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<html>
<head><title>Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory</title></head>
<body>
<h1>
Vitamin E: Estrogen antagonist, energy promoter, and anti-inflammatory
</h1>
<em><p>
Vitamin E, like progesterone and aspirin, acts within the cellular regulatory systems, to prevent
inflammation and inappropriate excitation. Since uncontrolled excitation causes destructive oxidations,
these substances prevent those forms of oxidation.
</p>
<p>
Molecules that can easily be oxidized and reduced can function as antioxidants, and vitamin E does
function as that kind of antioxidant in many chemical environments. But it is highly misleading to
consider that as the explanation for its many beneficial biological effects. That kind of reasoning
contributed to the use of the antioxidant carcinogens BHT and BHA as food additives and "antiaging"
supplements, and many other chemicals are being promoted on the basis of their abstract antioxidant
function.
</p>
<p>
Becoming aware of the real value of vitamin E will have far reaching implications in nutrition and
medicine.
</p>
<p>
In determining criminal or civil legal responsibility, the concept "should have known" is recognized and
used. In science, which is all about knowing, there is certainly a responsibility to be informed when
the subject involves the life and health of millions of people. The science establishment of government
and industry should be held responsible for the information it hides, destroys, or ignores for its own
benefit. The US government has an agency for prosecuting research fraud, but the concept is applied so
narrowly as to be meaningless, when deception has become the rule. And since it controls the court
system, govenment agencies and their functionaries won't be prosecuted, even when their crimes become
well known.
</p>
<p>
"Vitamin E was advocated as an effective treatment for heart disease by Dr. Ev<em>an Shute of London,
Ontario more than 50 years ago.</em>
<em> </em>
<em>His pioneering claims, which were unacceptable to the medical community at large, have been
confirmed by recent findings from epidemiologic studies and clinical trials.</em>
<em>" </em>
</p></em>
<hr />
<p>
Political scientists have recognized the process in which big corporations "capture" the governmental
agencies that were created to regulate them. The editorial boards of professional journals can be captured
even more cheaply than the agencies of government, and their influence can be even more valuable to
industry.
</p>
<p>
If science impinges upon the plans of an industry, it can be managed into compliance, when the industry
controls the journals and the agencies that fund research.
</p>
<p>
In the 1940s, it had already become clear to the estrogen industry that vitamin E research was impinging on
its vital interests.
</p>
<p>
The Manhattan Project, that created the atomic bomb, also created a generation of scientific and
bureaucratic zealots who ignored public health and safety to advance their projects and their careers, and
changed the way science was done. At exactly the same time, the pharmaceutical industry was using its
financial and political power to change the way medicine was practiced and taught, and the consequences for
world health rivalled those of the nuclear industry.
</p>
<p>
In 1933 the physician R.J. Shute was aware of the problems associated with toxemia of pregnancy or
preeclampsia. Especially among poorly nourished women, many pregnancies were complicated by circulatory
problems, including cyclic bleeding, thrombosis, stroke, and hypertension, and these difficult pregnancies
often ended in miscarriage or premature delivery, resulting in many serious health problems among the babies
that survived.
</p>
<p>
At that time, both estrogen and vitamin E were being widely studied, though the exact structure of the
tocopherol molecule wasn't defined until 1936-37. Vitamin E had been found to improve fertility of both male
and female animals, and to prevent intrauterine death of the embryo or fetus, so it was called the
"antisterility vitamin." Using it to prevent women from having miscarriages must have occurred to many
people.
</p>
<p>
Animal research in the 1930s was also showing that estrogen had many toxic effects, including causing
infertility or intrauterine death, connective tissue abnormalities, and excessive blood clotting. Dr. Shute
and his sons, Wilfred and Evan, were among those who considered vitamin E to be an antiestrogen. They found
that it was very effective in preventing the clotting diseases of pregnancy.
</p>
<p>
Other researchers, who knew that progesterone protected against the toxic effects of estrogen, described
vitamin E as the "progesterone-sparing agent," since so many of its antiestrogenic effects resembled those
of progesterone.
</p>
<p>
The Shute brothers began using vitamin E to treat circulatory diseases in general, rather than just in
pregnant women--blood clots, phlebitis, hypertension, heart disease, and diabetes all responded well to
treatment with large doses.
</p>
<p>
Vitamin E, as its name indicates, was the fifth type of "vitamin" factor to be identified, and it received
its name in 1922, even though its chemical structure hadn't been identified. The public quickly understood
and accepted that certain substances in food were essential for life and health, so by 1940 practically all
physicians were recommending the use of nutritional supplements.
</p>
<p>
If vitamin E was essential for human health, and achieved at least some of its amazing effects by opposing
estrogen, then the synthetic estrogen industry had a problem.
</p>
<p>
Edward L. Bernays had already been in business for decades, teaching corporations and governments how to
"engineer consent." After his work for the government to engineer support for entering the first world war,
Bernays' next big job was for the tobacco industry. To convince women to smoke cigarettes, to achieve
equality with men, he organized an Easter parade, Torches of Freedom, in which thousands of women marched
smoking their freedom torches. In association with the American Medical Association (the editor of JAMA
actually helped the tobacco industry design its campaigns), Bernays ran a campaign to convince Americans
that smoking was good for the health.
</p>
<p>
The drug industry began using his techniques in sometimes crude but always effective ways. Estrogen was
named "the female hormone;" natural hormones, including estrogen and progesterone, were claimed, without any
research, to be inactive when taken orally. Physician-shills were created to claim wonderful effects for
estrogen. The vitamin status of the tocopherols was denied; as recently as the 1970s (and maybe later),
university professors of dietetics were flatly saying "no one needs vitamin E."
</p>
<p>
Very little research showing the curative effects of vitamin E in human diseases was allowed to be
published, so it was only occasionally necessary to openly denounce vitamin E as worthless or dangerous. In
1981, the journal of the AMA published an article reviewing the "toxic" effects of vitamin E. Since I had
read all of the articles cited, I realized that the author was claiming that whenever vitamin E changed
something, the change was harmful, even though the original publication had described the effect as
beneficial.
</p>
<p>
Although JAMA was eventually forced to give up its revenue from cigarette advertising, it didn't suffer at
all, because of the vast advertising campaigns of the estrogen industry. JAMA obviously wouldn't want to
publish anything suggesting that vitamin E, or progesterone, or thyroid, might be beneficial because of its
antagonism of the harmful effects of estrogen.
</p>
<p>
Estrogen causes changes in the uterus that prevent implantation of the embryo, and that impair support for
its development if it has already implanted. It decreases the availability of oxygen to the embryo, while
vitamin E increases it.
</p>
<p>
My dissertation adviser, A.L. Soderwall, did a series of experiments in which he showed that providing
hamsters with extra vitamin E postponed the onset of infertility in middle age. In my experiments, vitamin E
increased the amount of oxygen in the uterus, correcting an oxygen deficiency produced either by
supplemental estrogen or by old age. Progesterone has similar effects on the delivery of oxygen to the
uterus.
</p>
<p>
In the 1940s, the official definition of vitamin E's activity was changed. Instead of its effectiveness in
preventing the death and resorption of embryos, or the degeneration of the testicles or brain or muscles, it
was redefined as an antioxidant, preventing the oxidation of unsaturated oils.
</p>
<p>
Although some people continued to think of it as a protective factor against thrombosis, heart attacks,
diabetes, and infertility, the medical establishment claimed that the prevention or cure of diseases in
animals wasn't relevant to humans, and that a mere antioxidant couldn't prevent or cure any human disease.
</p>
<p>
The experiments that led to the identification of vitamin E involved feeding rats a diet containing rancid
lard and, as a vitamin A supplement, cod liver oil. Both of these contained large amounts of polyunsaturated
oils.
</p>
<p>
From 1929 to the early 1930s, other researchers were claiming to have demonstrated that the polyunsaturated
fatty acids were nutritionally essential. These experiments, like the vitamin E experiments, were done on
rats, but the medical establishment was satisfied that rat experiments proved that humans need linoleic or
linolenic acid, while they refused to accept that vitamin E was essential for humans. When, in the 1940s, a
group of vitamin B6 researchers showed that the supposed "essential fatty acid deficiency" could be cured by
a supplement of vitamin B6, it became apparent that the polyunsaturated fatty acids slowed metabolism, and
reduced all nutritional needs. The thyroid hormone was powerfully suppressed by the "essential" fatty acids.
</p>
<p>
When we consider the two sets of experiments together, their outstanding feature is the toxicity of the
polyunsaturated oils, which in one kind of experiment suppressed metabolism, and in the other kind of
experiment created a variety of degenerative conditions.
</p>
<p>
By the late 1940s and early 1950s, estrogens of various sorts had been synthesized from hydrocarbons, and
were being recommended to prevent miscarriages, because "estrogen is the female hormone." The meat industry
had found that the polyunsaturated oils were valuable in animal feed, since they suppressed metabolism and
made it cheaper to fatten the animals, and these antithyroid oils were next marketed as "heart protective"
human foods, though by suppressing the thyroid and destroying vitamin E, they actually contributed to both
heart disease and cancer. (Giving estrogen to livestock to improve their feed efficiency, and to people "to
prevent heart attacks," was an interesting parallel to the oil promotional campaigns.)
</p>
<p>
The influence of the food oil industry kept researchers away from the idea that these oils were not safe for
food use, and instead tended to support the idea that vitamin E is just an antioxidant, and that the seed
oils were the best way to get vitamin E in the diet.
</p>
<p>
The antifertility effects of the polyunsaturated oils, demonstrated in the vitamin E experiments, weren't at
the time understood to have anything to do with estrogen's antifertility effects. But to understand vitamin
E, I think we have to consider the close interactions between estrogen and the polyunsatured fatty acids
(PUFA). Their actions are closely intertwined, and are antagonized by a variety of energizing and
stabiliizing substances, including saturated fats, progesterone, thyroid, vitamin E, and aspirin.
</p>
<p>
Generally, chemicals that inhibit enzymes are toxic, producing some sort of symptom or deterioration. But a
group of enzymes related to estrogen and PUFA are inhibited by these protective substances. Although under
our present diet, these enzymes metabolize the PUFA, in the fetus and newborn they act on our endogenous
fats, the series related to the Mead acids. The Mead acid is antiinflammatory, and broadly protective. The
dietary PUFA interfere with these natural protective substances,
</p>
<p>
The enzymes that, if we didn"t eat PUFA, would be regulating the Mead series, being activated in response to
stress, would be producing antistress substances, which would limit the stress reaction. But as we become
increasingly saturated with the anti-vitamin E fats, these enzymes, instead of stopping inflammation,
promote it and cause tissue injury. The remaining stress limiting factors, such as progesterone, by
correcting the distortions caused by stress, tend to eliminate the conditions which activated the
enzymes--in a very indirect form of inhibition.
</p>
<p>
Many of the events involved in inflammation are increased by estrogen, and decreased by vitamin E. Estrogen
causes capillaries to become leaky; vitamin E does the opposite. Estrogen increases platelet aggregation,
and decreases a factor that inhibits platelet aggregation; vitamin E does the opposite.
</p>
<p>
Excess clotting is known to be caused by too much estrogen, and also by a vitamin E deficiency.
</p>
<p>
Clotting leads to fibrosis, and there is clear evidence that vitamin E prevents and cures fibrotic diseases,
but this still isn't generally accepted by the powerful medical institutions. Estrogen and polyunsaturated
fats increase fibrosis.
</p>
<p>
Estrogen increases progstaglandin synthesis, vitamin E decreases their synthesis; estrogen increases the
activity of the enzymes COX and LOX, vitamin E decreases their activitiy. (Jiang, et al., 2000; Ali, et al.,
1980; Parkhomets, et al., 2001.) Estrogen releases enzymes from lysosomes, vitamin E inhibits their release.
Beta-glucuronidase, one of these enzymes, can release estrogen at the site of an inflammation.
</p>
<p>
Estrogen often increases intracellular calcium and protein kinase C, vitamin E has generally opposite
effects.
</p>
<p>
The polyunsaturated fatty acids and their derivatives, the prostaglandins, act as effectors, or amplifiers,
of estrogen's actions.
</p>
<p>
If vitamin E is acting as a protectant against the polyunsaturated fatty acids, that in itself would account
for at least some of its antiestrogenic effects.
</p>
<p>
Besides antagonizing some of the end effects of the toxic fatty acids, vitamin E inhibits lipolysis,
lowering the concentration of free fatty acids (the opposite of estrogen"s effect), and it also binds to,
and inactivates, free fatty acids. The long saturated carbon chain is very important for its full
functioning, and this saturated chain might allow it to serve as a substitute for the omega -9 fats, from
which the Mead acid is formed. The unsaturated tocotrienols have hardly been tested for the spectrum of true
vitamin E activity, and animal studies have suggested that it may be toxic, since it caused liver
enlargement.
</p>
<p>
One possibly crucial protective effect of vitamin E against the polyunsaturated fatty acids that hasn't been
explored is the direct destruction of linolenic and linoleic acid. It is known that <strong>bacterial
vitamin E is involved in the saturation of unsaturated fatty acids, and it is also known that intestinal
bacteria turn linoleic and linolenic acids into the fully saturated stearic acid.</strong>
</p>
<p>
<strong>"No metabolic function is known for alpha-tocopherolquinol or its quinone other than as a cofactor
in the biohydrogenation of unsaturated fatty acids that can be carried out by only a few
organisms."</strong>
</p>
<p>
<strong>
<em>P.E. Hughes and S.B. Tove, 1982.</em></strong>
</p>
<p>
<strong><em>"Linoleic acid was significantly decreased (P &lt; 0.001) and there was a significant rise (P
&lt; 0.05) in its hydrogenation product, stearic acid. Linolenic acid was also significantly
decreased. . . ." "The study provides evidence that bacteria from the human colon can hydrogenate
C18 essential polyunsaturated fatty acids."</em></strong>
</p>
<p>
<em>
F.A. Howard &amp; C.
</em>
<em>Henderson, 1999</em>
</p>
<p>
Because of the way in which the decision to call vitamin E a simple antioxidant was conditioned by the
historical setting, there has been a reluctance, until recently, to give much weight to the pathogenicity of
lipid peroxidation and free radicals, partly because lipid peroxidation is only a minor part of the toxicity
of the polyunsaturated oils, and there was little support for the investigation of the real nature of their
toxicity. This environment has even distorted the actual antioxidant value of the various forms of vitamin
E. (For example, see Chen, et al., 2002.)
</p>
<p>
The people who say that vitamin E is nothing but an antioxidant sometimes take other antioxidants, with, or
instead of, vitamin E. BHT, BHA, and many natural compounds (derived from industrial and agricultural
wastes) are often said to be "better than vitamin E" as antioxidants. Anything that can be oxidized and
reduced (melatonin, estrogen, tryptophan, carotene, etc.) will function as an antioxidant in some system,
but in other circumstances, it can be a pro-oxidant.
</p>
<p>
The people who think there is benefit in the abstract "antioxidant" function seem to be thinking in terms of
something that will, like a ubiquitous fire department, put out every little fire as soon as it starts. I
think it's more appropriate to think of the biological antioxidant systems as programs for controlling the
arsonists before they can set the fires.
</p>
<p>
Since the requirement for vitamin E decreases as the consumption of unsaturated fats decreases, the
requirement, if any, would be very small if we didn't eat significant quantities of those fats.
</p>
<p>
In the years since the tocopherols were identified as vitamin E, the material sold for research and for use
as a nutritional supplement has changed drastically several times, even when it has been given a specific
chemical identity, such as mixed tocopherols or d-alpha tocopherol. Variations in viscosity and color,
caused by changes in the impurities, have undoubtedly influenced its biological effects, but the ideology
about its antioxidant value has kept researchers from finding out what a particular batch of it really is
and what it really does.
</p>
<p>
<strong>"We compared the effect of a mixed tocopherol preparation with that of alpha-tocopherol alone on
superoxide dismutase (SOD) activity and iNOS expression in cultured myocytes exposed to
</strong>
<strong>H-R." "Both tocopherol preparations attenuated cell injury. . . ." "However, mixed-tocopherol
preparation was much superior to alpha-tocopherol in terms of myocyte protection. . . ." "Lack of
efficacy of commercial tocopherol preparations in clinical trials may reflect absence of gamma- and
delta-tocopherols."</strong>
</p>
<p>
<strong>Chen<em>
H, Li D, Saldeen T, Romeo F, Mehta JL,Biochem Biophys Res Commun 2002 "Mixed tocopherol preparation
is superior to alpha-tocopherol alone against hypoxia-reoxygenation injury."</em></strong>
</p>
<p>
Keeping our diet as free as possible of the polyunsaturated fats, to create something like the "deficiency"
state that is so protective (against cancer, trauma, poison, shock, inflammation, infection, etc.) in the
animal experiments, seems preferable to trying to saturate ourselves with antioxidants, considering the
imperfectly defined nature of the vitamin E products, and the known toxicity of many of the other
antioxidants on the market.
</p>
<p>
The carcinogenic properties of the polyunsaturated fats have been known for more than 50 years, as has the
principle of extending the life span by restricted feeding. More recently several studies have demonstrated
that the long lived species contain fewer highly unsaturated fats than the short lived species. <strong
>Restriction of calories prevents the lipids in the brain, heart, and liver from becoming more unsaturated
with aging.</strong>
(Lee, et al., 1999; Laganiere, et al., 1993; Tacconi, et al., 1991; R. Patzelt-Wenczler, 1981.)
</p>
<p>
When cells are grown in tissue culture without the "essential fatty acids," they become "deficient," and in
that state are very resistant to chemical injury, and can be grown indefinitely. Besides being a simple
demonstration of the way in which the polyunsaturated fats sensitize cells to injury (Wey, et al., 1993),
these experiments must be an embarrassment to the people who base their argument for the oils" essentiality
on a supposed requirement for "making cell membranes." Since the cells can multiply nicely in their
deficient state, we have to conclude that the oils aren"t needed for "membranes," or maybe that cells resist
injury better "without membranes."
</p>
<p>
In the opposite direction, an excess of insulin or prolactin, or a deficiency of vitamin E, increases the
activity of the enzymes that convert linoleic acid into the more highly unsaturated fatty acids. Excess
insulin and prolactin are crucially involved in many degenerative diseases.
</p>
<p>
The highly unsaturated fats suppress respiration in many ways, and these trends toward increased
unsaturation with aging, endocrine stress, and vitamin E deficiency parallel the life-long trend toward
lower energy production from respiration. Many studies show that vitamin E can protect and improve
mitochondrial energy production. (Kikuchi, et al., 1991; Donchenko, et al., 1990, 1983; Guarnieri, et al.,
1981, 1982.) But the state of so-called essential fatty acid deficiency not only makes mitochondria very
resistant to injury, it greatly intensifies their energy production. Vitamin E supplementation is seldom as
effective as the absence of the toxic oils.
</p>
<p>
Many nutrition charts no longer list liver as a good source of vitamin E, but a large portion of an animal"s
vitamin E is in its liver. This bias in the dietetic literature can be traced to various sources, but a
major influence was the campaign in the 1970s by the drug companies that had patented new forms of synthetic
"vitamin A." They had physicians and professors fabricate stories about the great toxicity of natural
vitamin A, and placed the stories in national magazines, to clear the field for their supposedly non-toxic
products, which have turned out to be disastrously toxic. The result is that many people have fearfully
stopped eating liver, because of its vitamin A. The other vitamins in liver, including vitamin K, function
very closely with vitamin E, and the stably stored forms of vitamin E are likely to be a good approximation
for our needs.
</p>
<p>
There is still a strong division between what people can say in their professional publications, and what
they believe. A man who was influential in designating vitamin E as an antioxidant, M.K. Horwitt, complained
when the government raised its recommended vitamin E intake by 50%, because it wasn"t supported by new data,
and because millions of people get only ten milligrams per day and "are healthy." But he has been taking 200
mg daily (plus aspirin) for many years. He apparently doesn't have very much confidence in the ideas he
advocates publicly.
</p>
<p><h3>REFERENCES</h3></p>
<p>
Prostaglandins Med 1980 Feb;4(2):79-85. <strong>Inhibition of human platelet cyclooxygenase by
alpha-tocopherol.</strong> Ali M, Gudbranson CG, McDonald JW. Alpha-tocopherol, an inhibitor of platelet
aggregation, was evaluated for its<strong>
effects on the synthesis of thromboxane and prostaglandins. A dose-dependent reduction in thromboxane B2
and prostaglandin D2 synthesis was observed with</strong>
approximately 60% inhibition at 5.0 IU or alpha-tocopherol. Alpha-tocopherol produced a time-dependent,
irreversible inhibition.
</p>
<p>
Int J Vitam Nutr Res 2001 Jan;71(1):18-24. <strong>Vitamin E and the prevention of atherosclerosis.</strong>
Bron D, Asmis R. "Recent new findings have shed new light<strong>
on the physiological role of vitamin E and suggest that it has a much broader array of biological
activities than originally expected. In addition to its well described role as an antioxidant, it is
becoming evident that vitamin E also can modulate the immune system, suppress local and chronic
inflammation, reduce blood coagulation and thrombus formation, and enhance cell function and
survival."</strong>
</p>
<p>
Plast Reconstr Surg 1981 Nov;68(5):696-9. <strong>The effectiveness of alpha-tocopherol (vitamin E) in
reducing the incidence of spherical contracture around breast implants.</strong> Baker JL Jr. Vitamin E
appears to be a safe, simple, and inexpensive means of reducing the number of postoperative capsular
contractures following breast augmentation. The synthetic form of vitamin E (alpha-tocopherol) is
recommended to avoid nausea or skin eruptions in patients with oily skin, which are frequently encountered
when the natural form is taken. No harmful side effects have been noted in any of the patients to date.
Vitamin E has no effect on coagulation systems and does not cause excessive bleeding either during or after
surgery. The recommended dosage of synthetic vitamin E is 1000 IU, b.i.d., for 2 years beginning 1 week
before surgery. If no contracture exists at that time, the dosage may be reduced to 1000 IU daily
thereafter.
</p>
<p>
Carcinogenesis 1999 Jun;20(6):1019-24. <strong>Decrease in linoleic acid metabolites as a potential
mechanism in cancer risk reduction by conjugated linoleic acid.</strong> Banni S, Angioni E, Casu V,
Melis MP, Carta G, Corongiu FP, Thompson H, Ip C.
</p>
<p>
Mech Ageing Dev 1978 Nov;8(5):311-28. <strong>Anomalous vitamin E effects in mitochondrial oxidative
metabolism.</strong> Baumgartner WA, Hill VA, Wright ET. Three different vitamin E effects, suggestive
of specific antioxidant effects, were discovered in the protective action of vitamin E against respiratory
decline (a decrease in mitochondrial respiration attributed to a "leakage" of electron transport radicals).
<strong>
No correlation was found between respiraotry decline and random lipid peroxidation.</strong> The
mechanisms behind two of the three atypical vitamin E effects were defined. Both involve an artifact in the
TBA assay for lipid peroxidation. This artifact occurs when TBA assays are carried<strong>
out in the presence of sucrose and acetaldehyde; the latter is produced from ethanol, the solvent used
to add vitamin E to preparations. The artifact in the TBA assay for peroxidations appears also to be
responsible for differing interpretations of the hepatotoxic effect of ethanol.</strong>
</p>
<p>
Eur J Biochem 1990 Mar 10;188(2):327-32. <strong>Polychlorinated biphenyls increase fatty acid desaturation
in the proliferating endoplasmic reticulum of pigeon and rat livers.</strong> Borlakoglu JT,
Edwards-Webb JD, Dils RR.
</p>
<p>
Nutr Cancer 2000;38(1):87-97. <strong>Effects of topical and oral vitamin E on pigmentation and skin cancer
induced by ultraviolet irradiation in Skh:2 hairless mice.</strong> Burke KE, Clive J, Combs GF Jr,
Commisso J, Keen CL, Nakamura RM. <strong>"Results showed that the skin concentrations of Eol, as well as
levels in the adipose tissue, were increased after topical application. Mice treated with each form of
vitamin E showed no signs of toxicity and had significantly less acute and chronic skin damage induced
by UV irradiation, as indicated by reduced inflammation and pigmentation and by later onset and lesser
incidence of skin cancer."</strong>
</p>
<p>
Am J Physiol 1991 Jun;260(6 Pt 2):R1235-40. <strong>Acute phase response in exercise. II. Associations
between vitamin E, cytokines, and muscle proteolysis.</strong> Cannon JG, Meydani SN, Fielding RA,
Fiatarone MA, Meydani M, Farhangmehr M, Orencole SF, Blumberg JB, Evans WJ.
</p>
<p>
Vrach Delo 1990 Dec;(12):6-8. <strong>[The effect of tocopherol and nicotinic acid on the microcirculation
and blood coagulability in patients with ischemic heart disease]</strong> Chernomorets NN, Kotlubei GV,
Vatutin NT, Zhivotovskaia IA, Gnilitskaia VB, Alifanova RE, Lobach EIa, Mal'tseva NV, Mitrofanov AN.
"Complex treatment using tocopherol acetate produced a positive effect on the coagulation properties of the
blood and did essentially influence the fibrinolytic activity and microcirculation. Tocopherol plus
nicotinic acid resulted in normalization of the blood coagulation process,<strong>
favoured activation of fibrinolysis and improvement of the microcirculatory bed."</strong>
</p>
<p>
Free Radic Biol Med 1991;10(5):325-38. <strong>Oxidative status and oral contraceptive. Its relevance to
platelet abnormalities and cardiovascular risk.</strong> Ciavatti M, Renaud S. INSERM Unit 63, Bron,
France. <strong>"Oral contraceptive (OC) use is a risk for thrombogenic events."</strong> "From these data
we conclude that: <strong>
1. OC use modifies slightly but significantly the oxidative status in women and in animals by decreasing
in plasma and blood cells the antioxidant defenses</strong> (vitamins and enzymes). 2. The changes in
the oxidative status are related to an increase in plasma lipid peroxides apparently responsible for the
hyperaggregability and possibly the imbalance in clotting factors associated with the OC-induced
prethrombotic state. <strong>
3. These effects of OC appear to be increased by a high intake of polyunsaturated fat and counteracted
by supplements of vitamin E.</strong> 4. The risk factors acting synergistically with OC, have all been
shown to increase platelet reactivity."
</p>
<p>
Bol Med Hosp Infant Mex 1980 May-Jun;37(3):457-67. <strong>[Jaundice caused by microangiopathic hemolysis
associated to septicemia in the newborn]</strong>
Covarrubias Espinoza G, Lepe Zuniga JL. "These infants with over 3% fragmented cells<strong>
were found to have a significant association with: sepsis, jaundice, crenated RBC's, low levels of
hemoglobin, increased reticulocyte count, and low vitamin E levels."</strong>
</p>
<p>
Endocrinology 1992 Nov;131(5):2482-4. <strong>Vitamin E protects hypothalamic beta-endorphin neurons from
estradiol neurotoxicity.</strong> Desjardins GC, Beaudet A, Schipper HM, Brawer JR.<strong>
"Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin
neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced
neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free
radicals in local peroxidase-positive astrocytes.</strong> In this study, we examined whether treatment
with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol.
<strong>Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic
beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the
latter is mediated by free radicals.</strong>
<strong>Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic
ovarian condition which have been shown to result from the EV-induced hypothalamic pathology."</strong>
</p>
<p>
Free Radic Biol Med 2000 Dec 15;29(12):1302-6. <strong>Hyperinsulinemia: the missing link among oxidative
stress and age-related diseases?</strong>
Facchini FS, Hua NW, Reaven GM, Stoohs RA. <strong>"Other proaging effects of insulin involve the inhibition
of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide
(NO). The hypothesis that hyperinsulinemia accelerates aging also offers a</strong>
<strong>metabolic explanation for the life-prolonging effect of calorie restriction</strong> and of
mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans."
</p>
<p>
J Bacteriol 1982 Sep;151(3):1397-402. <strong>Occurrence of alpha-tocopherolquinone and
alpha-tocopherolquinol in microorganisms.</strong>
Hughes PE, Tove SB. "Both alpha-tocopherolquinol and alpha-tocopherolquinone were found in 56 of 93 strains
of microorganisms examined." "Those microorganisms that did not contain alpha-tocopherolquinol or
alpha-tocopherolquinone tended to fall into two groups. One group consisted of gram-positive, anaerobic or
facultative bacteria with a low content of guanine and cytosine, and the second group encompassed all of the
filamentous microorganisms studied<strong>." "No metabolic function is known for alpha-tocopherolquinol or
its quinone other than as a cofactor in the biohydrogenation of unsaturated fatty acids that can be
carried out by only a few organisms."</strong>
</p>
<p>
J Biol Chem 1980 Dec 25;255(24):11802-6. <strong>Identification of deoxy-alpha-tocopherolquinol as another
endogenous electron donor for biohydrogenation.</strong> Hughes PE, Tove SB.
</p>
<p>
J Biol Chem 1980 May 25;255(10):4447-52. <strong>Identification of an endogenous electron donor for
biohydrogenation as alpha-tocopherolquinol.</strong> Hughes PE, Tove SB. "The ratio of
alpha-tocopherolquinone produced to fatty acid reduced was 2:1 when the tocopherol derivatives were
extracted aerobically. When the extraction was carried out anaerobically, the ratio was 1. It is suggested
that the oxidation of 2 molecules of alpha-tocopherolquinol, each to the semiquinone, provides the electrons
required for the reduction of the cis-bond of the conjugated dienoic fatty acid."
</p>
<p>
Lett Appl Microbiol 1999 Sep;29(3):193-6. <strong>Hydrogenation of polyunsaturated fatty acids by human
colonic bacteria.</strong> Howard FA, Henderson C. Emulsions of the fatty acids linoleic (C18:2 n-6),
alpha-linolenic (C18:3 n-3) and arachidonic acid (C20:4 n-6) were incubated for 4 h under anaerobic
conditions with human faecal suspensions. <strong>Linoleic acid was significantly decreased (P &lt; 0.001)
and there was a significant rise (P &lt; 0.05) in its hydrogenation product, stearic acid. Linolenic
acid was also significantly decreased (P &lt; 0.01), and significant increases in C18:3 cis-trans
isomers (P &lt; 0.01) and linoleic acid (P &lt; 0.05) were seen. With each acid, there were
non-significant increases in acids considered to be intermediates in biohydrogenation. The study
provides evidence that bacteria from the human colon can hydrogenate C18 essential polyunsaturated fatty
acids.</strong>
However, with arachidonic acid there was no evidence of hydrogenation.
</p>
<p>
Prostaglandins Leukot Essent Fatty Acids 1998 Dec;59(6):395-400. <strong>Modulation of rat liver lipid
metabolism by prolactin.</strong> Igal RA, de Gomez Dumm IN, Goya RG.
</p>
<p>
Clin Chim Acta 1994 Mar;225(2):97-103. <strong>Vitamin E and the hypercoagulability of neonatal
blood.</strong> Jain SK, McCoy B, Wise R. <strong><hr /></strong>"
</p>
<p>
Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9. <strong>gamma-tocopherol and its major metabolite, in
contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial
cells.</strong> Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN<strong>. "Cyclooxygenase-2
(COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its
associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol
(gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and
IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively."
"The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather
than affecting protein expression or substrate availability, and appeared to be independent of
antioxidant activity."</strong>
"The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration,
suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate
reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in
lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess
anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease
prevention."
</p>
<p>
Biosci Biotechnol Biochem 1992 Sep;56(9):1420-3.<strong>
Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the
spontaneously hypertensive rat (SHR).</strong> Koba K, Abe K, Ikeda I, Sugano M. Both alpha-tocopherol
and a 1:1.7 mixture of alpha-tocopherol and tocotrienols at a 0.2% dietary level significantly depressed the
age-related increase in the systolic blood pressure of spontaneously hypertensive rats (SHRs) after 3 weeks
of feeding. <strong>The aortic production of prostacyclin was increased 1.5 times both by alpha-tocopherol
and a tocotrienol mixture, suggesting a possible relevance to their hypotensive</strong> effect. These
vitamins did not influence the delta 6- and delta 5-desaturase activities of liver microsomes, <strong>but
fatty acid profiles of the liver phospholipids predicted a reduction of linoleic acid
desaturation.</strong> These effects were in general more clear with tocotrienols than with
alpha-tocopherol. Platelet aggregation by 5 microM ADP remained uninfluenced. Thus, tocotrienols may have
effects on various lipid parameters somewhat different from those of alpha-tocopherol.
</p>
<p>
Gerontology 1993;39(1):7-18. <strong>Modulation of membrane phospholipid fatty acid composition by age and
food restriction.</strong>
Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and microsomal membrane preparations were
analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid
composition." <strong>"The data revealed characteristic patterns of age-related changes in ad libitum (AL)
fed rats:</strong>
<strong>membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively,
while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately
40%, and 22:5 content almost doubled making the peroxidizability index increase with age.</strong>"
"<strong>We concluded that the membrane-stabilizing action of long-term calorie restriction relates to the
selective modification of membrane long-chain polyunsaturated fatty acids during aging.</strong>"
</p>
<p>
Free Radic Biol Med 1999 Feb;26(3-4):260-5. <strong>Modulation of cardiac mitochondrial membrane fluidity by
age and calorie intake.</strong> Lee J, Yu BP, Herlihy JT. <strong>"The fatty acid composition of the
mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty
acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the
differences."</strong>
"Considered together, these results suggest that DR <strong>maintains the integrity of the cardiac
mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid
profile."</strong>
</p>
<p>
Lipids 2001 Jun;36(6):589-93. <strong>Effect of dietary restriction on age-related increase of liver
susceptibility to peroxidation in rats.</strong> Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
</p>
<p>
Jpn J Pharmacol 1979 Apr;29(2):179-86. <strong>
Effect of linoleic acid hydroperoxide on liver microsomal enzymes in vitro.</strong> Masuda Y, Murano T.
"Rat liver microsomes incubated with linoleic acid hydroperoxide (LAHPO) lost cytochrome P-450 specifically
among the enzymes of microsomal electron transport systems. The loss of cytochrome P-450 content and
glucose-6-phosphatase activity by LAHPO was accompanied by an increase in malondialdehyde (MDA) production."
"These results suggest the possibility that the loss of microsomal enzyme activities during lipid
peroxidation may be attributed<strong>
largely to a direct attack on enzyme proteins by lipid peroxides rather than</strong>
indirectly to a structural damage of microsomal membranes resulting from peroxidative breakdown of membrane
lipids."
</p>
<p>
Ukr Biokhim Zh 2001 Jan-Feb;73(1):43-7. <strong>[Effect of alpha-tocopherol, tocopheryl quinone and other
complexes with tocopherol-binding proteins on the activity of enzymes metabolizing arachidonic
acid]</strong> Parkhomets' VP, Silonov SB, Donchenko HV. Palladin Institute of Biochemistry, National
Academy of Science of Ukraine, Kyiv. alpha-Tocopherol, tocopherylquinon jointly with the proteins tocopherol
acceptors from cytosole <strong>were identified to inhibit the activity of 5-lipoxigenase and so the
synthesis of leukotriene A4 at the early stages providing for A4 hydrolase activation and C4
synthesase,</strong> as well as accelerate leukotrienes B4 and C4 synthesis at the further stages
respectively changing the final spectrum of leukotriens in the organism tissues. Firstly, the leading role
of proteins complexes capable to strengthen the effect of alpha-tocopherol and tocopherylquinon on
arachidonic acid oxidative metabolism was determined.
</p>
<p>
Int J Vitam Nutr Res 1981;51(1):26-33. <strong>[Effect of vitamin E on the synthesis of polyunsaturated
fatty acids]</strong> Patzelt-Wenczler R. The formation of polyunsaturated fatty acids is influenced by
vitamin E. The enzyme of the endoplasmic reticulum isolated from rat liver responsible for chain elongation
and desaturation showed higher activity under vitamin E-deficiency. The activity was raised both per mg
protein and per mg DNA. The application of alpha-Tocopherol to the vitamin E-deficient animals caused the
normalization of the enzyme activity within 48 hours. This indicates a regulatory function of
alpha-Tocopherol in the process of oxidation.
</p>
<p>
Lipids 2001 May;36(5):491-8. <strong>Correlation of fatty acid unsaturation of the major liver mitochondrial
phospholipid classes in mammals to their maximum life span potential.</strong>
Portero-Otin M, Bellmunt MJ, Ruiz MC, Barja G, Pamplona R.
</p>
<p>
Free Radic Biol Med 1999 Oct;27(7-8):729-37. <strong>Age-dependent increase of collagenase expression can be
reduced by alpha-tocopherol via protein kinase C inhibition.</strong> Ricciarelli R, Maroni P, Ozer N,
Zingg JM, Azzi A. "Our in vitro experiments with skin fibroblasts suggest that alpha-tocopherol may protect
against skin aging by decreasing the level of collagenase expression, which is induced by environmental
insults and by aging."
</p>
<p>
Prostaglandins Leukot Essent Fatty Acids 1991 Oct;44(2):89-92. <strong>Inhibition of PGE2 production in
macrophages from vitamin E-treated rats.</strong> Sakamoto W, Fujie K, Nishihira J, Mino M, Morita I,
Murota S.
</p>
<p>
Int J Vitam Nutr Res 1990;60(1):26-34. <strong>The influence of vitamin E on rheological parameters in high
altitude mountaineers.</strong> Simon-Schnass I, Korniszewski L. <strong>"The erythrocyte filterability
was unaltered in the vitamin E group in comparison with baseline but was significantly impaired in the
control group."</strong>
</p>
<p>
Neurobiol Aging 1991 Jan-Feb;12(1):55-9. <strong>Aging and food restriction: effect on lipids of cerebral
cortex.</strong> Tacconi MT, Lligona L, Salmona M, Pitsikas N, Algeri S. In experimental animals dietary
restriction reduces the body weight increase due to aging, increases longevity and delays the onset of
age-related physiological deterioration, including age-related changes in serum lipids. Little is known
about the influence of food restriction on brain lipids, whose concentration and composition have been shown
to change with age. We studied whether some biochemical and biophysical parameters of rat brain membranes,
known to be modified with age, were affected by a diet low in calories, in which 50% of lipids and 35% of
carbohydrates have been replaced by fibers. The diet was started at weaning and maintained throughout the
animal's entire life span. Animals fed the low calorie diet survived longer and gained less body weight than
standard diet fed rats. Age-related increases in microviscosity, cholesterol/phospholipid and
sphingomyelin/phosphatidylcholine ratios were <strong>reduced or restored to the levels of young animals in
cortex membranes of 32 old rats fed the low calorie diet, while the age-related increase in mono- to
polyunsaturated fatty acid ratios in phospholipids was further raised.</strong> In conclusion we have
shown that a diet low in calories and high in fibers affects lipid composition in the rat brain, <strong>in
a direction opposite to that normally believed to reduce age-related deterioration of brain
functions</strong>.
</p>
<p>
Toxicol Appl Pharmacol 1993 May;120(1):72-9. <strong>Essential fatty acid deficiency in cultured human
keratinocytes attenuates toxicity due to lipid peroxidation.</strong> Wey HE, Pyron L,<strong>
Human keratinocytes are commonly grown in culture with a serum-free medium. Under these conditions,
keratinocytes become essential fatty acid deficient (EFAD), as determined by gas chromatographic
analysis of cell phospholipid fatty acid composition. Exposure of EFAD keratinocytes for 2 hr to
concentrations of t-butyl hydroperoxide (tBHP) up to 2 mM did not result in toxicity assessed by lactate
dehydrogenase (LDH) release and only a small indication of lipid peroxidation assessed by the release of
thiobarbituric acid-reactive substances</strong> (TBARS). Addition of 10 microM linoleic acid (LA) to
serum-free medium alleviated the EFAD condition by increasing the phospholipid content of LA and its
elongation and desaturation products, arachidonic acid and docosatetraenoic acid. Exposure of
LA-supplemented keratinocytes to tBHP resulted in significant LDH (at 1 and 2 mM tBHP) and TBARS (tBHP
concentration dependent) release. TBARS release was also significantly elevated in unexposed LA-supplemented
keratinocytes (basal release). Co-supplementation with the antioxidant,<strong>
alpha-tocopherol succinate (TS) prevented tBHP (1 mM)-induced LDH release in LA-supplemented cultures.
TS supplementation also attenuated the effect of tBHP on TBARS release, but when compared to
TS-supplemented EFAD cultures, LA</strong> supplementation still led to increased tBHP-induced TBARS
release. Keratinocyte cultures are potentially useful as an alternative to animals in toxicology research
and testing. It is important, however, that the cell model provide a response to toxic insult similar to
that experienced in vivo. Our results suggest that fatty acid and antioxidant nutrition of cultured
keratinocytes are important parameters in mediating the toxic effects of lipid peroxidation.
</p>
<p>
Cancer Lett 1997 Jan 1;111(1-2):179-85. <strong>Subcutaneous, omentum and tumor fatty acid composition, and
serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors
preferentially utilize polyunsaturated fatty acids?</strong> Yam D, Ben-Hur H, Dgani R, Fink A, Shani A,
Berry EM.
</p>
<em>
AC Chan, J. of Nutrition, 1998</em>
"The response-to-injury hypothesis explains atherosclerosis as a chronic inflammatory response to injury of the
endothelium, which leads to complex cellular and molecular interactions among cells derived from the
endothelium, smooth muscle and several blood cell components. Inflammatory and other stimuli trigger an
overproduction of free radicals, which promote peroxidation of lipids in LDL trapped in the subendothelial
space. Products of LDL oxidation are bioactive, and they induce endothelial expression and secretion of
cytokines, growth factors and several cell surface adhesion molecules. The last-mentioned are capable of
recruiting circulating monocytes and T lymphocytes into the intima where monocytes are differentiated into
macrophages, the precursor of foam cells. In response to the growth factors and cytokines, smooth muscle cells
proliferate in the intima, resulting in the narrowing of the lumen. Oxidized LDL can also inhibit endothelial
production of prostacyclin and nitric oxide, two potent autacoids that are vasodilators and inhibitors of
platelet aggregation. Evidence is presented that vitamin E is protective against the development of
atherosclerosis. Vitamin E enrichment has been shown to retard LDL oxidation, inhibit the proliferation of
smooth muscle cells, inhibit platelet adhesion and aggregation, inhibit the expression and function of adhesion
molecules, attenuate the synthesis of leukotrienes and potentiate the release of prostacyclin through
up-regulating the expression of cytosolic phospholipase A2 and cyclooxygenase. Collectively, these biological
functions of vitamin E may account for its protection against the development of atherosclerosis."
<p>
6: Early Hum Dev 1994 Nov 18;39(3):177-88 Vitamin A and related essential nutrients in cord blood:
relationships with anthropometric measurements at birth. Ghebremeskel K, Burns L, Burden TJ, Harbige L,
Costeloe K, Powell JJ, Crawford M. Institute of Brain Chemistry and Human Nutrition, Queen Elizabeth
Hospital for Children, London, UK. Following the advice given by the Department of Health to women who are,
or may become pregnant, not to eat liver and liver products because of the risk of vitamin A toxicity, the
concentrations of vitamins A and E, and copper, magnesium and zinc in cord blood were investigated. The
study was conducted in Hackney, an inner city area of London. Esters of vitamin A were not detected in any
of the samples, indicating that there was no biochemical evidence of a risk of toxicity. Indeed, vitamin A
correlated significantly with birthweight, head circumference, length, and gestation period. There was also
a significant positive relationship between zinc and birthweight. In contrast, copper showed a negative
correlation with birthweight and head circumference. Vitamin E and magnesium were not associated with any of
the anthropometric measurements, although magnesium showed an increasing trend with birthweight. The data
suggest that most of the mothers of the subjects studied may have been marginal with respect to vitamins A
and E and zinc. In those with low birthweight babies. a higher intake would have improved their nutritional
status and possibly the outcome of their pregnancy. For these low-income mothers, liver and liver products
are the cheapest and the best source of vitamins A and E, haem iron, B vitamins and several other essential
nutrients; hence the advice of the Department of Health may have been misplaced.
</p>
<p>
© Ray Peat 2006. All Rights Reserved. www.RayPeat.com
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