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Serious adverse health effects have been reported with the use of vaping products, including neurologic disorders and e-cigarette or vaping product use-associated lung injury (EVALI). Vitamin E acetate, likely added as a diluent to cannabis-containing products, was linked to EVALI. Literature searches were performed on vitamin E and vitamin E acetate-associated neurotoxicity. Blood brain barrier (BBB) penetration potential of vitamin E and vitamin E acetate were evaluated using cheminformatic techniques. Review of the literature showed that the neurotoxic potential of inhalation exposures to these compounds in humans is unknown. Physico-chemical properties demonstrate these compounds are lipophilic, and molecular weights indicate vitamin E and vitamin E acetate have the potential for BBB permeability. Computational models also predict both compounds may cross the BBB via passive diffusion. Based on literature search, no experimental nonclinical studies and clinical information on the neurotoxic potential of vitamin E via inhalation. Neurotoxic effects from pyrolysis by-product, phenyl acetate, structurally analogous to vitamin E acetate, suggests vitamin E acetate has potential for central nervous system (CNS) impairment. Cheminformatic model predictions provide a theoretical basis for potential CNS permeability of these inhaled dietary ingredients suggesting prioritization to evaluate for potential hazard to the CNS., (Copyright © 2021. Published by Elsevier Inc.)

Hypothesis: Glaucoma is effectively treated by prostaglandin analogs. Low corneal bioavailability (<5%) of daily-instilled prostaglandin drops complemented by frequent application results in low patient compliance (<50%). One alternative route is ocular delivery via commercial hydrogel contact lens. Commercial lenses, however, release prostaglandins rapidly in a few hours owing to their small molecular size, resulting in toxic side-effects. Here, the feasibility of sustained prostaglandin, namely bimatoprost and latanoprost delivery by vitamin-E integrated polymeric hydrogels is explored. Inclusion of these barriers is expected to augment transport resistance and influence delivery rates., Experiments: Lens immersion in vitamin-E concentrated ethanol is done to enable formation of nano-barrier depots., Findings: Pilot in vitro studies indicate that ACUVUE® OASYS® and ACUVUE® TruEye™ lenses loaded with ∼0.2 g of vitamin-E/g of hydrogel effectively prolong bimatoprost dynamics by 10-40-fold, delivering therapeutic dosages for >10 days. Incorporation of vitamin-E into the lenses retains visible light transmission and other properties. Further, vitamin-E integration does not influence latanoprost transport. An in vivo model involving coupled mass transport in the lens and post-lens tear film (POLTF) domains predicts >50% corneal bioavailability of bimatoprost delivered via modified lenses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypothesis: Vitamin E has interesting biological functions for the cosmetic and pharmaceutical industry because it can act as a fat-soluble antioxidant, as well as peroxyl radical scavenger. However, this vitamin is formed by a group of compounds that include tocopherols (γ-tocopherols, α-tocopherol) characterized by their poor solubility in water, what implies the need of using stabilizing agents such as biosurfactants or minerals, in order to make them soluble or stable in formulations composed by water and oil., Experiments: In this work, it has been evaluated the synergic effect between a mining silicate mineral (mica) and a biosurfactant extract, obtained from corn steep liquor, to stabilize emulsions containing water and a non-aqueous soluble antioxidant consisting of Vitamin E, through the use of a triangular design., Findings: The results show that the presence of biosurfactant extract improves the emulsion volume up to 70% after 22 days, for an emulsion composed of Vitamin E and biosurfactant, whereas the mica component was able to increase the emulsion stability until values of 80% after 30 days of experiment, for those emulsions containing 10% of mica. Hence, both novel ingredients produce a synergistic effect on the Pickering emulsions carried out in the study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oxaliplatin is a promising antitumor drug, but its effectiveness is limited by its side effects in vivo. In this study, we introduced an Oxaliplatin prodrug (Oxa(IV)) self-controlled release strategy, in which Oxa(IV) is encapsulated by TPGS functionalized mesoporous silica nanoparticles (MSNs), and its release is controlled by biological stimuli, such as acidic environments in tumor tissue and high concentrations of reductants in cancer cells. Despite the lack of auxiliary "gatekeepers" to MSNs, this simplified model of Oxa(IV)-MSNs-TPGS could fine-tune the movements of the drug release. Furthermore, we utilized a prodrug approach to avoid the side effects of Oxaliplatin, and we used TPGS groups to reduce multidrug resistance (MDR). Finally, the toxicity of Oxa(IV)-MSNs-TPGS to a human lung adenocarcinoma cell line (A549) in vitro was significantly lower than that of Oxaliplatin. This model demonstrates the considerable potential of a simple self-controlled release system with multiple functions., (Copyright © 2018. Published by Elsevier Inc.)

Fast dissolving nanofiber (NF) composed of poly(vinyl alcohol) (PVA) and d-α-tocopheryl polyethylene glycol succinate (TPGS) was developed for locoregional delivery of phloretin to oral cancers. PVA/TPGS/phloretin NF with 321nm mean diameter and >90% drug entrapment efficiency was fabricated by an electrospinning method. Transformation of drug from crystalline to amorphous state was identified by solid-state studies. NF structure was changed to nanoparticles after its dispersing in the aqueous medium. PVA/TPGS/phloretin NF exhibited fast wetting property and smaller hydrodynamic size of dispersion, compared with PVA/phloretin NF. The amphiphilic property of TPGS also contributed to the improved drug release from PVA/TPGS/phloretin NF. The anticancer activities of phloretin, via the inhibition of glucose uptake into the cancer cells, in NFs were assessed in YD-9 cells (oral squamous cell carcinoma from buccal cheek). The antiproliferation efficacy of PVA/TPGS/phloretin NF was significantly higher than that of phloretin solution and PVA/phloretin NF (p<0.05). Higher apoptotic events were also observed in PVA/TPGS/phloretin NF group rather than phloretin solution and PVA/phloretin NF groups (p<0.05). All these results support that PVA/TPGS/phloretin NF can be a promising fast dissolving formulation for the treatment of oral cancers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Novel graphene oxide (G)-and d-α-Tocopheryl polyethylene glycol 1000 succinate (T)-doped polyethersulfone (P) hollow fiber membranes (GTP HFMs) were efficiently prepared. GTP HFMs were found to be a desirable biocompatible substrate for attachment and proliferation of human embryonic kidney-293 (HEK-293) cells. Significantly high porosity (94.58±1.1%), low contact angle (61.1±2.5°), low hemolysis (0.58% in batch mode and 0.64% in continuous mode), low terminal complement complex activation (SC5b-9 marker level ∼6.73ng/mL), prolonged blood coagulation time, and low platelet adhesion were measured for GTP HFMs indicating the superior suitability of GTP HFMs for blood-contact applications. Further, SEM and confocal laser microscopy studies showed the significantly high HEK-293 cells attachment and proliferation on GTP HFMs which was corroborated by results of glucose consumption analysis and MTT cell proliferation assay. High ultrafiltration coefficient (110±3mL/m 2 /h/mmHg), and albumin solute rejection (94.87±0.5%) were also measured for GTP HFMs. Thus, these results clearly indicated that the synergistic effect of additives improved the biocompatibility and ultrafiltration in GTP HFMs. The developed GTP HFMs can potentially be used for simultaneous/sequential cells attachment and proliferation, and ultrafiltration applications such as the bioartificial kidney., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study has been actually performed with the aim to develop vitamin E derived vesicles individually from a surface active ionic liquid (1-Hexadecyl-3-Methylimidazolium chloride ([C 16 mim]Cl)) and a common cationic amphiphile (benzyldimethylhexadecylammonium chloride (BHDC)) and also to investigate their consequent breakdown in presence of bile salt molecule. From this study, it is revealed that the rotational motion of coumarin 153 (C153) molecule is hindered as the vitamin E content is increased in the individual micellar solution of [C 16 mim]Cl and BHDC. The extent of enhancement in rotational relaxation time is more pronounced in case of [C 16 mim]Cl-vitamin E solutions than in the BHDC-vitamin E vesicular aggregates which confirms the greater rigidity of the former vesicular system than the later one. Moreover, the effect of bile salt in the vitamin E forming vesicular assemblies have also been unravelled. It is found that the large area occupancy by the steroidal backbone of the bile salt plays a crucial role towards the enlargement of the average surfactant head group area. This results in disintegration of the vesicles composed of vitamin E and consequently, vesicles are transformed into mixed micellar aggregates. From the anisotropy measurement it is found that the rotational motion of C153 is more hindered in the [C 16 mim]Cl/BHDC-NaCh mixed micelles compared to that inside the individual vesicles. The fluorescence correlation spectroscopic (FCS) study also confirms that the mixed micelles have a more compact structure than that of the [C 16 mim]Cl-vitamin E and BHDC-vitamin E vesicles. Altogether, the micelle to vesicle transition involving any vitamin and their disruption by bile salt would be an interesting investigation both from the view point of basic colloidal chemistry and towards the generation of new drug delivery vehicle due to their unique microenvironment. Therefore, in future, these systems can be utilised as vehicle for the transport and as well as delivery of drugs and as probable reactor in nanomaterial synthesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Nanosuspension is one of the most promising strategies to improve the oral bioavailability of insoluble drugs. The existing techniques applied to produce nanosuspensions are classified as "bottom-up" or "top-down" methods, or a combination of both. Curcumin (CUR), a Biopharmaceutics Classification System (BCS) class IV substance, is a promising drug candidate in view of its good bioactivity, but its use is limited due to its poor solubility and permeability. In the present study, CUR nanosuspensions were developed to enhance CUR oral bioavailability using a cost-effective method different from conventional techniques., Results: The physicochemical properties of CUR nanosuspensions were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The crystalline state of CUR in different nanosuspensions analyzed using differential scanning calorimeter (DSC) and X-ray diffraction analysis (PXRD) confirmed its amorphous state. In vitro dissolution degree of the prepared CUR nanosuspensions using TPGS or Brij78 as stabilizer was greatly increased. Pharmacokinetic studies demonstrated that the oral bioavailability of CUR was increased 3.18 and 3.7 times after administration of CUR/TPGS nanosuspensions or CUR/Brij78 nanosuspensions, when compared with the administration of CUR suspension., Conclusions: CUR nanosuspensions produced by our cost-effective method could improve its oral bioavailability. In addition, the low-cost and time-saving method reported here is highly suitable for a fast and inexpensive preparation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Alpha-tocopherol (vitamin E) is a plant-derived antioxidant that is essential for human health. Studies with humans and with animal models of vitamin E deficiency established the critical roles of the vitamin in protecting the central nervous system, and especially the cerebellum, from oxidative damage and motor coordination deficits. We review here the established roles of vitamin E in protecting cerebellar functions, as well as emerging data demonstrating the critical roles of alpha-tocopherol in preserving learning, memory and emotive responses. We also discuss the importance of vitamin E adequacy in seemingly unrelated neurological disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Oil-in-water nanoemulsions are finding increasing use as delivery systems to encapsulate lipophilic bioactive components in functional food, personal care, and pharmaceutical products. We investigated the influence of a water-soluble cosolvent (glycerol) on the formation, stability, and properties of vitamin E acetate-loaded nanoemulsions (VE-NEs) prepared by spontaneous emulsification. VE-NEs were formed by titration of a mixture of vitamin E acetate, carrier oil (MCT) and non-ionic surfactant (Tween 80) into an aqueous glycerol solution with continuous mixing. Cosolvent concentration had an appreciable effect on the particle size produced, with the smallest mean droplet diameters (d<50 nm) being formed at 40 and 50 wt% glycerol. Nanoemulsions (d<100 nm) containing 10% vitamin E acetate could be produced at relatively low surfactant concentrations (5%) using these high glycerol levels. The turbidity of the NEs decreased at high glycerol concentrations due to the reduction in droplet size and refractive index contrast. The long-term stability of the VE-NEs was strongly influenced by glycerol concentration and storage temperature. VE-NEs containing 40% glycerol were relatively stable to droplet growth when stored at 5 and 20°C, but a rapid increase in droplet size and turbidity occurred during storage at 37°C. Temperature scanning experiments (20-80-20°C) indicated that a steep and irreversible increase in turbidity occurred during heating, which was around 70°C in the absence of glycerol and 60°C in the presence of 40% glycerol. Droplet instability was attributed to an increase in the rate of Ostwald ripening and/or coalescence as the temperature was increased, associated with dehydration of the non-ionic surfactant head-group leading to a reduction in phase inversion temperature. Dilution (100×) of VE-NEs containing glycerol with water considerably improved their stability to droplet growth, especially at high storage temperatures. This study provides important information about the effect of glycerol on the formation, stability and physical properties of VE-enriched NEs suitable for food, personal care, and pharmaceutical products., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Vitamin E is an essential micronutrient for humans and animals due to its antioxidant and non-antioxidant biological activities. In this study, an emulsion titration assay was used to quantify the kinetics and extent of vitamin E and vitamin E acetate solubilization in model mixed micelles. The composition of the mixed micelles was designed to mimic those produced during digestion of lipids in the human small intestine: bile salts, phospholipids, and free fatty acids. Initially, the optimum conditions required to form model mixed micelles were established. The solubilization capacities of vitamin E and vitamin E acetate in the mixed micelles were then compared. The solubilization capacity of the mixed micelles for vitamin E was higher than that for vitamin E acetate, which was attributed to differences in the ability of the vitamin molecules to be incorporated into the micelle structure. The solubilization capacities also depended on the composition of the mixed micelles: micelle solubilization of vitamin E was increased by the presence of phospholipid (DOPC), but did not depend strongly on the presence of free fatty acid (octanoic acid or linoleic acid). Overall, this research has important implications for understanding the digestion, absorption, and transportation of vitamin E in the human gastrointestinal tract and for designing suitable delivery systems to increase its bioaccessibility., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Colloidal delivery systems are needed to incorporate oil-soluble vitamins into aqueous-based foods and beverage products. In this study, we encapsulated vitamin E acetate into oil-in-water nanoemulsions produced using either a low-energy method (Emulsion Phase Inversion, EPI) or a high energy method (microfluidization). Oil-in-water nanoemulsions (d<200 nm) could be produced using both low- and high-energy methods from a non-ionic surfactant (Tween 80) and medium chain triglycerides (MCTs). The influence of surfactant-to-oil ratio (SOR) on lipid digestion and vitamin bioaccessibility of EPI nanoemulsions was determined using a gastrointestinal tract (GIT) model that simulated the mouth, stomach, and small intestine. There were increases in the size and negative charge of the oil droplets after passage through the GIT, which was attributed to droplet coalescence and changes in interfacial composition. The rate and extent of lipid digestion decreased with increasing surfactant concentration, but the bioaccessibility of vitamin E acetate was high in all of the samples (>95%). No appreciable influence of the preparation method (low-energy versus high-energy) on lipid digestion and vitamin bioaccessibility was observed. The major advantage of the EPI method for forming nanoemulsions is that no expensive equipment is required, but relatively high surfactant concentrations are needed compared to microfluidization., (Copyright © 2013 Elsevier Inc. All rights reserved.)

There is considerable interest in using nanoemulsions as delivery systems for lipophilic bioactive ingredients, such as oil-soluble vitamins. Nanoemulsions can be fabricated using either high-energy or low-energy methods, but the latter offer advantages in terms of low cost, higher energy efficiency, and simplicity of implementation. In this study, the emulsion phase inversion (EPI) method was used to produce food-grade nanoemulsions enriched with vitamin E acetate. The EPI method simply involves titrating water into a mixture containing oil and surfactant, which initially leads to the formation of a water-in-oil emulsion that then inverts into an oil-in-water emulsion. Oil composition, surfactant type, and surfactant-to-oil ratio (SOR) were all found to influence the particle size distribution of the systems produced. Nanoemulsions with a mean particle diameter of 40 nm could be produced at a final system composition of 2 wt% MCT, 8 wt%vitamin E acetate, and 20 wt% Tween 80. The EPI method was shown to be unsuitable for producing nanoemulsions from label-friendly surfactants, such as Quillaja saponin, whey protein, casein, and sucrose monoesters. The EPI method was more effective at producing nanoemulsions at high SOR than microfluidization, but much less effective at low SOR., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Oil-in-water nanoemulsions are finding increasing use as delivery systems to encapsulate lipophilic bioactive components in functional food, personal care, and pharmaceutical products. We have investigated the influence of system composition and preparation conditions on the particle size of vitamin E acetate (VE)-loaded nanoemulsions prepared by spontaneous emulsification. This method relies on the formation of very fine oil droplets when an oil/surfactant mixture is added to water. The oil-to-emulsion ratio content was kept constant (10 wt.%) while the surfactant-to-emulsion ratio (%SER) was varied (from 2.5 to 10 wt.%). Oil phase composition (vitamin E to medium chain triglyceride ratio) had a major effect on particle size, with the smallest droplets being formed at 8 wt.% VE and 2 wt.% MCT. Surfactant type also had an appreciable impact on particle size, with TWEEN® 80 giving the smallest droplets from a group of food-grade non-ionic surfactants (TWEEN® 20, 40, 60, 80, and 85). Surfactant-to-emulsion ratio also had to be optimized to produce fine droplets, with the smallest droplets being formed at SER=10 wt.%. Particle size could also be reduced by increasing the temperature and stirring speed used when the oil/surfactant mixture was added to water. By optimizing system composition and homogenization conditions we were able to form VE-loaded nanoemulsions with small mean droplet diameters (d<50 nm) and low polydispersity indexes (PDI<0.13). The spontaneous emulsification method therefore has great potential for forming nanoemulsion-based delivery systems for food, personal care, and pharmaceutical applications., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This study has investigated the micellar properties of the d-alpha-tocopheryl polyethylene glycol succinate esters 400 (TPGS 400) and 1000 (TPGS 1000) in terms of critical micellar concentration (CMC), apparent aggregation number (N(agg)), microviscosity and micropolarity using steady state fluorescence techniques and fluorescent probes. In addition it has compared these properties against those of a Triton-type surfactant such as Triton X-100. The CMC values for TPGS 400, TPGS 1000 and Triton X-100 were 1.51 mM, 0.02 mM and 0.19 mM, respectively. The N(agg) values for TPGS 1000 and Triton X-100 were, respectively, 10 and 63. Due to the cloudiness of its aqueous solutions, no attempt was made to evaluate the microviscosity and to obtain the N(agg) for TPGS 400. Microviscosity at the probe site for all three surfactants was high and rather similar in spite of differences among their CMC values. The ability of TPGS 400 and TPGS 1000 to provide an environment for the fluorescence quenching of micelle-solubilized pyrene appears to be associated with their hydrophobic aromatic domains. To our knowledge the present study is the first attempt at systematically studying the micellar properties of the two most widely used TPGS compounds and of comparing these properties against each other and against those of an established nonionic surfactant.

Mast cells play an important role in the immune system by interacting with B and T cells and by releasing several mediators involved in activating other cells. Hyperreactivity of mast cells and their uncontrolled accumulation in tissues lead to increased release of inflammatory mediators contributing to the pathogenesis of several diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and allergic disorders such as asthma and allergic rhinitis. Interference with mast cell proliferation, survival, degranulation, and migration by synthetic or natural compounds may represent a preventive strategy for the management of these diseases. Natural vitamin E covers a group of eight analogues-the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols, but only alpha-tocopherol is efficiently retained by the liver and distributed to peripheral tissues. Mast cells preferentially locate in the proximity of tissues that interface with the external environment (the epithelial surface of the skin, the gastrointestinal mucosa, and the respiratory system), what may render them accessible to treatments with inefficiently retained natural vitamin E analogues and synthetic derivatives. In addition to scavenging free radicals, the natural vitamin E analogues differently modulate signal transduction and gene expression in several cell lines; in mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration. In this chapter, the possibility that vitamin E can prevent diseases with mast cells involvement by modulating signal transduction and gene expression is evaluated.

Tocopherols and tocotrienols, parent congeners in the vitamin E family, function as phenolic antioxidants. However, there has been little interest in their quinone electrophiles formed as a consequence of oxidation reactions, even though unique biological properties were suggested by early studies conducted immediately after the discovery of vitamin E. Oxidation of tocopherols and tocotrienols produces para- and ortho-quinones, and quinone methides, while oxidation of their carboxyethyl hydroxychroman derivatives produces quinone lactones. These quinone electrophiles are grouped in two subclasses, the nonarylating fully methylated alpha-family and the arylating desmethyl beta-, gamma-, and delta-family. Arylating quinone electrophiles form Michael adducts with thiol nucleophiles, provided by cysteinyl proteins or peptides, which can be identified and quantified by tetramethylammonium hydroxide thermochemolysis. They have striking biological properties which differ significantly from their nonarylating congeners. They are highly cytotoxic, inducing characteristic apoptotic changes in cultured cells. Cytotoxicity is intimately associated with the induction of endoplasmic reticulum stress and a consequent unfolded protein response involving the pancreatic ER kinase (PERK) signaling pathway that commits overstressed cells to apoptosis. The step-function difference between arylating and nonarylating tocopherol quinones is conceivably the basis for distinct biological properties of parent tocopherols, including the epigenetic modification of a histone thiol, the ceramide pathway, natriuresis, and the activity of COX-2, NF-kappaB, PPARgamma, and cyclin. The role of alpha-tocopherol in the origin and evolution of the western hominin diet, the so-called "Mediterranean" diet, and the prominence of alpha-tocopherol in colostrum, mother's milk, and infant nutrition are considered. Finally, the discordance introduced into the diet by arylating tocopherol quinone precursors through the wide use of vegetable oils in deep-frying is recognized.

Vitamin E is a generic term that refers to a family of compounds that is further divided into two subgroups called tocopherols and tocotrienols. All natural forms of tocopherols and tocotrienols are potent antioxidants that regulate peroxidation reactions and controls free radical production within the body. However, it is now firmly established that many of the biological actions mediated by individual vitamin E isoforms are not dependent on their antioxidant activity. Furthermore, synthetic ether derivatives of vitamin E that no longer possess antioxidant activity also display a wide range of biological activities. One of the most intriguing therapeutic applications for natural vitamin E and vitamin E derivatives currently being investigated is their use as anticancer agents. Specific forms of vitamin E display potent apoptotic activity against a wide range of cancer cell types, while having little or no effect on normal cell function or viability. Experimental studies have also determined that the intracellular mechanisms mediating the apoptotic effects of specific vitamin E compounds display great diversity in different types of caner cells and has been found to restore multidrug resistant tumor cells sensitivity to chemotherapeutic agents. These findings strongly suggest that some natural and synthetic analogues of vitamin E can be used effectively as anticancer therapy either alone or in combination to enhance the therapeutic efficacy and reduce toxicity of other anticancer agents.

Perhaps not surprisingly, vitamin E which has been touted to be potentially beneficial for a variety of disorders, including cancer, heart disease, and even Alzheimer's disorder, based on its function as an antioxidant has failed to withstand the scrutiny of recent, double-blinded, placebo-controlled clinical trials, including failure to provide science-based support for vitamin E as a potent anticancer agent. Although less studied, vitamin E forms other than RRR-alpha-tocopherol or synthetic all-rac-alpha-tocopherol show promise as anticancer agents in preclinical studies. This chapter will (1) review basic information about natural and synthetic vitamin E compounds as well as vitamin E analogues, (2) summarize the current status of human intervention trials, (3) review data from preclinical cell culture and animal model studies of vitamin E compounds and novel vitamin E-based analogues in regards to future potential for cancer treatment, and (4) summarize some of the insights that have been gained into the anticancer mechanisms of action of vitamin E-based compounds which are providing interesting insights into their potent proapoptotic effects, which include restoration of apoptotic signaling pathways and blockage of prosurvival signaling events.

Human alpha-tocopherol transfer protein (alpha-TTP) plays a central role in vitamin E homeostasis: mutations in the protein are a cause of a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED). Despite normal dietary intake of vitamin E, affected individuals suffer from a relative deficiency of this essential lipophilic antioxidant. Disease-associated mutations in alpha-TTP impair its ability to prevent the degradation and excretion of alpha-T. Recently, we and others solved the crystal structures of alpha-TTP bound to a molecule of (2R, 4'R, 8'R)-alpha-T, which has led to a better understanding of the molecular basis of its biochemical activity. Surprisingly, the ligand was found buried in the hydrophobic core of the protein, completely sequestered from the aqueous milieu. In this chapter, the implications of the structure of alpha-TTP bound to its ligand regarding the mechanism of alpha-T retention are discussed. A comparison to a crystal structure of the apo form of alpha-TTP indicates a possible specific conformational change that allows the entry and exit of the ligand. The effect of known disease-associated point mutations is examined in light of the crystal structure as well as recent biochemical studies. Despite the knowledge gained from these studies, the exact molecular mechanism by which alpha-TTP retains alpha-T remains enigmatic and will likely prove a fruitful area for future research.

Vitamin E compounds are biologically essential fat-soluble antioxidants derived from 6-chromanol. This chapter covers the representative literature on the preparation of various stereoisomeric forms and homologues of tocopherols and tocotrienols, and of respective starting materials and intermediates. The industrially most relevant (all-rac)-alpha-tocopherol is generally built up by coupling of arenes with aliphatic precursors. For the synthesis of optically active vitamin E components, various strategies are compiled. In approaches to chiral chroman and side chain building blocks, a broad variety of methods from the repertoire of asymmetric synthesis were applied, that is optical resolution and use of chiral pool starting materials and chiral auxiliaries in stoichiometric as well as catalytic amounts, including catalysis by metal complexes, microorganisms, and enzymes. Most efforts were directed to (2R,4'R,8'R)-alpha-tocopherol due to its prominent biological activity. Syntheses of different stereoisomers (and mixtures thereof) and (beta-, gamma-, delta-) homologues of tocopherols and tocotrienols, as well as methods for their interconversion, are also described.

Natural vitamin E includes eight chemically distinct molecules: alpha-, beta-, gamma-, and delta-tocopherols and alpha-, beta-, gamma-, and delta-tocotrienols. More than 95% of all studies on vitamin E are directed toward the specific study of alpha-tocopherol. The other forms of natural vitamin E remain poorly understood. The abundance of alpha-tocopherol in the human body and the comparable efficiency of all vitamin E molecules as antioxidants led biologists to neglect the non-tocopherol vitamin E molecules as topics for basic and clinical research. Recent developments warrant a serious reconsideration of this conventional wisdom. The tocotrienol subfamily of natural vitamin E possesses powerful neuroprotective, anticancer, and cholesterol-lowering properties that are often not exhibited by tocopherols. Current developments in vitamin E research clearly indicate that members of the vitamin E family are not redundant with respect to their biological functions. alpha-Tocotrienol, gamma-tocopherol, and delta-tocotrienol have emerged as vitamin E molecules with functions in health and disease that are clearly distinct from that of alpha-tocopherol. At nanomolar concentration, alpha-tocotrienol, not alpha-tocopherol, prevents neurodegeneration. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. Recently, it has been suggested that the safe dose of various tocotrienols for human consumption is 200-1000/day. A rapidly expanding body of evidence supports that members of the vitamin E family are functionally unique. In recognition of this fact, title claims in publications should be limited to the specific form of vitamin E studied. For example, evidence for toxicity of a specific form of tocopherol in excess may not be used to conclude that high-dosage "vitamin E" supplementation may increase all-cause mortality. Such conclusion incorrectly implies that tocotrienols are toxic as well under conditions where tocotrienols were not even considered. The current state of knowledge warrants strategic investment into the lesser known forms of vitamin E. This will enable prudent selection of the appropriate vitamin E molecule for studies addressing a specific health need.

The presence and activity of vitamin E in the organism as well as its role in disease prevention depend, as for any other microconstituent in food, on a number of factors related to its release from the food matrix, extent of absorption, and metabolic fate. Biotransformation can be defined as the sum of processes in which vitamin E compounds are altered by the body. It involves the bioactivation and production of reactive metabolites, a series of processes generally referred to as "vitamin E metabolism." This chapter will provide an overview of the known and less known steps of vitamin E biotransformation in humans. Due to recent advances related to the biological activities and metabolic processing of vitamin E compounds, particular attention will be given to the description of the formation, identification, and functions of vitamin E metabolites. The hypothesis of a transformation-dependent bioactivation of vitamin E represents an intriguing and emerging aspect of research that deserves further investigation.

To understand how vitamin E fulfills its functions in membranes and lipoproteins, it is necessary to know how it associates with the lipid components of these structures and the effects its presence has on their structure and stability. Studies of model membrane systems containing vitamin E have proved to be an informative approach to address these questions. A review of the way vitamin E interacts with phospholipid bilayers, how it distributes within the structure, its motional diffusion characteristics, and orientation has been undertaken. The effect of vitamin E on membrane stability and permeability has been described. The tendency of vitamin E to form complexes with certain phospholipids is examined as is the way modulation of protein functions takes place. Finally, recent evidence relevant to the putative role of vitamin E in protecting membranes from free radical attack and the consequences of lipid oxidation in lipoproteins and membranes is examined.

The term vitamin E is used to describe eight lipophilic, naturally occurring compounds that include four tocopherols and four tocotrienols designated as alpha-, beta-, gamma-, and delta-. The most well-known function of vitamin E is that of a chain-breaking antioxidant that prevents the cyclic propagation of lipid peroxidation. Despite its antioxidant function, dietary vitamin E requirements in humans are limited only to alpha-tocopherol because the other forms of vitamin E are poorly recognized by the hepatic alpha-tocopherol transfer protein (TTP), and they are not converted to alpha-tocopherol by humans. In attempts to gain a better understanding of vitamin E's health benefits, the molecular regulatory mechanisms of vitamin E have received increased attention. Examples of these mechanisms include: (1) the role of the hepatic alpha-TTP in preferentially secreting alpha-tocopherol into the plasma, (2) phase I and phase II metabolism of vitamin E and the potential impact for drug-vitamin E interactions, and (3) the regulation of biliary excretion of vitamin E by ATP-binding cassette protein(s). It is expected that the continued studies of these regulatory pathways will provide new insights into vitamin E function from which additional human health benefits will evolve.