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There are eight different natural forms of vitamin E from a biochemical standpoint. Broadly, vitamin E can be subdivided into two separate groups: the tocopherols and the tocotrienols. Each of these has four separate forms: alpha, beta, delta, and gamma-tocopherol, and alpha, beta, delta, and gamma-tocotrienol.
Beyond the natural forms of vitamin E, synthetic versions also exist. When produced chemically, each type of vitamin E has eight possible structures due to what is called “stereoisomer centers.” These centers can be formed in two ways that are mirror images of each other. While the natural form has all three stereoisomer centers in the right-handed configuration, the synthetic version is an equal mix of all eight forms, including seven forms not typically found in natural versions of the vitamin.
The natural version of alpha-tocopherol is referred to as either RRR-alpha-tocopherol, all-rac-alpha-tocopherol, or historically as D-alpha tocopherol. The synthetic version is often called DL-alpha-tocopherol. The L indicates the presence of the left-handed, synthetic versions of the nutrient that have reduced vitamin E activity.
As a nutrient, vitamin E, like vitamin C, plays a role in antioxidant defenses. Vitamin E is fat-soluble, meaning it readily dissolves and disperses in fats and lipids. In the body, vitamin E is the primary fat-soluble antioxidant that protects from free radical damage. Nutritional sources of vitamin E include oils, nuts, and seeds.
Free radicals are unstable molecules. They generally have an unpaired, reactive electron. Since electrons prefer to be in pairs, this lone electron will rip an electron from another molecule, damaging that molecule and often producing another free radical.
Antioxidants help counter this damaging process. Antioxidants have spare electrons that they can safely transfer to free radicals, effectively quenching the process. In the body, a balance is needed between free radicals and antioxidants to keep things functioning normally.
Free radicals are typically inflammatory. As such, antioxidants, in general, display anti-inflammatory activity. However, vitamin E has other anti-inflammatory activities beyond its antioxidant potential.
Different forms of the vitamin have been shown to more directly inhibit inflammatory pathways. Some forms of the vitamin also appear to help maintain healthy cells while encouraging cells that are damaged or diseased to die before they can reproduce and grow out of control.
The main form of vitamin E found throughout the body is RRR-alpha-tocopherol. RRR-alpha-tocopherol, in a recent meta-analysis of clinical studies, was shown to have anti-inflammatory properties. Tumor necrosis factor-alpha (TNF-alpha) is a well-known inflammatory signaling molecule throughout the body. TNF-alpha is implicated in the disease process of numerous autoimmune inflammatory conditions. It is often targeted directly by standard medications to help decrease inflammation. In human trials, dosages greater than 700 mg/day of RRR-alpha-tocopherol reduced TNF-alpha significantly. Further research is needed to determine what clinical benefits may be possible for using the vitamin in decreasing TNF-alpha.
While studies have been conducted on the benefits of RRR-alpha-tocopherol for heart disease, the latest research is quite mixed. Numerous studies with negative findings used the synthetic version of vitamin E, which clouds the results since synthetic vitamin E is chemically distinct from natural varieties.
Individuals who consume higher quantities of vitamin E from food have been shown to be at reduced risk for heart disease. The two largest natural vitamin E supplementation trials for heart disease prevention had opposing results, indicating the need for more clinical trials on natural RRR-alpha-tocopherol’s effects. Due to the mixed nature of the research, it’s hard to draw any conclusions on the impact of natural vitamin E and heart disease.
Fatty liver disease is a condition correlated with obesity and diabetes. Metabolic changes, inflammation, and changes in gut flora cause a buildup of fat in the liver. Over time, the condition can progress to liver scarring and liver failure. The condition is often underdiagnosed and ignored until more severe liver problems manifest. Current estimates suggest a staggering number of people have the condition—approximately 25% of the world’s population. With increasing rates of diabetes and obesity, it is likely only going to get worse.
One of the most well-proven potential uses of natural alpha-tocopherol in the published research is for fatty liver disease. In fact, a recent review touted two “drugs” that they claimed were effective: pioglitazone (a standard drug) and vitamin E. Other reviews have come to similar conclusions, describing vitamin E as helping treat the inflammatory component of the condition in non-diabetics, although stressing that we still need more research.
The current evidence suggests some potential benefits with RRR-alpha-tocopherol for cognitive decline and dementia. However, it’s worth noting that vitamin E does not appear effective for prevention.
In patients who already have cognitive decline or early Alzheimer’s dementia, data suggests that vitamin E, as RRR-alpha-tocopherol, may slow the condition’s progression. While there is some variability in the research, on the whole, it does suggest some potential with the vitamin.
Compared to alpha-tocopherol, there is a lot less research on RRR-gamma-tocopherol, although areas of interest are beginning to emerge. Evidence suggests that RRR-gamma-tocopherol is more effective in protecting from nitrogen dioxide-free radicals than RRR-alpha-tocopherol.
Damage from nitrogen dioxide, called nitrosative damage, can negatively affect DNA and inflammation, which could lead to chronic diseases such as heart disease and neurodegenerative (brain) disorders. Early studies suggest that RRR-gamma-tocopherol is better at preventing cell death and DNA damage from “nitrosative stress.”
Other evidence is beginning to show the direct effects of gamma-tocopherol on inflammatory pathways. An important enzyme involved with inflammation is cyclooxygenase (COX-1 and COX-2), the same enzymes targeted by aspirin and other non-steroidal anti-inflammatory drugs. At relevant concentrations, RRR-gamma-tocopherol inhibits COX-2 enzymes.
Early evidence suggests that the unique properties of RRR-gamma-tocopherol may have a role in helping the respiratory system, especially with certain types of asthma. Obesity can increase risks for a form of asthma with excess neutrophils (white blood cells) irritating the airways in the lungs. This type of inflammation is often not responsive to corticosteroids used for asthma treatment. One research group has found that this type of inflammation in asthma is responsive to RRR-gamma-tocopherol and argues that it appears to be one of the first safe, cheap, and effective treatments.
While known to exist, little research has explored the function and clinical effects of both RRR-beta tocopherol and RRR-delta-tocopherol. They are both typically found in much lower quantities than alpha or gamma-tocopherol.
Similar to their tocopherol brethren, tocotrienols have four forms. When used as a supplement, they are frequently provided as a mix that includes all four. Not surprisingly, they also appear to have antioxidant and anti-inflammatory activity, although clinical studies are starting to unravel some potentially distinct advantages of the tocotrienols versus the tocopherols.
Still, it’s worth noting that our understanding of the tocotrienols and their physiological effects is in its infancy. More research is clearly needed to flesh out and understand their full range of effects.
Kidney disease is a difficult-to-treat condition that usually has a slow but steady progression to kidney failure. Standard approaches include treating high blood pressure and blood sugar issues in patients to help slow the progression. Approximately 40% of patients with diabetes eventually develop kidney failure. No standard treatment approaches have been shown to improve kidney function.
In patients with diabetic kidney disease, supplementation with mixed tocotrienols was shown to improve kidney function over the course of a year. While preliminary, these findings are exciting since few treatment approaches have been shown to improve kidney function.
The early stages of bone loss are called osteopenia. Women after menopause often have increased levels of bone loss. An early trial using tocotrienols in post-menopausal women with osteopenia was found to decrease bone loss and improve bone turnover. The authors hypothesized that tocotrienols improved bone loss through their antioxidant effects.
Animal studies have suggested that alpha-tocotrienol can protect brain cells. In rat and dog models of stroke, animals supplemented with alpha-tocotrienol showed enhanced brain cell protection and better outcomes.
A recent two-year study treated patients with brain white matter lesions—an early sign of brain degeneration—with mixed tocotrienols. While no significant difference was seen at one year, after two years of supplementation, the patients on placebo had worsening brain lesions, whereas the patients on tocotrienols remained unchanged. The results suggest that tocotrienols may slow or halt the progression of brain degeneration, a precursor to cognitive decline and dementia.
Early clinical trials also suggest the benefits of tocotrienols on cholesterol levels. One small study found that a mix of palm tocotrienols decreased cholesterol by 10%. A separate study evaluated 100 mg of a tocotrienol-rich rice bran extract and found a 20% reduction in cholesterol with a 25% reduction in “bad” LDL cholesterol.
Like RRR-alpha-tocopherol, tocotrienols appear to hold promise in protecting the liver. A clinical trial using tocotrienols for treating fatty liver disease found a halt in the disease process. In addition, at one year, more patients had a reversal of their fatty liver disease with tocotrienols compared to placebo. Other studies have also suggested benefits with tocotrienols on late-stage liver disease.
While some studies have made headlines by claiming significant risks from vitamin E, overall, vitamin E appears quite safe when used properly. The Institute of Medicine has set a maximum daily dose of 1000 mg for RRR-alpha-tocopherol. In high doses, vitamin E has blood-thinning effects, which can contribute to bleeding episodes, so it’s likely best to stay under the maximum dose.
It’s also interesting to note that supplementation of RRR-alpha-tocopherol alone depletes RRR-gamma-tocopherol. This could be part of the problem with high doses of only RRR-alpha-tocopherol without the other forms of natural vitamin E.
The natural forms of vitamin E appear to have some interesting potential benefits. Getting plenty of natural vitamin E from the diet, or supplementing with mixed tocopherol and tocotrienols, may have a place in helping with certain conditions. However, more research is still needed to draw firm conclusions and expand our understanding.
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By Dr. Scott Buesing, N.D.
