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Life Extension Magazine

LE Magazine April 2006
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What Makes Gamma Tocopherol Superior to Alpha Tocopherol

By Lyle MacWilliam, MSc, FP

While the alpha tocopherol form of vitamin E has long been valued as a potent antioxidant, its little-known cousin, gamma tocopherol, may be equally important in promoting health and protecting against disease. Found in nuts, seeds, and vegetable oils, gamma tocopherol accounts for about 70% of the vitamin E in the North American diet.

Unlike alpha tocopherol, gamma tocopherol is a potent defender against disease-provoking compounds in the body known as reactive nitrogen oxides. Furthermore, gamma tocopherol has been found to reduce inflammation,1 regulate factors that guard against certain cancers,2-5 and activate genes involved in protecting against Alzheimer’s disease.6,7

The latest research should compel all health-conscious adults to take a closer look at gamma tocopherol, a previously underestimated member of the vitamin E family.

Beyond Alpha Tocopherol

Regular consumption of natural vitamin E has long been purported to lower the risk of degenerative disease. Laboratory evidence and data from epidemiological and retrospective studies show that abundant dietary intake of vitamin E can help ward off heart disease8-11 and keep several cancers at bay.12-14 While many published studies examine the effects of the alpha tocopherol form of vitamin E, scientists increasingly are turning their attention to gamma tocopherol.

Gamma tocopherol has distinctive chemical properties that differentiate it from alpha tocopherol and may explain the observed differences in the biological effects of these two forms of vitamin E. One of these differences makes gamma tocopherol a more effective trap for reactive nitrogen oxides,15,16 toxic compounds that must be removed from the body. As recent studies have shown, the accumulation of reactive nitrogen oxides in body tissues undoubtedly plays a central role in the etiology of several degenerative diseases.1

Trapping Reactive Nitrogen Oxides

Two particularly damaging free radicals are nitrogen dioxide and peroxynitrite. Nitrogen dioxide is a mutagenic metabolite and a major constituent of vehicle exhaust and cigarette smoke.17-19 Peroxynitrite is a dangerous oxidant created in activated phagocytes, which are a type of white blood cell.16,20,21 The formation of these toxic compounds is an integral part of the inflammation process, and their stable end products have been detected in both animals and humans with chronic inflammation.22 Inflammation induced by activated phagocytes is a major contributor to the development of cancer, cardiovascular disease, and several neurodegenerative disorders.23,24

Gamma tocopherol plays a pivotal role in quenching this type of inflammation.22 In a landmark study at the University of California, Berkeley, researchers established that alpha tocopherol and gamma tocopherol exhibit dramatically different anti-inflammatory activities.16 Despite alpha tocopherol’s superior antioxidant abilities, gamma tocopherol is required to remove peroxynitrite and other nitrogen- containing toxins that are responsible for initiating the inflammatory response. Acting through a mechanism unavailable to alpha tocopherol, gamma tocopherol reacts with and removes these harmful reactive nitrogen oxides, thereby helping to subdue the inflammatory cascade.

The Berkeley findings support previous studies that demonstrate gamma tocopherol’s superior ability to neutralize reactive nitrogen oxides.25,26 This has led researchers to conclude that gamma tocopherol plays a vital complementary and synergistic role to its alpha counterpart in the prevention of inflammatory diseases.22 These findings also explain why studies using only high doses of alpha tocopherol often fail to produce significant clinical benefits.

Inhibiting Other Inflammatory Events

Gamma tocopherol and its major metabolite can also reduce inflammation by inhibiting the cyclooxygenase-2 enzyme. Cyclo-oxygenase-2 is central to inflammatory processes and associated diseases such as cancer and vascular disease. Gamma tocopherol’s ability to block the production of this inflammatory mediator is not shared by alpha tocopherol.27,28

Preliminary evidence shows that gamma tocopherol may help protect against the onset of type I diabetes. Gamma tocopherol is more effective than its alpha analog in protecting pancreatic cells from the damaging effects of interleukin 1-beta. This inflammation-signaling protein is secreted by macrophages (specialized white blood cells responsible for the destruction of pathogens) activated by exposure to reactive nitrogen oxides.29

In a study of mammals, administration of gamma tocopherol reduced several powerful inflammatory mediators, including leuko-triene B4 and tumor necrosis factor-alpha. The study investigators noted that this provides evidence that gamma tocopherol exerts anti-inflammatory activity in vivo (within the body) that may have important implications for human disease prevention and treatment.30

Complementary Antioxidant Effects

According to conventional wisdom concerning vitamin E, alpha tocopherol is the premier antioxidant in the tocopherol family. Recently, however, several investigators have reported that the relative antioxidant potentials of alpha and gamma tocopherol vary considerably.1,31

Both forms of vitamin E are known to inhibit the formation of destructive superoxide radicals and reduce the oxidation of fats and low-density lipoproteins in the blood—all risk factors for cardiovascular disease. Surprisingly, researchers at the University of Uppsala in Sweden found that gamma tocopherol was even more effective than alpha tocopherol in reducing several pro-thrombotic (contributing to clot formation) events associated with such forms of oxidative stress.32

THE EIGHT FORMS OF VITAMIN E

Discovered in 1922, vitamin E is not a single compound, but rather an entire family of compounds with eight structurally related forms, or isomers. The eight isomers are made up of four tocopherols (alpha, beta, gamma, and delta tocopherol) and four tocotrienols, also known by their alpha, beta, gamma, and delta forms. The distinct structures of these tocopherols and tocotrienols confer unique chemical characteristics to each of the eight forms of vitamin E. While all forms of vitamin E are potent membrane-soluble antioxidants, only two—alpha tocopherol and gamma tocopherol—are predominant in nature.

Humans and other animal species cannot synthesize their own vitamin E and therefore must acquire this nutrient from plants, which are the only organisms capable of manufacturing it.

Similarly, supplementation studies show that the combination of gamma tocopherol and alpha tocopherol can afford better protection against DNA damage than alpha tocopherol alone.33 Moreover, University of Arkansas researchers discovered that a mixture of tocopherols is superior to alpha tocopherol in reducing oxidative damage in cultured muscle tissue. The authors propose that the lack of efficacy of commercial vitamin E supplements reported in clinical trials may reflect an absence of the gamma and delta tocopherol forms.34

Finally, a European study reveals that both gamma tocopherol and the ratio of gamma tocopherol to alpha tocopherol are important nutritional markers related to the antioxidant and protective benefits of the traditional Mediterranean diet.13 The Mediterranean diet has been associated with greater longevity and a lower prevalence of many age-related diseases.

Protecting Against Cardiovascular Disease

The alpha form of vitamin E decreases oxidative damage to the arterial lining, reduces dangerous aggregation and clumping of blood cells, delays clot formation,32 and enhances the activity of a known vascular dilator. It also inhibits smooth muscle proliferation (involved in the plaque-forming process),11 improves the stability of fatty plaques, enhances the function of cells lining the arteries, regulates vascular tone, and fights inflammation.35 Despite these impressive preliminary findings, however, clinical trials of alpha tocopherol alone have yielded mixed results concerning its cardioprotective effects.

The answer to this mystery may reside in the previously undiscovered benefits of gamma tocopherol and other forms of vitamin E. Since high-dose alpha tocopherol supplementation dramatically reduces gamma tocopherol levels, alpha tocopherol’s benefits may be overshadowed by the adverse effects of diminished gamma tocopherol levels.36-38

Although less is known about gamma tocopherol than about alpha tocopherol, recent evidence suggests that the gamma form is an important weapon in defending against cardiovascular disease. Several investigations confirm that higher tissue concentrations of gamma tocopherol are associated with lower rates of illness and death due to cardiovascular events.28

In fact, several studies show that patients with advanced cardiovascular disease exhibit normal plasma levels of alpha tocopherol but have substantially lower levels of gamma tocopherol.39-41 In a seven-year follow-up study of more than 334,000 postmenopausal women with no previous heart disease, greater intake of dietary vitamin E—consisting predominantly of gamma tocopherol—was strongly associated with a lower risk of death from cardiovascular disease. The data did not appear to demonstrate a similarly protective role for supplemental alpha tocopherol.8

Numerous animal studies likewise suggest that gamma tocopherol may provide powerful protection for the heart. In laboratory rats, supplementation with gamma tocopherol reduced platelet aggregation and clot formation even more effectively than alpha tocopherol.32 In addition, gamma tocopherol at physiological doses was more effective than alpha tocopherol in enhancing the activity of superoxide dismutase (SOD), an antioxidant enzyme that may help reduce the risk of cardiac events.42

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