Early Discoveries and Understanding of Vitamin E

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This entry is adapted from the peer-reviewed paper 10.3390/agriculture13081526

Vitamin E, consisting of four tocopherols and four tocotrienols, with α-tocopherol as the most biologically active form, has a significant history in scientific research. It was first identified in the 1920s for its role in preventing neonatal mortality in rats. Over time, its chemical structure was elucidated, and its importance in the immune system, skin health, anti-inflammatory properties, and hormonal balance was revealed.

vitamin E history animal nutrition production activity

1. Introduction

Vitamin E plays a critical role in animal nutrition by serving as a potent lipid-soluble antioxidant as well as contributing to anti-inflammation, immune function, and gene expression regulation. As an antioxidant, it protects cell membranes and other lipid-containing structures from oxidative damage caused by free radicals ^[1]. Thereby, vitamin E is the major chain-breaking antioxidant inhibiting lipid peroxidation, a physiological function that is not provided by other dietary or endogenous antioxidants ^[2]. This makes it crucial for preserving cell integrity, particularly in tissues that are susceptible to oxidative stress, such as the liver, lungs, and muscles ^[3].

The significance of vitamin E in animal nutrition cannot be overestimated, as it has been recognized as an indispensable micronutrient for optimal health, growth, and development in livestock ^[4]. Throughout the past century, numerous studies and advancements have been made in understanding the crucial role vitamin E plays in livestock production. A deficiency of vitamin E can impair immune responses and increase the susceptibility of animals to infectious diseases. Furthermore, hypovitaminosis E has been linked to reduced reproductive performance in animals, including decreased fertility rates and increased embryonic mortality ^[5].

For livestock, optimizing vitamin E status is particularly important for animal health and production. In dairy cattle, supplementation with vitamin E has been demonstrated to enhance milk yield and lower the occurrence of mastitis ^[6]^[7]^[8]. In poultry, it has been associated with better growth rates, egg production, and hatchability ^[9]^[10]. Likewise, in swine, vitamin E supplementation has been proven to enhance meat quality, reduce stress, and increase growth rates ^[11]^[12]^[13]^[14].

To ensure that animals receive adequate amounts of vitamin E, it is common practice to add this micronutrient as synthetic dl-α-tocopheryl acetate to animal feeds. However, determining the optimal level of vitamin E supplementation can be challenging, as the requirements for this nutrient can vary depending on the species, age, and health status of the animal, as well as other factors ^[15].

2. Early Discoveries and Understanding of Vitamin E

Last year marked the 100th anniversary of the discovery of vitamin E in 1922, which was made by Herbert McLean Evans, an embryologist and endocrinologist, and his co-worker Kathrine Julia Scott Bishop, a medical physician and trained anatomist, while working at Berkeley University in California/USA. The two scientists observed that female rats fed on a purified diet had good growth and development and stayed healthy, but could not reproduce, as the embryos died and were resorbed after some 10 days of gravidity. However, when the semi-synthetic diet was supplemented with fresh green leaves of lettuce or dried alfalfa meal, a sudden restoration of fertility in previously sterile rats could be observed ^[16]. At first, the researchers believed that vitamin C, which had already been discovered at that time and was known not to be essential for growth, was necessary for pregnancy. However, they quickly realized that only the fat-soluble components of the leaves had led to a good result. After testing the hydro- and lipophilic extracts of various wheat by-products from a nearby flour mill, the two scientists discovered a new fat-soluble dietary lipophilic compound that causes sterility in rats when lacking in the feed ^[16].

The unknown dietary substance was initially called factor X, but it was soon renamed vitamin E by Barnett Sure ^[17] and Herbert Evans ^[18]. Evans and Bishop later demonstrated that male rats with diets lacking the new fat-soluble vitamin E also experienced sterility ^[18], leading to the vitamin’s subsequent designation as the “anti-sterility vitamin”. In the same year, Evans and his co-worker George Burr prepared a potent concentrate of vitamin E by saponification of wheat germ oil, which proved to possess high biological potency ^[19]. Wheat germ oil-based concentrates were used in many further experiments on vitamin E and served as a source for the development of the first commercial vitamin E products in the 1930s.

In 1936, Evans and his co-workers isolated two compounds with vitamin E activity from wheat germ oil, for which they proposed the names α-tocopherol and ß-tocopherol ^[20]. Soon afterward, a third active factor, γ-tocopherol, was found in cottonseed oil by Evans’ working group ^[21], and in 1947, a fourth tocopherol, named δ-tocopherol, was isolated from soybean oil ^[22]. In 1936, Evans and his co-workers suggested the nomenclature α-tocopherol, the childbirth-bearing alcohol, for the new compound based on the Greek terms “tokos” for childbirth, “phero” for to bear, and “-ol” indicating an alcohol. This designation was proposed by George Miller Calhoun, a classical philologist and professor of Greek at the University of California ^[20].

Therefore, the discovery of vitamin E by Evans and Bishop in 1922 ^[16] resulted in the identification and isolation of several tocopherols. Their dedication and contributions to the study of vitamin E will continue to be celebrated and studied for years to come.

3. Vitamin E’s Chemical Structure and Biological Activity

The chemical structure of vitamin E was elucidated by the German chemist Erhard Fernholz in 1938 ^[23] while working in the USA. Fernholz proposed a structural formula that regarded α-tocopherol as a substituted 6-hydrocarbon with a long aliphatic sidechain attached to a pyran ring (Figure 1). Prior to this, in 1937, Fernholz ^[24] had studied the thermal decomposition of α-tocopherol and formed durohydro quinone and an aliphatic hydrocarbon. Shortly after Fernholz’s proposal, the Swiss chemist Paul Karrer achieved the chemical synthesis of α-tocopherol for the first time ^[25]^[26]. Karrer condensed trimethyl hydroquinone with phytol bromide derived from natural phytol, using zinc chloride as a catalyst. However, Karrer was not sure at that time regarding the chemical structure of the molecule he synthesized. He tended to assume a coumaran ring instead of the proposed chroman ring by Fernholz.

Figure 1. Structural formula for α-tocopherol.

The first semi-synthetic tocopherol synthesized by Karrer consisted of two different stereoisomers and was initially called dl-α-tocopherol or 2-ambo-α-tocopherol. Shortly after the first synthesis of α-tocopherol, Bergel and co-workers of Lister-Institute in London, UK, and Lee Irvin Smith and co-workers of the University of Minnesota, Minneapolis, MN, USA, accomplished the synthesis of α-tocopherol as well ^[27]^[28].

The biological activity of the synthesized compound in the common rat resorption-gestation test was confirmed by Otto Isler ^[29], who accomplished an analog synthesis of vitamin E with Paul Karrer simultaneously.

Finally, the chroman ring as a constituent of α-tocopherol was confirmed with the help of UV spectra and other comparative model tests by Walter John at Göttingen University in Germany ^[30]^[31]. Furthermore, Walter John validated the chemical structure of α-tocopherol proposed by Fernholz and isolated ß-tocopherol simultaneously. John showed that ß-tocopherol differs from α-tocopherol only by one methyl group less at the chroman ring. He published more than 24 papers and book chapters on vitamin E-related topics in his short scientific career between 1937 and 1942.

In conclusion, the discovery of vitamin E’s chemical structure by Fernholz and the synthesis of α-tocopherol by Karrer were significant milestones for this essential micronutrient. Walter John’s confirmation of the chroman ring in α-tocopherol and work on synthesizing vitamin E derivatives contributed to scientific understanding, though his work is largely unrecognized outside of German journals.

4. The Discovery of Vitamin E’s Unique Physiological Function as Chain-Breaking Antioxidant and the Antioxidant Network

In 1924, Henry Albright Mattill, a biochemist from the University of Iowa in Iowa City, IA, USA, conducted a study on the effects of milk consumption on reproduction. Along with his colleagues, he observed that rats became sterile when lard was added to their milk-based regimen. This led them to conclude that the fat content of a diet, in addition to vitamin E, affects reproduction. They proposed the hypothesis that the requirement for vitamin E increases with the amount of fat in the nutritional intake ^[32].

Three years later, in 1927, Mattill ^[33] reported another finding: The destruction of vitamin E in the presence of fat, particularly unsaturated fats. Building on this discovery, Mattill delved into further research on the autoxidation of fats. In collaboration with Marian Cummings, he put forward the idea that the oxidation of vitamin E could potentially safeguard other substances, such as vitamin A, from oxidation. They suggested that vitamin E possesses “antioxidant activity” and posited that its physiological role may lie in its ability to counteract oxidation ^[34]. It is worth noting that these early studies demonstrated the physiological consequences of the absence of antioxidant protection in lipids, namely, the sterility of rats.

A significant breakthrough in understanding the antioxidant role of vitamin E came from the research conducted by Aloys Tappel, a food biochemist at the University of California Davis/USA, during the 1950s. Alongside his colleagues, Tappel demonstrated that vitamin E effectively inhibits lipid peroxidation in living organisms. Through experiments conducted on isolated mitochondria and vitamin E-deficient animals, they observed elevated levels of lipid peroxidation in the liver, resulting in compromised mitochondrial stability ^[35]^[36].

In the early 1980s, Graham Burton and Kathrin Ingold, researchers from the National Research Council of Canada, conducted chemical investigations into the antioxidant properties of vitamin E and other phenolic compounds. They elucidated the chemical structure of α-tocopherol, which proved to be optimal for scavenging peroxyl radicals due to its hydroxylated chromanol ring with significant methylation. Furthermore, they noted that α-tocopherol possesses ideal characteristics for in vivo localization alongside lipids, thanks to its phytyl side chain ^[37]. Based on their findings, Burton and Ingold proposed that the primary, if not sole, function of α-tocopherol in living organisms is to act as an antioxidant. They even presented a reaction scheme for α-tocopherol in Figure 2 ^[38]. Subsequently, through studies involving individuals deficient in vitamin E, Burton and his colleagues demonstrated that α-tocopherol serves as the predominant chain-breaking antioxidant in vivo ^[2].

Figure 2. Inhibition of lipid peroxidation by vitamin E ^[38]. In the first step, the initiation phase, a fatty acid radical (RO*) is produced upon exposure of a fatty acid to light, heat, or trace elements. In the second step, the propagation phase, RO* reacts with oxygen to form a highly reactive peroxyl radical (ROO*), which oxidizes an adjacent fatty acid, leading to a chain reaction. Ultimately, the chain reaction comes to an end when ROO* radicals react with each other, the termination phase, or when a chain-breaking antioxidant such as vitamin E reacts with ROO*, the inhibition phase.

Finally, Lester Packer, a molecular and cell biologist from the University of California (Berkeley, CA, USA), made a significant observation regarding the combat against oxidative stress in cells. He recognized the importance of multiple antioxidants working together in what he referred to as “the antioxidant network” (Figure 3). Packer’s findings revealed that vitamin E and other antioxidants undergo oxidation but are subsequently recycled, forming a highly effective and precise defense system that adapts to oxidative stress ^[39]^[40]^[41].

Figure 3. The antioxidant network (modified from Packer and Obermüller-Jevic, 2002 ^[41]). In cells, several antioxidants are present in both lipophilic and hydrophilic compartments. Lipid peroxides and other radicals are scavenged and reduced by vitamin E, leading to the formation of vitamin E radicals. In a subsequent chain reaction, vitamin E gets recycled by vitamin C and other antioxidants.

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Yauheni Shastak

Ute Obermueller-Jevic

Wolf Pelletier

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Update Date: 14 Aug 2023

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