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Excerpt from the 2021 study: "Vitamin E: How much is enough, too much and why!" by Maret G. Traber & Brian Head
A short excerpt from this 2021 study:
"Vitamin E: How much is enough, too much and why!" by Maret G. Traber & Brian Head
Link to the pay-walled study:
https://doi.org/10.1016/j.freeradbiomed.2021.10.028
The excerpt is from under the headline 8: "Vitamin E safety concerns":
"We propose based on the constellation of symptoms that vitamin E’s adverse consequences are dependent upon depletion of tissue vitamin K. We postulate that the negative effects of excessive α-T supplementation are due to tissue vitamin K depletion because vitamin K-dependent proteins are involved in blood clotting, bone calcification, brain function, prevention of vascular calcification, and cancer prevention [249]. This is a serious issue because vitamin K insufficiency is highly prevalent; 25% of Americans in the Multiethnic Study of Atherosclerosis had nearly undetectable serum phylloquinone (<0.1 nmol/L) [250]. Vitamin K is a cofactor required for γ-carboxylation of glutamic acids (Glu) forming γ-carboxy-glutamic acids (Gla). This post-translational mechanism activates vitamin K-dependent blood clotting proteins [251–255]. However, a more sensitive biomarker of inadequate vitamin K status [256,257] is the abnormal calcification of soft tissues, especially artery walls (e.g. vascular calcification [258]). Most of the known vitamin K-dependent proteins prefer menaquinone-4 (MK-4) for Gla-formation [259]. MK-4’s importance in preventing abnormal and regulating normal calcification [257] suggests that the adverse consequences of α-T supplements result from dysregulation of calcium status caused by vitamin K inadequacy. Mechanistically, how α-T supplementation adversely impacts tissue MK-4 concentrations, however, is not known. For example, when rats were given large daily, subcutaneous α-T injections (equaling 0.5 g in a week), we found that brain MK-4 was depleted as much as 50% in a week, regardless of whether the diet contained the MK-4 precursors, menadione or phylloquinone [260,261]. It is unknown how α-T excess interferes with vitamin K status, but based on the known interaction of these two vitamins, a prudent course of action for α-T supplement users is to consume a diet rich in green and leafy vegetables to insure adequate vitamin K intakes."
Thank you @david, I almost missed this post.
I will drop this here since we are talking about vitamin E.
"Although there are plenty of antioxidants present in the diet, only α-tocopherol is a vitamin. α-Tocopherol's special role is that of a fat-soluble antioxidant that prevents the propagation of lipid peroxidation. It is likely that there are specific lipids, probably derived from PUFAs (such as docosahexaenoic acid) that are essential for life and that vitamin E protects (10). The α-tocopherol is the most efficient and safest of the vitamin E forms. The α-tocopheroxyl radical is relatively long-lived (178), and it can be reduced to α-tocopherol by water-soluble antioxidants, such as ascorbic acid (179). Other forms of vitamin E, when they become radicals, are more reactive and can readily form adducts that are potentially cytotoxic (180).
The safety of α-tocopherol can also be inferred from the relative lack of specific mechanisms for its metabolism. The other non-α-tocopherol forms are readily metabolized by xenobiotic pathways, likely because these forms are not effective as antioxidants and therefore should be removed promptly from the body. The tocotrienols may be a special case, because the unsaturated tail potentially could interfere with MK-4’s role in carboxylating vitamin K-dependent proteins in tissues." Mechanisms for the prevention of vitamin E excess - PMC (nih.gov)
I was just watching Dr. Maret Traber's webinar about vitamin E on YouTube, very interesting.
"Although plants make all kind of different forms of vitamin E molecules with antioxidant activity, you don't need them all. What you need is alpha-tocopherol. It's really important for the liver, the brain, the eyes and during pregnancy."- Dr. Maret Traber All You Wanted To Know About Vitamin E But Were Afraid To Ask - YouTube
Same webinar faq at the end on similarities about vE and vK structure.
"the tails are the same and so you eat spinach that has phylloquinone, the ubi-81 enzyme clips off the tail, puts on an unsaturated tail that looks like tocotrienols. I think this is the reason body gets rid of tocotrienols. They don't want to mess up menoquinone-4 (MK4). So the body is actually making vitamin K2 and it's really important in the brain." - Dr. Maret Traber
Dr. Traber also said that if you supplement vE then you should only take alpha-tocopherol form, nothing else. She said if you have 400 IU alpha tocopherol supplement then it would be best to take it just once a week.
Hi everyone, I just logged in to the Forum. I can humbly confirm that I am having good results from using Alpha Tocopherol from the Now Foods brand (in extra virgin olive oil but obtained from soy). I am only 33 years old but 10 years ago I started to aggravate degenerative processes already written in my genetics... I have just performed a muscle biopsy to try to have a targeted diagnosis, hopefully not to the detriment of the motor neurons even if the symptoms exactly mimic ALS slowly progressing (neurological and skeletal muscle). Sorry for the digression but the Alpha tocopherol form together with very few other molecules slows down the degeneration of my brain and allows me to think. I'm also trying to limit vitamin A to treat the liver and intestines as well as general inflammation but it seems difficult to stop certain chronic dynamics. Thanks everyone for the information! I hope I have good reading skills today.
Welcome Leo! Yes, alpha tocopherol is the only form that is a vitamin. It crosses the blood brain barrier and it's very important for brain function and muscle function too.
If help i found this in a recent Study,but non Remember what specific form ( 8 isomeri).
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Interesting.
The tocotrienols may be a special case, because the unsaturated tail potentially could interfere with MK-4’s role in carboxylating vitamin K-dependent proteins in tissues.
She doesn't provide any reference for this unfortunately.
The only other time she mentions K2 is here and these two studies referenced used alpha tocopherol:
Plant-derived phylloquinone (vitamin K1) has a 20 carbon phytyl side chain, while menaquinones (MK) have multiple prenyl units, as indicated by their suffix number (e.g., MK-n) (167). The liver converts phylloquinone to menadione, which is then converted to MK-4 synthesis by UbiA prenyltransferase containing 1 (UbiA1) (168, 169). Importantly, it appears that vitamin E interferes with this process, as extrahepatic tissue vitamin K1 and MK-4 concentrations were lower in rats fed a high vitamin E diet (170) or injected with vitamin E (171). Additionally, high-dose vitamin E supplementation (1,000 IU) in humans increased the degree of under-γ-carboxylation of prothrombin (proteins induced by vitamin K absence-factor II, PIVKA-II) (172). The mechanism by which vitamin E interferes with vitamin K status is unknown.
If alpha tocopherol depletes K2 why is she saying "tocotrienols may be a special case"?
Other forms of vitamin E, when they become radicals, are more reactive and can readily form adducts that are potentially cytotoxic (180).
I don't think this is entirely correct.
Studies in Vitamin E: Biochemistry and Molecular Biology of Tocopherol Quinones
Tocopherols and tocotrienols, parent congeners in the vitamin E family, function as phenolic antioxidants. However, there has been little interest in their quinone electrophiles formed as a consequence of oxidation reactions, even though unique biological properties were suggested by early studies conducted immediately after the discovery of vitamin E. Oxidation of tocopherols and tocotrienols produces para‐ and ortho‐quinones, and quinone methides, while oxidation of their carboxyethyl hydroxychroman derivatives produces quinone lactones. These quinone electrophiles are grouped in two subclasses, the nonarylating fully methylated α‐family and the arylating desmethyl β‐, γ‐, and δ‐family. Arylating quinone electrophiles form Michael adducts with thiol nucleophiles, provided by cysteinyl proteins or peptides, which can be identified and quantified by tetramethylammonium hydroxide thermochemolysis. They have striking biological properties which differ significantly from their nonarylating congeners. They are highly cytotoxic, inducing characteristic apoptotic changes in cultured cells. Cytotoxicity is intimately associated with the induction of endoplasmic reticulum stress and a consequent unfolded protein response involving the pancreatic ER kinase (PERK) signaling pathway that commits overstressed cells to apoptosis. The step‐function difference between arylating and nonarylating tocopherol quinones is conceivably the basis for distinct biological properties of parent tocopherols, including the epigenetic modification of a histone thiol, the ceramide pathway, natriuresis, and the activity of COX‐2, NF‐κB, PPARγ, and cyclin. The role of α‐tocopherol in the origin and evolution of the western hominin diet, the so‐called “Mediterranean” diet, and the prominence of α‐tocopherol in colostrum, mother's milk, and infant nutrition are considered. Finally, the discordance introduced into the diet by arylating tocopherol quinone precursors through the wide use of vegetable oils in deep‐frying is recognized.
This sounds like alpha tocotrienol is also nonarylating.
This is a quote from reference 180:
Two quinones compared in this study, α-and γ-TQ, are oxidation products of α- and γ-T, members of the vitamin E family that are synthesized by plants. Plants synthesize a number of phenolic antioxidants, α-, β-, γ-, and δ-T congeners in the vitamin E family (37), which are oxidized to nonarylating α-TQ, and arylating β-, γ-, and δ-TQ. Interestingly, tocopherol congeners, which are precursors of arylating quinones, β-, γ-, and δ-T, are the major components of most vegetable oils, including corn (85%), soy (95%), flax (99%), and borage (98%) (38). Animals, however, selectively retain the only phenolic antioxidant precursor in the vitamin E family that produces a nonarylating quinone, α-T, as ≈85% of tissue tocopherol (39, 40). We showed in this work that arylating quinones have profound biologic effects, ER stress and cytotoxicity, in animal cells. The role of ER stress in the pathogenesis of various diseases has been revealed by many studies (21–25, 41). Is it possible, as we have suggested (40), that the selection of the nonarylating quinone precursor α-T confers an evolutionary benefit in animal cells?
This is an interesting hypothesis. It's curious that soy oil whose consumption is correlated with the rise in disease in the US is high in gamma T. When seed oils high in gamma T are heated they form significant amounts of toxic gamma tocopheryl quinone:
The same researchers as reference 180:
Studies in Vitamin E: Biochemistry and Molecular Biology of Tocopherol Quinones
The multifaceted biological properties of vitamins are overwhelming. The discovery of their specific and often unanticipated effects needed the developing matrix of systems biology which was not available to the basic scientist and clinician during the early years of vitamin research. For example, “vitamin E,” which was first called factor X and is now recognized as a family of tocopherols and tocotrienols, was first described as an accessory food factor that prevented fetal death and resorption in the laboratory rat (Evans and Bishop, 1922). It was studied intensely by nutritionists, physiologists, and chemists in this “Golden Age” of vitamin research, and by the late 1930s its fundamental biological and chemical properties seemed to have been explained. The biological properties of tocopherol quinones, the subject of this chapter, are hidden in this early history, a period which is the subject of several excellent reviews (Evans 1962, Mason 1977, Mattill 1939, Smith 1940). We were guided to the original literature by Mattill, who is most often remembered for identifying “vitamin E” as an antioxidant (Wolf, 2005).
Refined diets deficient in “vitamin E,” as measured by a rat fertility test assay, were used initially in studies on biological effects and these studies naturally focused on sterility. “Vitamin E” is widely distributed in nutrients and deficient diets were difficult to prepare. The problem was apparently solved by a procedure in which “vitamin E” in natural foods was destroyed by oxidation when foods were treated with ferric chloride in ether (Waddell and Steenbock, 1928). This “vitamin E‐deficient” diet had biological effects that were, unexpectedly, very different from highly refined deficient diets. The ferric chloride‐treated diet was associated with high toxicity in rats (Taylor and Nelson, 1930), lymphoblastoma in chicks (Adamstone, 1936), and “nutritional muscular dystrophy” in guinea pigs and rabbits (Goettsch and Pappenheimer, 1931). Most importantly, these effects depended on the composition of the diet. For example, a dramatic toxic effect was observed when the diet was based on oxidized wheat germ oil, while a lesser effect was observed when the diet was based on oxidized cod liver oil. This observation suggested to the original investigators (Taylor and Nelson, 1930) that different biological effects of the “vitamin E deficiency” diets could not be related solely to the absence of “vitamin E,” and ferric chloride caused oxidation might convert “vitamin E” or some as yet unknown agent in the diet to a cytotoxic derivative. Shortly after the effects of a “vitamin E” deficiency through oxidative degradation were first reported, other investigators found that “vitamin E,” extracted from wheat germ with ether and then concentrated by evaporation, produced transplantable sarcomas in several rat strains but not in mice or guinea pigs (Rowntree et al., 1937). Oxidation induced by wet ether extraction was implied in this work since neither cold‐pressed nor hydrocarbon‐extracted wheat germ oil produced sarcomas. The study was immediately repeated by several well‐known nutritionists who could not reproduce the observation in experiments that did not replicate exactly the original procedure (Carruthers 1938, Day 1938, Evans 1939). The question of “vitamin E” oxidation to a carcinogenic derivative was not pursued in part because the chemical structure and properties of “vitamin E” had not been established at this time.
An intense period of chemical studies followed and established the structures and properties of congeners within the “vitamin E family.” A number of investigators began to associate the term tocopherol with specific chemical compounds. Three crystalline allophanates, α‐, β‐, and γ‐tocopherols (α‐, β‐, and γ‐T), were isolated from a vitamin E concentrate of wheat germ oil (Evans et al., 1936), an observation that began a long series of studies which showed wide variations in the tocopherol content of foods such as the presence of α‐T alone in cod liver oil (Sheppard et al., 1993). A chroman structure was proposed for α‐T (Fernholz, 1938), which was subsequently synthesized from trimethylhydroquinone and phytyl bromide by a zinc‐catalyzed condensation reaction (Karrer et al., 1938a). The β‐ and γ‐T (Fig. 1) were each shown to contain one less methyl group attached to the chroman ring (Emerson, 1938). The oxidation of tocopherols produced substituted 1,4‐benzoquinones that were demonstrated with ferric chloride and other oxidizing agents (John 1938, Karrer 1938b). The conclusions reached in the early literature are sustained in many more recent studies. Thus, even in 1938, sufficient data were available to reexamine and perhaps explain the striking differences in cytotoxicity found between ferric chloride‐treated wheat germ and cod liver oils, but the subject was not explored at that time.
We hypothesized that, as an early study had suggested (Taylor and Nelson, 1930), the cytotoxicity of oxidized oils was due not merely to the destruction of “vitamin E” but to the synthesis of cytotoxic oxidation products. Cod liver oil contains only α‐T and will yield only α‐tocopherol quinone (α‐TQ) when it is treated with the oxidizing agent ferric chloride. In contrast, wheat germ oil contains α‐, β‐, γ‐, and δ‐T (Sheppard et al., 1993) and will yield α‐, β‐, γ‐, and δ‐TQ, when it is oxidized. Therefore, the differences between refined diets where “vitamin E” is eliminated and oxidized diets where “vitamin E” is destroyed might be explained by the oxidation of tocopherols to their quinone electrophiles. Furthermore, the differences between cod liver and wheat germ oil diets might be explained by the formation of tocopherol quinone electrophiles with very different biological properties. We tested this hypothesis by comparing the effects of purified α‐TQ with purified γ‐TQ, and found a step‐function difference in cytotoxicity between the two quinones (Lindsey et al., 1985). This step‐function difference is the subject of our chapter.
Just out of interest it's tocopheryl quinone that inhibits vitamin K-dependent carboxylase.
Normally I think the tocopheryl radical gets recycled by C or GSH but it can become a quinone:
Traber writes:
Importantly, the differences in antioxidant activities of the various vitamin E forms are relatively minor, whereas the differences in biologic activities are quite striking (10).
and:
Vitamin E, Antioxidant and Nothing More
All of the naturally occurring vitamin E forms, as well as those of synthetic all rac-α-tocopherol, have relatively similar antioxidant properties, so why does the body prefer α-tocopherol as its unique form of vitamin E?
Yet she concludes your referenced article with this:
The other non-α-tocopherol forms are readily metabolized by xenobiotic pathways, likely because these forms are not effective as antioxidants and therefore should be removed promptly from the body.
Huh?
I've previously posted about some of the incredible findings that have come out of tocotrienol research. Tocotrienols due to their molecular structure are more effective antioxidants than tocopherols.
Quote from tim on November 14, 2023, 3:11 amI've previously posted about some of the incredible findings that have come out of tocotrienol research. Tocotrienols due to their molecular structure are more effective antioxidants than tocopherols.
Well astaxanthin is also very effective antioxidant, but it's not a vitamin. People get all kinds of adverse effects from astaxanthin like erectile problems. Alpha tocopherol has been shown to actually recover lost erectile function.
I just yesterday watched one of Garrett Smith's testimonials where his male patient had low testosterone and zero libido and poor erectile function. Smith was able to raise the testosterone level to very impressive high numbers, but the patient still has zero libido and poor erectile function. Could it be that this patient lacks vitamin e because of vA toxicity and the diet that Smith recommends does not contain enough vE at all. Also Smith avoids vE because he thinks it's a toxin.
the tails are the same and so you eat spinach that has phylloquinone, the ubi-81 enzyme clips off the tail, puts on an unsaturated tail that looks like tocotrienols. I think this is the reason body gets rid of tocotrienols. They don't want to mess up menoquinone-4 (MK4). So the body is actually making vitamin K2 and it's really important in the brain.
How does the body differentiate between K2 and CoQ10 then? They are both isoprenoid quinones whereas tocotrienols are not quinones.
^ Menaquinone
^ CoQ10
^ Beta Tocotrienol