Vitamin E FAMILY - the Science - part 1

Will the REAL VITAMIN E please stand up 

For over 75 years, the US National Institutes of Health (NIH) Agencies involved in deciding the fate of vitamin E units and forms appear to have been shortsighted in picking only one to be called Vitamin E or given E units. Nature provides at least 8 similar related vitamin E forms in food. And after years of conflicting and disappointing study results using only this single form of Vitamin E, a few Scientists have gone back to testing all 8 family forms of Vitamin E and are reporting increased POSITIVE RESULTS. It turns out, either many or all of the 8 forms of vitamin E are needed together to protect health and not just the single one picked as Vitamin E, d'alpha tocopherol. ref  Read the following studies and see if you reach the same conclusion. Now, it might be that the other 7 related forms should get their own vitamin name and functions if the Government doesn't want to include them with their big brother, Vitamin E as d'alpha tocopherol.

PRECAUTION: Any vitamin E research study not including both groups, tocopherols and tocotrienols, may miss the true benefits for the family of vitamin E. Plus, many studies just test the alpha tocopherol form by itself, and use the inferior synthetic form in most to boot. ref

Check out the results of these 6 studies. Yes, of course, many of the cancer studies are on animals and still need human testing, but they are still very powerful in revealing how the different forms of E family function. Plus the cancer studies on cell lines inhibited by the family of vitamin E are from humans. Here is a study on Vitamin E forms in humans and dementia. ref

https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/     <General vitamin E knowledge

1. δ- and γ-tocopherols (Delta & Gamma), but not α-tocopherol (alpha), inhibit COLON carcinogenesis in azoxymethane-treated F344 rats

Cancer Prev Res (Phila). 2012 Apr;5(4):644-54. doi: 10.1158/1940-6207.CAPR- 11-0521. Epub 2012 Feb 24. http://www.ncbi.nlm.nih.gov/pubmed/22366914

Abstract         The cancer preventive activity of vitamin E has been extensively discussed, but the activities of specific forms of tocopherols have not received sufficient attention. Herein, we compared the activities of δ-tocopherol (δ-T), γ-T, and α-T in a colon carcinogenesis model. Male F344 rats, seven weeks old, were given two weekly subcutaneous injections of azoxymethane (AOM) each at a dose of 15 mg/kg body weight. Starting 1 week before the AOM injection, the animals were maintained on a modified AIN76A diet, or the same diet containing 0.2% of δ-T, γ-T, α-T, or a γ-T-rich mixture of tocopherols (γ-TmT), until the termination of the experiment at 8 weeks after the second AOM injection. δ-T treatment showed the strongest inhibitory effect, decreasing the numbers of aberrant crypt foci by 62%. γ-T and γ-TmT were also effective, but α-T was not. Immunohistochemical analysis showed that δ-T and γ-T treatments reduced the levels of 4-hydroxynonenal and nitrotyrosine and the expression of cyclin D1 in the colon, preserved the expression of PPAR-γ, and decreased the serum levels of prostaglandin E2 and 8-isoprostane. Supplementation with 0.2% δ-T, γ-T, or α-T increased the respective levels of tocopherols and their side- chain degradation metabolites in the serum and colon tissues. Rather high concentrations of δ-T and γ-T and their metabolites were found in colon tissues. Our study provides the first evidence for the much higher cancer preventive activity of δ-T and γ-T than α-T in a chemically induced colon carcinogenesis model. It further suggests that δ-T is more effective than γ-T. PMID: 22366914              Another colon cancer study here.

2. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

Cancer Lett. 2016 Feb 1;371(1):71-8. doi: 10.1016/j.canlet.2015.11.010. Epub 2015 Nov 12. http://www.ncbi.nlm.nih.gov/pubmed/26582657

Abstract      Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), beta-tocopherol (β-T), gamma tocopherol (γ-T) and delta tocopherol (δ-T). The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2- amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A- humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200  mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki- 67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. 

CONCLUSIONS: These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. PMID: 26582657

3. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma

Clin Cancer Res. 2009 Jun 15;15(12):4242-9. doi: 10.1158/1078-0432.CCR-08- 3028. Epub 2009 Jun 9.

PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis.

EXPERIMENTAL DESIGN: Female Sprague Dawley rats were treated with N-methyl-N- nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells.

RESULTS: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer.

CONCLUSION: The results suggest that gamma- and delta- tocopherols may be effective agents for the prevention of breast cancer. PMID: 1950915

4. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 Breast Cancer

http://www.ncbi.nlm.nih.gov/pubmed/22964476

Cancer Prev Res (Phila). 2012 Nov;5(11):1310-20. doi: 10.1158/1940- 6207.CAPR-12-0263. Epub 2012 Sep 10

Abstract

Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU- treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P < 0.01) and 7.1 ± 0.7 g (P < 0.01), respectively. Tumor multiplicity was also reduced in δ- and γ- tocopherol treatment groups by 42% (P < 0.001) and 32% (P < 0.01), respectively. In contrast, α-tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α- tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer. PMID: 22964476

5. High plasma levels of (certain) vitamin E forms and reduced Alzheimer's disease risk in advanced age. http://www.ncbi.nlm.nih.gov/pubmed/20413888

Abstract J Alzheimers Dis. 2010;20(4):1029-37.
In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer's disease (AD) among oldest-old individuals in a population- based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (alpha-, beta-, gamma, and delta-tocopherol; alpha-, beta-, gamma-, and delta-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32-0.94) for total tocopherols, 0.46 (0.23-0.92) for total tocotrienols, and 0.55 (0.32-0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of beta-tocopherol (HR: 0.62, 95% CI 0.39-0.99), whereas alpha-tocopherol, alpha- tocotrienol, and beta-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): alpha- tocopherol: 0.72 (0.48-1.09); alpha-tocotrienol: 0.70 (0.44-1.11); beta-tocotrienol: 0.69 (0.45-1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to alpha-tocopherol alone, whose efficacy in interventions against AD is currently debated.

NOTE: Later research from same group on vitamin E study dementia

6. Supplementation of Diets with only α-Tocopherol Reduces Serum Concentrations of γ- and δ-Tocopherol in Humans^1,2 

Abstract

Despite promising evidence from in vitro experiments and observational studies, supplementation of diets with α-tocopherol has not reduced the risk of cardiovascular disease and cancer in most large-scale clinical trials. One plausible explanation is that the potential health benefits of α-tocopherol supplements are offset by deleterious changes in the bioavailability and/or bioactivity of other nutrients. We studied the effects of supplementing diets with RRR-α-tocopheryl acetate (400 IU/d) on serum concentrations of γ- and δ-tocopherol (gamma and delta) in a randomized, placebo-controlled trial in 184 adult nonsmokers. Outcomes were changes in serum concentrations of γ- and δ-tocopherol from baseline to the end of the 2-mo experimental period. Compared with placebo, supplementation with α-tocopherol reduced serum γ-tocopherol concentrations by a median change of 58% [95% CI = (51%, 66%), P < 0.0001], and reduced the number of individuals with detectable δ-tocopherol concentrations (P < 0.0001). Consistent with trial results were the results from baseline cross-sectional analyses, in which prior vitamin E supplement users had significantly lower serum γ-tocopherol than nonusers. In view of the potential benefits of γ- and δ-tocopherol, the efficacy of α-tocopherol supplementation may be reduced due to decreases in serum γ- and δ-tocopherol levels. Additional research is clearly warranted.

Government Health Scientists long ago failed to appreciate Mother Nature's wisdom of family activities by establishing only alpha tocopherol as vitamin E. But, now you know to overcome these shortcomings and wisely use the vitamin E family of elements nature offers for building health.

Precaution: While all the different forms of vitamin E family have roles in health, it is important to respect natural ratios and not overdue, especially the alpha and gamma tocopherol levels. The exact ratios are still under debate. It may be that different health conditions may need different levels. But an overall ratio is probably best to satisfy most conditions.

Precaution 2: There are studies showing a negative association of higher gamma tocopherol levels for some breast cancer research. Remember, that these are mainly from just looking at dietary sources wtih a blood analysis to determine levels. Unfortunately, diets high in safflower, corn, and soy oils will yield higher gamma tocohperol levels. It may very well be the higher vegetable oil fat omega 6 ratio to omega 3 that is the real element and not just gamma levels that caused this negative association. ref article 

Precaution 3: There is also the possibility that the disease itself may influence tocopherol levels, increasing one and lowering the other. This factor has seen little research so far. Remember that cancer generates a process that lowers vitamin D. Thus, lower vitamin D levels would be seen in cancer patients but was not necessarily a precipitating factor before the disease.

Precaution 4: The SELECT study looking into potential prostate cancer benefits from vitamin E and selenium was stopped at the halfway point when slightly increased prostate cancer risk was found in the vitamin E only group as well as the vitamin E and selenium group. ref The selenium only group also exhibited a slightly elevated diabetes risk. Logical factors have been found for these results.

EXAMPLE using Vitamin E Family on Heart Disease

Theories were put forth that vitamin E as d'alpha tocopherol should help hearts survive attacks from oxygen radicals. Many studies were undertaken but results kept coming up short on benefits. Finally, a Doctor decided to measure the alpha tocopherol levels against other vitamin E family members in heart patients versus healthy people. He discovered that the alpha tocopherol levels were the same in both groups. It was another vitamin E family member than measured lower, gamma tocopherol, in heart patients. ref ref Thus, the question: If alpha tocopherol is not lower in heart patients, why would increasing it help? Doesn't it make more sense to increase the low level of gamma tocopherol instead? pos study> ref ref <neg study

Most likely, there is a ratio balance needed between the vitamin E tocopherol family members that needs to be studied and respected when supplement amounts are considered. ref <on prostate cancer future studies. ref

Here is a study on Vitamin E as only alpha tocopherol on CAD, coronary heart disease that shows a negative effect as vitamin E increased. ref The family members of vitamin E probably exert counter balancing effects together to control negative aspects of just one form alone.

Remember: Alpha tocopherol has a carrier protein to hold it in blood plasma longer than the other vitamin E family members. This will keep alpha tocopherol at higher levels in plasma. Thus, the levels in plasma for the other vitamin E family members may be a factor of conditions in the body rather than just under dietary control. Plus, the other tocopherol E members are all capable of being converted into the alpha form when more of it is needed, but not vice versa. And there is most likely an interference factor when large amounts of alpha tocopherol are supplemented that further blocks the other family members out of absorption, or some other mechanism that lowers their amounts found in plasma. The other E members are found in some tissues and organs other than blood plasma. 

VITAMIN E TERM CLARIFICATION

Difficult to believe after the science presented above, but here is a paper form Researchgate that still recently said d-alpha tocopherol is the only form that should be called vitamin E. The theory is correct in that alpha tocopherol is the only vitamin E family member riding on a transport protein, a-TTP. If the gene producing this transport protein is damaged, the other vitamin E forms would not be able to prevent Ataxa with vitamin E deficiency disease, even though they can be converted into alpha tocopherol when more is needed. It is the lack of the transport protein that causes this disease. High dose vitamin E has been shown to help mitigate neurodamage and reduce symptoms. Funny, some of the other vitamin E family members also have potential in this brain activity area.

How can the significance of the other vital functions from the other vitamin E family members be ignored?

TOCOTRIENOLS, the other vitamin E family members, See part 2 of Vitamin E science

NOTE: Here is lastest on Tocotrienols and diseases. Check out the many charts. ref

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544065/ < New Study 2022

The other vitamin E family members serve some vital functions like cholesterol control, nitrogen radical elimination, brain function maintenance, and certain cancer inhibition actions. Alpha tocopherol by itself lacks the ability to handle these conditions, some of which it does not touch at all. The authors of this paper seem to only be concerned with one disease condition, vitamin E deficiency disease due to damage of the alpha tocopherol transporter protein, a-TTP.

Maybe to gain advantage for all these functions, true vitamin E should include all the tocopherols, which of course would always include alpha tocopherol. And the four related tocotrienols should also be a factor, just best taken separately to avoid absorption interference. SYNERGY!

PRECAUTION: The correct ratio(s) between the eight different vitamin E family forms for supplements is still under debate. These may vary according to different conditions, genetics, and overall diet. Thus, the precautionary principle is in play and lower dosages are preferred.

Clarification of excess or isolated Alpha Tocopherol on reduction of other Vitamin E members

While it may seem logical as some Scientists have assumed that the interference happens by blocking out intestinal absorption channels, there is also evidence could the interference is with cellular pathways by again blocking out enzyme activity from getting to the other tocopherols, beta, delta, and gamma.

This possibility was shown for vitamin K reduction with higher Vitamin E alpha tocopherol intake. The next reference used an injection of vitamin E so it bypassed intestinal absorption reduction of vitamin K. ref