonly prescribed hydrophilic drugs. The extended release is achieved by loading lenses with vitamin E barriers. In vitro release studies are performed with control and vitamin E loaded lenses for both drugs loaded separately and then together in the same lens. The safety and efficacy of combination therapy by contacts are demonstrated in a Beagle model of glaucoma. Simultaneous loading of timolol and dorzolamide increases the release duration of both drugs. Also vitamin E incorporation is highly effective in increasing the release durations of both drugs to about 2-days. The lenses loaded with both drugs exhibited superior IOP reduction compared to eye drops with about 6-fold lower drug loading. More importantly, combination therapy by continuous wear of vitamin E loaded contact for 2-days, followed by a new set of contacts for another two days, reduced IOP during the 4days of wear time and for another 8days after removal of the contacts. Vitamin E loading is very effective for providing combination therapy by contact lenses due to the increase in release durations of several drugs. The contact lens based therapy reduces IOP with lower drug dose compared to eye drops and may significantly improve the compliance as the effect of the therapy lasts significantly longer than the wear-duration., (Copyright © 2015 Elsevier B.V. All rights reserved.)

It appears that the story on vitamin E and its role in human health remains incomplete. It is apparent that vitamin E supplementation involves many variables, some of which include its uptake from the intestine, the preference for α-tocopherol, transport by tocopherol specific proteins and lipid transporters and the differential metabolism of different vitamin E isoforms. The fundamental differences within population genetics can have significant implications for the effect that dietary supplementation might have on human health. When evaluating the efficacy of vitamin E prophylactic or therapeutic use in previous and future studies, it is critical to consider dosage to be administered, form of vitamin E and source (such as whether from synthetic or purified from natural sources). Further studies are needed to determine the effects of all vitamin E isoforms on cell growth, tumorigenicity, to clarify its possible use as an adjuvant to existing chemotherapeutics. The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study Group and Selenium and Vitamin E Cancer Prevention Trial (SELECT) studies along with the numerous studies of vitamin E should help guide the next chapter of vitamin E research., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cyclodextrin (CD) is widely used in the pharmaceutical and nutritional fields to form an inclusion complex with lipophilic compounds for the improvement of their aqueous solubility, stability and diffusibility under physiological conditions. In this study, we investigated the effect of the γ-tocotrienol (γT3) inclusion complex with CD on its oral bioavailability. Five-week-old C57BL6 mice were fed a vitamin E-free diet for 28 days, followed by the oral administration of 2.79 mg of γT3-rich fraction (TRF) extracted from rice bran or the equivalent dose (14.5 mg) of a CD inclusion complex with TRF (TRF/CD). The levels of γT3 in sequentially collected plasma were determined by LC-MS/MS. The pharmacokinetic study revealed that the plasma concentrations of γT3 were increased and peaked at 6 or 3 h after the oral administration of TRF or TRF/CD, respectively (C(max) values of 7.9±3.3 or 11.4±4.5 μM, respectively). The area under the curve of plasma γT3 concentration also showed a 1.4-fold increase in the group administered with TRF/CD compared with the TRF-only group. Furthermore, the mice that had received the TRF/CD tended to reduce the endotoxin shock induced by injection with lethal amounts of Escherichia coli lipopolysaccharide, compared with the mice that had received TRF alone. Taken together, our results suggest that the CD inclusion improved γT3 bioavailability, resulting in the enhancement of γT3 physiological activity, which would be a useful approach for the nutrition delivery system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Initially discovered in 1938 as a "fertility factor," vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-κB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

A method of analysis of a Vitamin E derivative D-tocopheryl acid succinate (TS) in biological fluids and commercially available products is necessary to study the kinetics of in vitro and in vivo metabolism, tissue distribution, and content uniformity. A simple and inexpensive high-performance liquid chromatographic method was developed for the direct determination of D-tocopheryl acid succinate in commercially available products, rat serum, and rat tissues. This method can also be applied to the determination of 15 Vitamin E derivatives. Rat serum (0.1 ml) was extracted with sodium dodecyl sulfate, ethanol, hexane, and then dried under nitrogen gas after addition of the internal standard, DL-alpha-tocopherol acetate. Separation was achieved on a C18 column with UV detection at 205 nm. The calibration curve for D-tocopheryl acid succinate was linear ranging from 0.025 to 100 microg/ml. The mean extraction efficiency was >92%. Precision of the assay was <5% (CV), and was within 5% at the limit of quantitation (0.025 microg/ml). Bias of the assay was lower than 5%, and was within 5% at the limit of quantitation. The assay was applied successfully to the serum and tissue distribution of D-tocopheryl acid succinate in rats, various Vitamin E derivatives, and content uniformity in commercially available products containing D-tocopheryl acid succinate.

Novel modes of administering antioxidants to improve delivery to targeted tissues or cells may be advantageous in preventing oxidant-induced pathologies. Vitamin E (alpha-tocopherol) has been shown to be protective in several models of liver injury. The objectives of this study were: (1) to determine if subcutaneously (s.q.) administered emulsified vitamin E enriched liver and hepatic subcellular fractions with the antioxidant and (2) to carry out a time-dependent analysis of serum and tissue vitamin E in rats receiving daily s.q. vitamin E. In the first experiment rats injected daily s.q. with emulsified vitamin E for 9 d increased serum, total liver, liver mitochondria, and liver microsomes by 8-, 16-, 30-, and 29-fold, respectively, compared with placebo injections. Similar enrichment was observed after intramuscular injections. In the second experiment, daily doses of s.q. vitamin E increased liver concentrations 40-fold by 9 d, which decreased to 22-fold by 18 d, whereas serum adjusted vitamin E levels maximized with a 24-fold increase by day 3 and plateaued thereafter. In conclusion, s.q. administration of emulsified vitamin E to rats resulted in substantially elevated serum and liver concentrations of alpha-tocopherol compared with levels achievable by dietary supplementation. The s.q. route of administration is a potentially effective parenteral mode of delivery of vitamin E for conditions in which hepatic oxidative stress is present.

Does cigarette smoking increase vitamin E utilization in vivo? A trial was carried out in 6 smokers and 5 nonsmokers of comparable ages and serum lipids. Subjects consumed 75 mg each d(3)-RRR and d(6)-all rac-alpha-tocopheryl acetates (natural and synthetic vitamin E, respectively) daily for 7 d with a standardized breakfast. Fasting blood samples were drawn on days -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 9, 14, 21 (negative days indicate supplementation). In both groups, plasma d(3)-alpha-tocopherol concentrations were approximately double of d(6)-alpha-tocopherol. At day 0, the %d(3) alpha-tocopherols (d(3)-alpha-tocopherol/total-alpha-tocopherol x 100) were similar in both smokers and nonsmokers. Subsequently, there was a trend toward a faster exponential disappearance of the plasma %d(3) alpha-tocopherol in smokers compared with nonsmokers (0.30 +/- 0.04 compared with 0.24 +/- 0.05, p =.0565). The calculated %d(3) half-lives were 55.6 +/- 7.4 h in smokers and 72.1 +/- 17.3 h in nonsmokers (p =.0630). By day 21, the %d(3) in smokers had decreased to 1.4% +/- 0.3% while it was 2.2% +/- 0.7% (p =.0418) in the nonsmokers. These data suggest that smoking increases plasma vitamin E disappearance, but further studies are needed to confirm this finding and to assess its cause.

Coenzyme Q (CoQ) was previously demonstrated in vitro to indirectly act as an antioxidant in respiring mitochondria by regenerating alpha-tocopherol from its phenoxyl radical. The objective of this study was to determine whether CoQ has a similar sparing effect on alpha-tocopherol in vivo. Mice were administered CoQ10 (123 mg/kg/day) alone, or alpha-tocopherol (200 mg/kg/day) alone, or both, for 13 weeks, after which the amounts of CoQ10, CoQ9 and alpha-tocopherol were determined by HPLC in the serum as well as homogenates and mitochondria of liver, kidney, heart, upper hindlimb skeletal muscle and brain. Administration of CoQ10 and alpha-tocopherol, alone or together, increased the corresponding levels of CoQ10 and alpha-tocopherol in the serum. Supplementation with CoQ10 also elevated the amounts of the predominant homologue CoQ9 in the serum and the mitochondria. A notable effect of CoQ10 intake was the enhancement of alpha-tocopherol in mitochondria. alpha-Tocopherol administration resulted in an elevation of alpha-tocopherol content in the homogenates of nearly all tissues and their mitochondria. Results of this study thus indicate that relatively long-term administration of CoQ10 or alpha-tocopherol can result in an elevation of their concentrations in the tissues of the mouse. More importantly, CoQ10 intake has a sparing effect on alpha-tocopherol in mitochondria in vivo.

The mechanisms and dynamics of antioxidant action of ubiquinol have been studied. Ubiquinol scavenges peroxyl radical faster than alpha-tocopherol. However, it is autooxidized rapidly to give hydroperoxyl radical and/or superoxide and hence its antioxidant potency is smaller than that of alpha-tocopherol. The side chain of ubiquinol reduces the mobility between the membranes. It was concluded that ubiquinol acts as a potent antioxidant in combination with alpha-tocopherol.

The conversion of alpha-tocopheryl quinone into alpha-tocopherol in humans has been demonstrated. A male subject was given an oral dose of 400 mg of alpha-3,5-[(C2H3)2]-tocopheryl quinone with an evening meal. Analysis of plasma 15 h later by lipid extraction and subsequent GC-MS single ion monitoring revealed the presence of alpha-[5,7-(C2H3)2]-tocopherol at a concentration of 0.4 microM, representing 0.8% of the total tocopherol in the plasma sample. This experiment clearly demonstrates that orally administered alpha-tocopheryl quinone is converted in a low overall yield to alpha-tocopherol in humans. The conversion to alpha-tocopherol of that portion of the quinone dose which was actually absorbed into the blood stream may, however, have been fairly efficient.

21-Aminosteroids have incited a great deal of interest owing to its ability to inhibit lipid peroxidation and prevent organ damage. The main mechanism by which 21-aminosteroids inhibit lipid peroxidation is similar to the naturally occurring chain-breaking antioxidant alpha-tocopherols. Therefore, to determine whether 21-aminosteroids offer any advantage over alpha-tocopherol, we compared their effects on an in vivo and in vitro models of renal injury. 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion. Acute administration 21-aminosteroid but not alpha-tocopherol, was attended by suppression of ischemia reperfusion-induced renal lipid peroxidation and injury. However, 4 weeks of dietary enrichment of rats with alpha-tocopherol (1000 IU/kg) was effective in suppressing these ischemia reperfusion-induced changes. In cell culture system, concurrent presence of 21-aminosteroid but not alpha-tocopherol abrogated H2O2-induced renal epithelial lipid peroxidation and injury. However, alpha-tocopherol was completely effective when cells were incubated with it for 14 h. Further, only the cells incubated with vitamin E for 14 h-but not for 1 or 3 h-had a significant increase in vitamin E content, which suggests that a delay in prompt cellular up take of vitamin E may explain its lack of acute effects. Thus, unlike alpha-tocopherol, 21-aminosteroid appears readily and completely available for its chain-breaking antioxidant activity both in vitro and in vivo. 21-Aminosteroids may, therefore, offer a therapeutic advantage over alpha-tocopherols in acute injury settings.

The bioavailability of RRR-alpha-tocopherol from the oral administration of RRR-alpha-tocopherol itself and its acetate and succinate esters was determined in healthy human subjects. Venous blood samples were withdrawn periodically over a 51-h period following oral administration of a gelatin capsule containing an equimolar mixture of RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate. In a second study, subjects received a capsule containing an equimolar mixture of RRR-alpha-tocopheryl acetate and RRR-alpha-tocopheryl succinate. In Study 1, RRR-alpha-tocopherol was absorbed at similar rates from both the free phenol, and the acetate ester and maximum plasma levels occurred at 12 h in most subjects. The extent of absorption of RRR-alpha-tocopherol varied considerably between subjects in absolute terms, but the relative absorption from the two forms was remarkably consistent, and a ratio of 1.0 was found for parameters of relative bioavailability in plasma. The concentration of RRR-alpha-tocopherol from each form was maximal at approximately 27 h in red blood cells and, as seen with the plasma data, there was a large interindividual variability. In Study 2, there was no significant difference in the extent of absorption of RRR-alpha-tocopherol from the acetate ester and the succinate ester, although there was an apparently higher initial rate of absorption from the acetate ester.

We hypothesized that alterations in lung vitamin E levels would impact the development of acute oxidative lung injury. We found that dietary induced deficiency of vitamin E diminished lung tissue levels of vitamin E and increased lung leak following intratracheal administration of interleukin-1 (IL-1) to rats. Conversely, rats administered vitamin E directly to the lungs as an inhaled aerosol (0.3-3 microns particles) formed by supercritical fluid aerosolization (SFA) had increased lung tissue vitamin E levels and decreased IL-1 induced lung leak compared to control rats. Lung myeloperoxidase (MPO) activities, reflecting neutrophil concentrations, were increased in rats given IL-1 intratracheally compared to rats given saline intratracheally but were not different for control or vitamin E depleted rats. Lung MPO activities in rats given IL-1 intratracheally were slightly higher in SFA vitamin E treated rats than in control rats. Our results suggest that vitamin E levels affect susceptibility to IL-1 induced, neutrophil-dependent lung injury. We speculate that supercritical fluid aerosol (SFA) delivery of vitamin E can rapidly increase lung vitamin E levels and decrease acute oxidative lung injury.

Free radicals may cause part of the irreversible injury which occurs during myocardial infarction and reperfusion. In the present study MDL 73404, a hydrophilic, cardioselective, free radical scavenger analogue of alpha-tocopherol, was evaluated for its effects on infarct size as well as on indicators of reperfusion injury. A pentobarbitone-anaesthetised rat model of coronary artery ligation (60 min; followed by 8 days of reperfusion) was used. Intravenous infusion of MDL 73404 (3 mg/kg per h) began 10 min before occlusion until 30 min after the onset of reperfusion. MDL 73404 reduced (P < 0.02) the elevated serum levels of thiobarbituric acid reactive substances and plasma levels of creatine phosphokinase (P < 0.01). An increase in cardiac output and heart rate together with a decrease (P < 0.01) in infarct size was evident in rats that had received MDL 73404, 8 days previously. Isolated infarcted hearts obtained from rats after 8 days of reperfusion had greater (P < 0.01) + dP/dt max, -dP/dt max, left ventricular systolic pressure and coronary flow after MDL 73404 compared to saline-treated controls. Infusion of [14C]MDL 73404, during the time of occlusion resulted in a concentration of 14.5 +/- 2.2 mg eq/g in the non-ischaemic ventricular tissue and a concentration of 3.0 +/- 0.4 mg eq/g in the area at risk. After infusion for the 30 min of reperfusion, 6.4 +/- 0.2 mg eq/g was detected in the non-ischaemic ventricular tissue but only 3.1 +/- 0.5 mg eq/g in the area at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion.