Elsevier

Vitamins & Hormones

Volume 76, 2007, Pages 281-308
Vitamins & Hormones

α‐Tocopherol Stereoisomers

https://doi.org/10.1016/S0083-6729(07)76010-7Get rights and content

Vitamin E comprises a group of compounds possessing vitamin E activity. α‐Tocopherol is the compound demonstrating the highest vitamin E activity, which is available both in its natural form as RRR‐α‐tocopherol isolated from plant sources, but more common as synthetically manufactured all‐rac‐α‐tocopherol. Synthetic all‐rac‐α‐tocopherol consists of a racemic mixture of all eight possible stereoisomers. Assessing the correct biological activity in form of bioavailability and biopotency has been a great challenge during many years as it is difficult to measure clinical endpoints in larger animals than rats and poultry. Thus, the biological effects in focus are resorption of fetuses, testicular degeneration, muscle dystrophy, anemia, encephalomalacia, and in recent years the influence of vitamin E on the immune system are the most important clinical markers of interest. For humans and animals, only different biomarkers or surrogate markers of bioactivity have been measured. In studies with rats, a good consistency between the classical resorption–gestation test and the bioavailability of the individual stereoisomers in fluids and tissues has been shown. For humans and other animals, only different biomarkers or surrogate markers of bioactivity have been measured, and due to the lack of good biological markers for bioactivities, bioavailability is often used as one of the surrogate markers for bioactivities with those limitations this must give. Therefore, a relatively simple analytical method, which allows analysis of the individual stereoisomers of α‐tocopherol, is an important tool in order to quantify relative bioavailability of the individual stereoisomers. The analytical method presented here allows the quantification of total tocopherol content and composition by normal phase HPLC and subsequent separation of the stereoisomers of α‐tocopherol as methyl ethers by chiral HPLC. Using this method, the α‐tocopherol stereoisomers are separated into five peaks. The first peak consists of the four 2S isomers (SSS‐, SSR‐, SRR‐, SRS‐), the second peak consists of RSS‐, the third peak consists of RRS‐, the fourth peak consists of RRR‐, and the fifth peak consists of RSR‐α‐tocopherol. The discussion on the bioavailability of RRR‐ and all‐rac‐α‐tocopheryl acetate has primarily been based on human and animal studies using deuterium‐labeled forms, whereby a higher biopotency of 2:1 (of RRR: all‐rac) has been demonstrated, differing from the accepted biopotency ratio of 1.36:1. In agreement with previous studies, the 2S‐forms exert very little importance for the vitamin E activity due to their limited bioavailability. We find notable differences between animal species with regard to the biodiscrimination between the 2R‐forms. Especially, cows preferentially transfer RRR‐ α‐tocopherol into the milk and blood system. The distribution of the stereoisomer forms varies from tissue to tissue, and in some cases, higher levels of the synthetic 2R‐forms than of the RRR‐form are obtained, for example, for rats. However, the biodiscrimination of the stereoisomers forms is influenced by other factors such as age, dietary levels, and time after dosage. More focus should be given on the bioactivity of the individual 2R‐forms rather than just the comparison between RRR‐ and all‐rac‐α‐tocopheryl acetate.

Introduction

Vitamin E is the exception to the paradigm that natural and synthetic vitamins are equivalent because their molecular structures are identical. Natural α‐tocopherol (RRR‐α‐tocopherol) is a single stereoisomer. Plants and other oxygenic, photosynthetic organisms are the only organisms able to synthesize tocopherols (DellaPenna, 2005), and since this synthesis is facilitated by stereo‐specific enzymes, the resulting tocopherols always posses the same stereochemical structure, namely the RRR‐structure (Fig. 1).

Synthetic α‐tocopherol (all‐rac‐α‐tocopherol) is produced commercially by a chemical reaction of tetramethylhydroquinone (TMHQ) with racemic isophytol (VERIS Research summary, 1999). Racemic isophytol is synthesized from isoprenoid units and since isophytol has three chiral centres the resulting α‐tocopherol has 23 possible conformations and thus yields a racemic mixture of all eight possible stereoisomers.

Section snippets

Presence in Food/Feed Ingredients

Commercial vitamin E supplements can be classified into several distinct categories: fully synthetic vitamin E (all‐rac‐α‐tocopherol), the most inexpensive, most commonly sold supplement forms usually as the acetate ester.

Most natural vitamin E is derived during refining of vegetable oils, mainly soybean oil, sunflower oil, and canola/rapeseed oil.

The natural sources of vitamin E can be divided into truly natural RRR‐ α‐tocopherol, where RRR‐α‐tocopherol is extracted and isolated directly from

Analytical Methods for Separation of α‐Tocopherol Stereoisomers

Analysis of the individual stereoisomers of α‐tocopherol is an important tool in order to quantify relative bioavailability of the individual stereoisomers (Jensen et al., 2006). Separations of the eight stereoisomers of α‐tocopherol are a great challenge and until now no single method allow the separation of all eight stereoisomers in one single chromatographic run (Nelis et al., 2000). The use of deuterium labeled α‐tocopherol in conjunction with GC‐MS (Ingold et al., 1987) or HPLC‐MS (

Bioavailability and Secretion into Milk

As discussed above, bioavailability is an important part of the term bioactivity and is quantitative measurable in blood, tissue, and excreta. In addition, the lack of good biological markers for bioactivities, bioavailability is often used as one of the surrogate markers for bioactivities with those limitations this must give (Blatt 2004, Jensen 2006). Therefore, results of α‐tocopherol stereoisomers in different animal species and humans are presented with the focus on bioavailability rather

α‐Tocopherol‐Binding Protein (α‐TTP)

In contrast to the relatively well‐investigated binding proteins for vitamins A and D, proteins that bind and transport vitamin E have only been identified in the past decade and many of their specific biological roles remain elusive. The term “tocopherol‐associated proteins” has been used to distinguish a molecularly defined family of proteins that are capable of binding α‐tocopherol (Zimmer et al., 2000) with a higher affinity than other tocopherols (Yamauchi et al., 2001) and are also

Conclusions

The discussion on the bioavailability of RRR‐ and all‐rac‐α‐tocopheryl acetate has primarily been based on human and animal studies using deuterium‐labeled forms, whereby a higher biopotency of 2:1 (of RRR: all‐rac) has been demonstrated, differing from the accepted biopotency ratio of 1.36:1. However, the quantitative separation of the individual stereoisomers of the 2R‐forms allow us to get a more detailed picture of the bioavailability of natural and synthetic vitamin E forms.

In agreement

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