In our last newsletter, I talked about how hysteria sells news. I also specifically mentioned a recent study that “proved” that “Vitamin Pills Are Useless.1 James Chapman. “Vitamin pills ‘are useless’.” Daily Mail. Accessed 8 Oct 2011. http://www.dailymail.co.uk/health/article-126453/Vitamin-pills-useless.html ” Or at least that’s what the mainstream media trumpeted in headline after headline. I was planning to explore the nonsensical aspects of that study in this newsletter, but Mike Adams over at Natural News.com has done a good job deconstructing it,2 Mike Adams. “Media hoax exposed: Recent attack on vitamins a fabricated scare campaign.” NaturalNews.com 16 Oct 2011. Accessed 24 Oct 2011. http://www.naturalnews.com/033883_vitamins_mortality_risk.html so instead, I can quickly cover a couple of key points in that absurd study and move on to another silly research project that also just released its results — one that very few people in the alternative community have yet commented on — the SELECT Study on Vitamin E and prostate cancer.
Absurdly, it has concluded that vitamin E causes prostate cancer. But more on that in a moment. First let’s briefly take a look at the “Vitamins are Useless” study.
Vitamins are not useless
One of the key misconceptions about this study is that it actually found health benefits for the vast majority of nutrients studied. Only two individual nutrients were singled out as harmful: folic acid and copper. But since those two ingredients are frequently found in multivitamins, the big “news” from the study was that multivitamins were identified as being “slightly” harmful. According to the study, those who use them have a 2.4% higher mortality rate than those who do not.3 Jaakko Mursu, PhD; Kim Robien, PhD; Lisa J. Harnack, DrPH, MPH; et al. “Dietary Supplements and Mortality Rate in Older Women – The Iowa Women’s Health Study.” Arch Intern Med. 2011;171(18):1625-1633. doi:10.1001/archinternmed.2011.445. http://archinte.ama-assn.org/cgi/content/abstract/171/18/1625
In addition to the fact that the data was massaged and manipulated to produce these results, there was a veritable mountain of essential questions left unanswered in the study. Did the multivitamins contain synthetic isolates, or naturally extracted isolates, or were they food based complete complexes? Were they mega dose vitamins or super low dose, basic RDI/DRV dose vitamins? Did people who took one kind of multivitamin fare better than those who took another?
Do these questions matter?
Duh! If the vast majority of multivitamin users in the study were using low dose, packed with synthetic, commercial, one-a-day type vitamins, it sure would. It would be like basing a report on the safety of the entire airline industry, on statistics gathered analyzing Cubana Airlines.4 David Whitley. “Airlines with the worst safety records.” Travel. Accessed 24 Oct 2011. http://travel.ninemsn.com.au/holidaytype/weird/7939387/airlines-with-the-worst-safety-records Frightening, but not particularly meaningful. If you want to read more about the silliness of this study, check out Mike’s article as referenced above. For now, though, we’ll move to the “other” vitamin-smack-talk study, also released a couple of weeks ago.
Vitamin E causes prostate cancer????
On October 12th, the researchers conducting the Selenium and Vitamin E Cancer Prevention Trial (aka the SELECT Study) published the results of their eight year investigation (the study actually ran from 2001 to 2008) by announcing that vitamin E supplementation not only does not help prevent prostate cancer; it actually increases your risk of getting it — substantially.5 Eric A. Klein, MD; Ian M. Thompson, Jr, MD; Catherine M. Tangen, DrPH; John J. Crowley, PhD; M. Scott Lucia, et al. “Vitamin E and the Risk of Prostate Cancer – The Selenium and Vitamin E Cancer Prevention Trial (SELECT).” JAMA 2011;306(14):1549-1556. http://jama.ama-assn.org/content/306/14/1549.abstract
Specifically, the study found that men over 50 who take 400 IU of vitamin E a day actually demonstrate a 17 percent increased risk of getting prostate cancer, which is statistically significant — particularly when calculated over a population of millions of men taking dedicated supplements and/or multivitamins with large doses of vitamin E. Even worse, the researchers found that vitamin E’s negative effects can continue even after men stop taking the supplement. In other words, according to the study, if you’re a man and you’ve been taking vitamin E for years and you stop now that you’ve read the report, you’re still screwed!
In summary, according to the researchers, “There just doesn’t seem to be a reason to be taking vitamin E if you are a man over 55 or 60.” Also, according to Eric Klein, one of the study’s authors, the study underscores “the importance of large-scale, population-based, randomized trials to accurately measure the benefit or harm of micronutrients such as diet supplements.”
Dr. Ian Thompson, another one of the study’s authors, may have added the pièce de résistance when, as a point of reference, he compared the vitamin E study to a study on beta-carotene that took place several years ago, stating that researchers once had high hopes that beta-carotene, a vitamin A precursor that is fat-soluble like vitamin E, might prevent lung cancer. But like vitamin E and prostate cancer, it had the opposite effect.
Wow again! (We’ll get back to this mind-bending statement a bit later.)
Enough of the nonsense
In truth, there is no surprise in these results. There is no “Wow” factor here. In fact, I predicted these results for this particular study back in 2004, not long after it started. And I quote:
Currently, one of the largest cancer studies in US history is underway: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). The study is taking place in the United States, Puerto Rico, and Canada. Its goal is to find out if taking selenium and/or vitamin E supplements can prevent prostate cancer in men age 50 or older. The SELECT trial is expected to stop recruiting patients in May 2006. The study will continue for 7 years after the last man has enrolled, meaning that each man will participate for 7 years or more, depending on when he joins the study. More than 400 sites in the United States, Puerto Rico, and Canada are taking part in the study. Over 32,000 men will participate in SELECT. Sounds impressive, yes?
Well here’s the catch.
The vitamin E they’re using is dl-alpha-tocopherol — the synthetic isolate form of vitamin E, the least effective form possible.
On the other hand, the selenium they’re using is l-selenomethionine, which is an organic, highly useable form of selenium. The study gets points for that.
But based on the forms of antioxidants being used, the results of the study are highly predictable even before it starts.
Vitamin E does not
There is little synergistic effect from the use of selenium and Vitamin E together.
There you go. At great savings to the American taxpayer, I’ve just given you the erroneous results that will be documented 13 years from now. What a waste!!
Well, here it is seven and a half years later (the study finished early), and except for the results on selenium by itself, the analysis was spot on. And as for selenium, the result doesn’t necessarily mean what the study says it does, but we’ll have to save that discussion for another time.
For now, though, does that make me some kind of seer for predicting these results so accurately so many years ago? Hardly! Everyone with a basic understanding of vitamin E was making the same prediction, even if they didn’t put it down on paper. But enough of that, let’s take a closer look at the details of the study to pick up some of the nuances of its stupidity.
We can begin with a little lesson in the history and chemical makeup of vitamin E.
What is vitamin E
As the old saying goes, you can’t tell the players without a scorecard. So let’s take a look at vitamin E and define what we’re talking about.
When most people think of vitamin E, they think of alpha-tocopherol — after all, that’s the chemical name listed on your vitamin bottle. But the surprising truth is that vitamin E is not a single substance. It is actually a complex of at least eight compounds. There are four tocopherols and four tocotrienols that are all identified as having vitamin E activity. Specifically, there are:
- Beta- tocotrienol
- Gamma- tocotrienol
- Delta- tocotrienol
Although natural health practitioners had been proclaiming the benefits of an unidentified substance in certain oils — especially wheat germ oil — for decades, it was not until 1922 that vitamin E was first “discovered,” and not until 1936 that tocopherols were actually isolated by researchers. Amazingly, it wasn’t until 1968, almost 50 years after first being discovered, that the Food and Nutrition Board of the US National Research Council actually acknowledged that vitamin E is an essential nutrient for humans. As for tocotrienols, they weren’t even identified and isolated until 1964, so any discussion of their essentiality was several decades off. But the question at hand is: if vitamin E actually has eight components, how did it come to be defined as just alpha-tocopherol?
As it turns out, alpha-tocopherol is the form of vitamin E that is the most absorbable, the most prevalent, and the most active in the human body.6 Jensen SK, Lauridsen C. “Alpha-tocopherol stereoisomers.” Vitam Horm. 2007;76:281-308. http://www.ncbi.nlm.nih.gov/pubmed/17628178 Thus, scientists just assumed it was the most important — thus making it the measure for vitamin E supplementation. Unfortunately:
- Just because it’s the most prevalent and most active, doesn’t necessarily make it the most important for your health.
- More recent studies have found that gamma-tocopherol may be more important, more essential. Gamma tocopherol plays an extremely important role defending against systemic inflammation caused by reactive nitrogen oxide compounds such as nitrogen dioxide and peroxynitrite — both of which are major components of automobile exhaust and cigarette smoke.7 Christen S, Jiang Q, Shigenaga MK, Ames BN. “Analysis of plasma tocopherols alpha, gamma, and 5-nitro-gamma in rats with inflammation by HPLC coulometric detection.” I. 2002 Nov;43(11):1978-85. http://www.ncbi.nlm.nih.gov/pubmed/12401897 Gamma-tocopherol may also protect against Alzheimer’s disease and prostate cancer8 Jiang Q, Wong J, Ames BN. “Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms.” Ann N Y Acad Sci. 2004 Dec;1031:399-400. http://www.ncbi.nlm.nih.gov/pubmed/15753180 ,9 Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN. “gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis.” Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17825-30. Epub 2004 Dec 13. http://www.ncbi.nlm.nih.gov/pubmed/15596715 — and most particularly relevant, especially when considering the results of the SELECT Study, there is the study that found that gamma-tocopherol inhibits cell proliferation and DNA synthesis in prostate cancer cells, whereas alpha-tocopherol does not.10 Gysin R, Azzi A, Visarius T. “Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins.” I 2002 Dec;16(14):1952-4. Epub 2002 Oct 4. http://www.ncbi.nlm.nih.gov/pubmed?term=12368234%20
- As for tocotrienols, there is abundant research that indicates that all four tocotrienols may be more important to your health and longevity11 Adachi H, Ishii N. “Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans.” J Gerontol A Biol Sci Med Sci. 2000 Jun;55(6):B280-5. http://www.ncbi.nlm.nih.gov/pubmed?term=10843344 than alpha-tocopherol — in fact, demonstrating 40-60 times the antioxidant activity.12 Serbinova E, Kagan V, Han D, Packer L. “Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol.” Free Radic Biol Med. 1991;10(5):263-75. http://www.ncbi.nlm.nih.gov/pubmed?term=1649783
- But most significant of all, studies now indicate that supplementing with high doses of alpha-tocopherol may decrease the body’s ability to absorb gamma-tocopherol, while at the same time, reducing the effects of tocotrienols that you do absorb13 Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. “Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans.” J Nutr. 1985 Jun;115(6):807-13. http://www.ncbi.nlm.nih.gov/pubmed?term=3998871 — again, an important consideration when evaluating the results of the SELECT Study.
The bottom line is that back in the early 1900’s, scientists didn’t know about the importance of all the other components of vitamin E. In the end, they made a logical but incorrect assumption: if alpha-tocopherol is the most prevalent form of vitamin E in the body, it must be the most important component and, therefore, the only one worth measuring. Thus, was born the standard of measuring vitamin E by its alpha-tocopherol content — which wouldn’t necessarily be a problem if it weren’t for the economics of manufacturing supplements. Quite simply, it’s much cheaper to just add one component to a supplement as opposed to eight. Yes, you could use a complete oil extract of all vitamin E components from a natural oil and just “list” its vitamin E content by measuring the alpha-tocopherol levels, but that would be so much more expensive than using just alpha-tocopherol — particularly if you could synthesize it from something much less expensive than natural vegetable oils. (And in fact only a small handful of manufacturers cared enough to do it right.)
In any case, thus was born synthetic alpha-tocopherol made from petroleum, turpentine, sugar, and artificial preservatives. Yum!
Natural VS synthetic alpha-tocopherol
Natural alpha-tocopherol, as found in foods and naturally sourced supplements, is known as d-alpha-tocopherol (aka RRR-alpha-tocopherol), whereas synthetic alpha-tocopherol, created in a laboratory, is known as dl-alpha-tocopherol (aka all-rac-tocopherol). What’s the difference?
Most supplement manufacturers (other than a handful of purists) would tell you there is none. Your doctor would tell you there is none. And most scientists, including the researchers running the SELECT Study, it would seem, would tell you there is none.
But they are wrong! There is a world of difference — recognized by those scientists who keep up-to-date on vitamin research, as well as anyone who actually understands holistic health.
How can there be such a difference of opinion?
The problem is that both natural and synthetic vitamin E have the same chemical formula: C29H50O2. And that similarity is enough for most scientists and today’s FDA. But, in fact, the way those atoms are arranged, although similar, varies between natural and synthetic versions. In truth, there are seven synthetic variations of alpha tocopherol (not one of which can be found in nature), and they are all arranged in various mirror images to the natural form in what is known as stereoisomers.
Stereoisomers: dextrorotatory VS levorotatory
There are three atoms (or stereocenters) in alpha-tocopherol (known as stereocenters 2,4, and 8) around which other atoms and atom groups can swap positions — mirroring their previous positions. The eight stereoisomers of alpha-tocopherol are chemically identical, differing only in the arrangement of the atoms grouped around these stereocenters. As you can see from the table below, three stereocenters means that the molecules can arrange themselves in eight variations — thus the eight stereoisomers.
You read the table from left to right. That means that the all natural form of alpha-tocopherol has all of the atoms or atom groups attached to the three stereo centers in their regular or R position. Or to look at it another way, all natural alpha-tocopherol is designated RRR. All of the other variations are synthetic since at least one stereocenter has shifted an atom group into its mirror position. For example, in synthetic variation 1, the CH3 atom group located at stereocenter 2 has flipped into its mirror position. It’s still there, just done a flip to the other side of the stereocenter into its S or stereo position. The atoms at the other two centers are unchanged. Thus synthetic 1 is designated SRR. As long as even one group is in the S position, the molecule is in a synthetic form — a form that has to be created in the lab, that does not exist in nature.
|Stereocenter 2||Stereocenter 4||Stereocenter 8|
It should be noted that the alpha-tocopherol used in the SELECT Study was identified as “all-racemic alpha-tocopherol acetate,” which means it was a mixture of all eight stereoisomers identified above. The important thing to understand about this mixture is that only one alpha-tocopherol molecule in eight is in the natural RRR-alpha-tocopherol form. That’s means only 12.5% of the total alpha-tocopherol ingested in the study was in the natural form. 87.5% was synthetic!
But the question is: why should it matter? If the molecules contain the exact same atoms and are virtually identical, other than certain groupings within the molecule being mirror images of each other, what difference does it make? After all, nutrition experts don’t seem to care, allowing all variations (synthetic and natural) to be used interchangeably on labels. And in fact, it’s impossible to notice any visual difference between the stereoisomers, except through detailed computer modeling…or by observing how polarized light passes through them. And in fact, that’s where the “d” and “l” in their names comes into play. D stands for dextrorotation (or right handed rotation) and L stands for levorotation (or left handed rotation). The natural form of alpha-tocopherol (d-alpha) bends polarized light to the right when it passes through the molecule. But all of the synthetic variations (l-alpha) rotate that same light to the left — in exactly the opposite direction. (dl indicates a blend of natural and synthetic molecules.)
And that should be a major clue — that if nature treats the synthetic forms very differently, perhaps your body does too.
There is no argument among scientists that actually keep up on the research that the natural d-alpha-tocopherol is more potent gram for gram than the synthetic dl-alpha tocopherol. In fact, many years ago, the natural form was officially recognized by the FDA, the World Health Organization, and the United States Pharmacopoeia as 36% more potent than the synthetic. But even at that, government sources might be understating the issue. A study done out of the Steacie Institute for Molecular Sciences, through the National Research Council of Canada, concluded that natural d-alpha-tocopherol is, in fact, twice as bioavailable as the synthetic.14 Burton GW, Traber MG, Acuff RV, Walters DN, Kayden H, Hughes L, Ingold KU. “Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E.” Am J Clin Nutr. 1998 Apr;67(4):669-84. http://www.ncbi.nlm.nih.gov/pubmed?term=9537614 Even more suggestive is a study done with pregnant women out of the Eastman Center for Nutrition Research at the James H Quillen College of Medicine (part of East Tennessee State University). Researchers there found that natural d-alpha tocopherol passed through the placentas of the pregnant women to their babies three times more efficiently than did the synthetic.15 Acuff RV, Dunworth RG, Webb LW, Lane JR. “Transport of deuterium-labeled tocopherols during pregnancy.” Am J Clin Nutr. 1998 Mar;67(3):459-64. http://www.ncbi.nlm.nih.gov/pubmed?term=9497190
But that doesn’t even tell the whole story. The FDA allows blended natural/synthetic dl-alpha-tocopherol to be labeled as “Natural E” even though it may contain as little as 5% natural alpha-tocopherol. As a result, oftentimes, even when you think you are buying 100% Natural E, you are not! It very well may be 95% synthetic. 100% natural vitamin E, when you actually get it, may be as much as 500% more effective than the synthetic — or the misleadingly labeled “natural.”
Back to beta-carotene
And lest I forget, remember Dr. Thompson’s comparison of the vitamin E study to the beta-carotene study that found that beta-carotene actually promoted lung cancer instead of protecting against it? As it turns out, that comparison was far more apt than Dr. Thompson intended. As with the vitamin E study, the researchers again chose to test an isolated synthetic form of the vitamin rather than the natural form in its full complex. Synthetic beta-carotene is made by extracting benzene rings from acetylene gas, and then attaching the benzene rings together to form 100% all-trans-beta-carotene. There is no natural food source in the world that contains 100% all-trans-beta-carotene. Natural beta-carotene, on the other hand, is made of two molecules — all-trans-beta-carotene and 9-cis-beta-carotene. In sources such as Dunaliella salina, the trans and cis forms of beta carotene are split approximately 50/50.
At one time, studies suggested that synthetic beta carotene actually was absorbed better and worked better than natural forms of beta carotene.16 John W. Erdman Jr., Angela J. Thatcher, Nicolle E. Hofmann, Janine D. Lederman, Stephanie S. Block, Christine M. Lee, and Shoshana Mokady. “All-trans ß-Carotene Is Absorbed Preferentially to 9-cis ß-carotene, but the Latter Accumulates in the Tissues of Domestic Ferrets (Mustela putorius puro). J. Nutr. November 1, 1998 vol. 128 no. 11 2009-2013 http://jn.nutrition.org/content/128/11/2009.full.pdf+html But subsequent studies in both animals and humans have demonstrated far more conclusively that natural beta carotene provides benefits that the synthetic form cannot match.17 A Ben-Amotz and Y Levy. “Bioavailability of a natural isomer mixture compared with synthetic all- trans beta-carotene in human serum.” Am J Clin Nutr May 1996 vol. 63 no. 5 729-734. http://www.ajcn.org/content/63/5/729.full.pdf+html And more to the point, studies have shown that pre-cancerous changes in people reverted to normal tissue with natural beta-carotene supplements, but not with synthetic supplements. As I mentioned, it was this same synthetic form of beta carotene that was used several years ago in a test of smokers that “proved” that “beta carotene” increases your risk of lung cancer.18 “Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial.” 22 July 2003. National Cancer Institute. Accessed 25 Oct 2011. http://www.cancer.gov/newscenter/qa/2003/atbcfollowupqa And as with the vitamin E study, no mention was made when the results were published that it was the inferior synthetic form of the vitamin precursor that was tested — not the natural form. And of course, as with natural vitamin E, beta-carotene does not exist in nature in an isolated form. It exists only as part of carotenoid complexes.
Why is this important?
Because, as with alpha-tocopherol, beta-carotene is not the most important of the carotenoids. It’s merely the one that government regulators have decided to use in calculating Recommended Daily Intake as a vitamin A precursor. Once again, the FDA and the USDA are several decades behind the times. Studies have shown that alpha-carotene, for example, is more powerful than beta-carotene and has a strong inhibitory effect on the proliferation of various types of cancer cells such as those affecting the lungs, stomach, cervix, breast, bladder and mouth.19 Murakoshi M, Takayasu J, Kimura O, Kohmura E, Nishino H, Iwashima A, Okuzumi J, Sakai T, Sugimoto T, Imanishi J, et al. “Inhibitory effects of alpha-carotene on proliferation of the human neuroblastoma cell line GOTO.” J Natl Cancer Inst. 1989 Nov 1;81(21):1649-52. http://www.ncbi.nlm.nih.gov/pubmed?term=2795693%20 It works by allowing normal cells to send growth-regulating signals to premalignant cells. And for that matter, lycopene, yet another part of the carotenoid complex as it is found in nature, is even more effective than either alpha- or beta-carotene when it comes to inhibiting the proliferation of cancer cells.20 Levy J, Bosin E, Feldman B, Giat Y, Miinster A, Danilenko M, Sharoni Y. “Lycopene is a more potent inhibitor of human cancer cell proliferation than either alpha-carotene or beta-carotene.” Nutr Cancer. 1995;24(3):257-66. http://www.ncbi.nlm.nih.gov/pubmed?term=8610045 So once again, by using an isolate for testing, the researchers left the most important part of the complex behind — not to mention reaping the harmful effects of using the synthetic form in the first place.
Truly, Dr. Thompson, your comparison of the two studies was remarkably apt!
Running a study on synthetic vitamin E isolate and then broadcasting the negative results as an indictment of “all” forms of vitamin E — especially considering that the scientific community has already acknowledged the inferiority of dl-alpha-tocopherol — is like running a study on the quality of fake Rolex watches and coming to the conclusion, based on that study, that all Rolex watches are junk…and then promoting those results to the gullible world press, desperate for any outrageous headline that can sell papers or boost ratings. It is false logic. It is sophistry. It is bad advice. It is unethical. And it is ultimately dangerous in that it will encourage many people to make a bad health choice when it comes to supplementation with vitamin E.
If you supplement with vitamin E, which is probably a good idea despite the study, make sure you use only the all natural form, and make sure it’s a complete vitamin E complex with all four tocopherols and all four tocotrienols. (If the label doesn’t specifically say that the supplement contains all eight naturally occurring Vitamin E compounds, then it doesn’t. As we’ve already discussed, when it comes to vitamin E, the word “natural” by itself doesn’t mean much.)
If you ever see another study again slamming vitamin E, check first to see if it was done using all natural, full-complex E. If not, you can throw the study in the trash where it belongs.
And if you opt for a multivitamin supplement, make sure you choose one that is food formed, or “grown” — not packed with synthetics and isolates.
|↑1||James Chapman. “Vitamin pills ‘are useless’.” Daily Mail. Accessed 8 Oct 2011. http://www.dailymail.co.uk/health/article-126453/Vitamin-pills-useless.html|
|↑2||Mike Adams. “Media hoax exposed: Recent attack on vitamins a fabricated scare campaign.” NaturalNews.com 16 Oct 2011. Accessed 24 Oct 2011. http://www.naturalnews.com/033883_vitamins_mortality_risk.html|
|↑3||Jaakko Mursu, PhD; Kim Robien, PhD; Lisa J. Harnack, DrPH, MPH; et al. “Dietary Supplements and Mortality Rate in Older Women – The Iowa Women’s Health Study.” Arch Intern Med. 2011;171(18):1625-1633. doi:10.1001/archinternmed.2011.445. http://archinte.ama-assn.org/cgi/content/abstract/171/18/1625|
|↑4||David Whitley. “Airlines with the worst safety records.” Travel. Accessed 24 Oct 2011. http://travel.ninemsn.com.au/holidaytype/weird/7939387/airlines-with-the-worst-safety-records|
|↑5||Eric A. Klein, MD; Ian M. Thompson, Jr, MD; Catherine M. Tangen, DrPH; John J. Crowley, PhD; M. Scott Lucia, et al. “Vitamin E and the Risk of Prostate Cancer – The Selenium and Vitamin E Cancer Prevention Trial (SELECT).” JAMA 2011;306(14):1549-1556. http://jama.ama-assn.org/content/306/14/1549.abstract|
|↑6||Jensen SK, Lauridsen C. “Alpha-tocopherol stereoisomers.” Vitam Horm. 2007;76:281-308. http://www.ncbi.nlm.nih.gov/pubmed/17628178|
|↑7||Christen S, Jiang Q, Shigenaga MK, Ames BN. “Analysis of plasma tocopherols alpha, gamma, and 5-nitro-gamma in rats with inflammation by HPLC coulometric detection.” I. 2002 Nov;43(11):1978-85. http://www.ncbi.nlm.nih.gov/pubmed/12401897|
|↑8||Jiang Q, Wong J, Ames BN. “Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms.” Ann N Y Acad Sci. 2004 Dec;1031:399-400. http://www.ncbi.nlm.nih.gov/pubmed/15753180|
|↑9||Jiang Q, Wong J, Fyrst H, Saba JD, Ames BN. “gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis.” Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17825-30. Epub 2004 Dec 13. http://www.ncbi.nlm.nih.gov/pubmed/15596715|
|↑10||Gysin R, Azzi A, Visarius T. “Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins.” I 2002 Dec;16(14):1952-4. Epub 2002 Oct 4. http://www.ncbi.nlm.nih.gov/pubmed?term=12368234%20|
|↑11||Adachi H, Ishii N. “Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans.” J Gerontol A Biol Sci Med Sci. 2000 Jun;55(6):B280-5. http://www.ncbi.nlm.nih.gov/pubmed?term=10843344|
|↑12||Serbinova E, Kagan V, Han D, Packer L. “Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol.” Free Radic Biol Med. 1991;10(5):263-75. http://www.ncbi.nlm.nih.gov/pubmed?term=1649783|
|↑13||Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. “Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans.” J Nutr. 1985 Jun;115(6):807-13. http://www.ncbi.nlm.nih.gov/pubmed?term=3998871|
|↑14||Burton GW, Traber MG, Acuff RV, Walters DN, Kayden H, Hughes L, Ingold KU. “Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E.” Am J Clin Nutr. 1998 Apr;67(4):669-84. http://www.ncbi.nlm.nih.gov/pubmed?term=9537614|
|↑15||Acuff RV, Dunworth RG, Webb LW, Lane JR. “Transport of deuterium-labeled tocopherols during pregnancy.” Am J Clin Nutr. 1998 Mar;67(3):459-64. http://www.ncbi.nlm.nih.gov/pubmed?term=9497190|
|↑16||John W. Erdman Jr., Angela J. Thatcher, Nicolle E. Hofmann, Janine D. Lederman, Stephanie S. Block, Christine M. Lee, and Shoshana Mokady. “All-trans ß-Carotene Is Absorbed Preferentially to 9-cis ß-carotene, but the Latter Accumulates in the Tissues of Domestic Ferrets (Mustela putorius puro). J. Nutr. November 1, 1998 vol. 128 no. 11 2009-2013 http://jn.nutrition.org/content/128/11/2009.full.pdf+html|
|↑17||A Ben-Amotz and Y Levy. “Bioavailability of a natural isomer mixture compared with synthetic all- trans beta-carotene in human serum.” Am J Clin Nutr May 1996 vol. 63 no. 5 729-734. http://www.ajcn.org/content/63/5/729.full.pdf+html|
|↑18||“Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial.” 22 July 2003. National Cancer Institute. Accessed 25 Oct 2011. http://www.cancer.gov/newscenter/qa/2003/atbcfollowupqa|
|↑19||Murakoshi M, Takayasu J, Kimura O, Kohmura E, Nishino H, Iwashima A, Okuzumi J, Sakai T, Sugimoto T, Imanishi J, et al. “Inhibitory effects of alpha-carotene on proliferation of the human neuroblastoma cell line GOTO.” J Natl Cancer Inst. 1989 Nov 1;81(21):1649-52. http://www.ncbi.nlm.nih.gov/pubmed?term=2795693%20|
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