Posted on 12th Jul 2009 @ 4:48 AM

There's No Such Thing as "Vitamin E"!

AOR Total E - 60 softgels

What's Missing from Your "Natural Vitamin E" Supplement

Imagine walking into your local health food store and
seeing a bottle on the shelf labeled simply "Vitamin B."
You'd be a little puzzled, wouldn't you? Maybe even curious
enough to pick up the bottle and see just what the label
meant.

Next imagine that it turned out that the pills in the bottle
contained just one B vitamin: thiamin. What would you think?
That the manufacturers didn't know what they were doing?
That someone was trying to dupe the gullible? That it was a
typo - that they had accidentally missed the "1" in "Vitamin
B1" (thiamin)?
Sure, you'd think, thiamin is one B vitamin, but what about
the rest of the B-complex? There's no such thing as just
"Vitamin B."
Exactly. While there are B vitamins, there is no one "vitamin
B." Instead, the B vitamins are a family: the "B complex." Just
because you're getting plenty of one B vitamin - niacin, say,
or riboflavin - doesn't mean that your needs for
pantothenate, or folic acid, or the rest of the B-complex are
being met. Not only does each B vitamin have its own unique
role to play in supporting your health, but the B complex
also works together, as a synergistic whole. You need the full
team on your side to enjoy the health benefits of the Bfamily
vitamins. In fact, supplementation with just part of the
B complex can even create an artificial deficiency in other
B vitamins.1
Most health-conscious people already know all of this. The
irony is that nearly every one of us falls into the exact same
trap when we buy "vitamin E."
Introducing the E Complex
Have a look at your "Natural Vitamin E" supplement. The
label probably reads something like this: "d-alpha
tocopherol ... 400 IU." That may seem perfectly
appropriate: after all, that's what vitamin E is, right?
Well, no - it's not. Alpha-tocopherol is no more "vitamin E"
than pyridoxine is "vitamin B." Like "vitamin B," vitamin E is
a complex - a family of eight molecules: four tocopherols
and four tocotrienols. These eight E-complex family
members work together in the body to support its health. As
we'll see, each member of the family has its own, unique
functions. No one family member can fully substitute for
another.
"But," you may say, "the vitamin E I bought says it contains

'Natural Mixed Tocopherols.' So it's complete, right?"

AOR Total E - 60 softgels

Unfortunately not - for two reasons.
First, even vitamin E "with mixed tocopherols" still leaves you
missing half of the E-complex: the tocotrienols. (We'll get
into the difference between tocopherols and tocotrienols -
and some of the reasons you'll want to be sure that you're
getting enough of this half of the vitamin E family - a little
later on). Second, the proportions of the different
tocopherols contained in most "mixed tocopherol"
supplements are completely unbalanced. These products
typically contain five times as much alpha-tocopherol as the
other three tocopherols combined - a heavy-handed
formulation which guarantees that you won't gain any
health benefits from these "other" vitamin E molecules.
It's now known that taking too much alpha-tocopherol
actually depletes your body of other E-complex vitamins.2-6
This fact is an unfortunate side-effect of our evolutionary
history. In the Darwinian struggle to pass on genes, there is
a powerful evolutionary pressure at work which selects traits
that ensure successful reproduction - sometimes even at the
expense of putting long-term health at risk. And of all the
members of t he E family, alpha-tocopherol contributes the
most to ensuring that pregnant animals successfully bring
their fetuses to term.7,8
But alpha-tocopherol makes up only a fraction of the total
vitamin E in food - and much of that is in the germ of
grains,9-13 which played no part in the diet that shaped our
evolution.14 So in order to ensure their reproductive fitness,
most animals - including humans - have evolved mechanisms
of selectively holding onto the small amount of alphatocopherol
found in our natural diets, at the expense of the
other E vitamins.15,16
This selective retention of alpha-tocopherol is a critical
evolutionary advantage if you're a Paleolithic huntergatherer,
living with the reality that your unborn child may
be lost to a simple nutritional deficiency in times of drought.
But it's a disaster if you're a modern human with access to a
reliable food supply - and to supplements that contain so
much alpha-tocopherol that they will rob your body of the
long-term health benefits of the other E-complex vitamins.
Vitamin E Special ADVANCES in orthomolecular research 1
2 ADVANCES in orthomolecular research Vitamin E Special
The best-studied example of this problem is alphatocopherol's
effect on gamma-tocopherol, which is the most
plentiful single E vitamin in food (as opposed to
supplements)9-13 and which holds out the most exciting
promise out of the tocopherol side of the vitamin E family.
After just three days of supplementing with 400 IU of
alpha-tocopherol, peoples' gamma-tocopherol levels
plummet by more than two-thirds (see Figure 1).3 In fact, as
little as 100 IU of alpha-tocopherol can force your gammatocopherol
levels down to 30% below what they would be
if you were taking no supplement at all.2 And after one
year of alpha-tocopherol supplementation, it may take as
much as two years to fully restore the body's alpha-togamma-
tocopherol ratio!5
Figure 1: Unbalanced alpha-tocopherol supplements deplete
your body of gamma-tocopherol. Redrawn from (2).
When alpha-tocopherol is taken at doses typical of most
"vitamin E" supplements, even counterbalancing it with an
equal amount of the "other" E vitamers isn't enough to
prevent this supplement-induced deficiency: the excessive
alpha-tocopherol still drives out gamma-, leaving your
levels 30% below what they would naturally be if you just
ate a regular diet.6 So the token amount of total tocopherols
other than alpha- contained in "mixed tocopherol" pills can't
hope to staunch the bleeding of this critical E vitamin from
your body. By contrast, even taking gamma-tocopherol
alone does not lower your alpha-tocopherol levels,17 and
taking supplemental tocotrienols actually boosts the alphatocopherol
level in your body.18,19
And (as we'll see), in addition to lowering the level of other
E-complex molecules in your body, supplements containing
too much alpha-tocopherol can directly counteract some of
the unique effects of the other E vitamins!
So what exactly can these "other" vitamin E molecules do
that alpha-tocopherol can't? The full answer to that question
will only come after many more years of research into this
emerging field of science. But we already have a lot of the
answers when it comes to two hot spots of vitamin E
research: gamma-tocopherol and the tocotrienols.
Gamma-Tocopherol
And the Smog Within
While we often tend to talk about "free radicals" as if they
were one faceless, undifferentiated horde of oxidative
enemies, they're actually more of a rag-tag mob than a
uniform army. Different free radicals are formed in
different ways, attack different targets, and are best
blocked by different antioxidants. CoQ10, for instance,
provides extremely effective defense against "lipid
peroxides" in cell membranes - but it's useless in defending
the body's proteins from "carbonylation" mediated by
unbound transition metals.
So one important reason to make sure that you're getting
the full spectrum of E vitamins is the fact that the unique
chemical structures of each of the vitamin E family members
gives them differing antioxidant roles in the body. For
instance, alpha-tocopherol and alpha-tocotrienol are the
most important and effective antioxidants when it comes to
protecting your biological membranes from free radicals
whose structure is based on oxygen20,21 - but they're almost
useless in defending you against the threat posed by
"reactive nitrogen species," such as peroxynitrite, nitroxyl,
and nitrogen dioxide.22-24
These nitrogen-based molecular vandals are the main class
of free radicals found in smog and cigarette smoke, and are
produced by the body during inflammation. As you may
know, there's a growing consensus in the scientific community
that inflammation lies at the heart of many age-related,
degenerative diseases: not just obvious ones like rheumatoid
arthritis, but also heart disease,25,26 cancer,27 and agerelated
neurodegenerative disorders (most notably
Alzheimer's disease).28 And there's now significant evidence
that much of the damage that inflammation inflicts on the
body is mediated by reactive nitrogen species.
But while the chemical structures of the "alpha-Es" make
them nearly powerless against these cellular arsonists,
gamma-tocopherol is very effective in trapping reactive
nitrogen species - many times more effective than its alphacousins.
22-24 As well, some evidence suggests that alphatocopherol
can play a role in dealing with nitrogen-based
Vitamin E Special ADVANCES in orthomolecular research
free radicals - not directly, but by lending a helping hand
to gamma-tocopherol, restoring it to active duty after it is
"injured" in the battle against the reactive nitrogen foe.29
Even when all they had to go on were the results of a few
test-tube studies and some anomalies in the previous vitamin
E research, the importance of fighting off reactive nitrogen
species led pioneering gamma-tocopherol researchers at
the University of California to suggest that "Because alphatocopherol
supplementation suppresses gamma-tocopherol
levels, a combination of the two tocopherols that better
reflects the ratios found in our diet may be more useful as
a supplement than the formulations currently available."22
Just a few years later, documentation has replaced
educated speculation as, one after another, studies have
reached the conclusion that gamma-tocopherol protects
against age-related, inflammation-linked degenerative
disease where alpha-tocopherol fails.
Gamma-Tocopherol Against Prostate Cancer
Older studies of alpha-tocopherol's effects on a man's risk
of prostate cancer have been rife with seeming
contradictions. One large study (the ATBC trial)30 found that
a low-dose (50 milligram) alpha-tocopherol supplement
reduced the risk of prostate cancer. Yet the results of a
previous study suggest that high-dose alpha-tocopherol
may actually increase prostate cancer risk.31,32 The
suggestion of a greater vulnerability was there at doses
exceeding 100 IU of alpha-tocopherol, and it became
stronger when scientists looked at a subgroup of men taking
400 IU.31
The latest study to investigate the subject33 may have
resolved the issue - by looking at the whole vitamin E
picture, instead of at alpha-tocopherol in isolation. This
study found that men who have the most gamma-tocopherol
in their blood are an astounding five times less likely to
develop prostate cancer than men whose blood gammatocopherol
levels are lowest. In the same study, alphatocopherol
and selenium levels were also found to be
protective, but only in men whose gamma-tocopherol levels
were also high: if gamma-tocopherol was low, then neither
of these other nutrients provided any benefits!
When researchers then looked back at the results of a
previous epidemiological study, they re-analyzed the results
and uncovered the same association.34 This result was also
consistent with a previous study in Japanese men,35 which
seemed to hint that gamma-tocopherol - but not alphatocopherol
- made men less likely to fall prey to this deadly
disease.
Why would gamma-tocopherol be so important in warding
off cancer of the prostate? No one can say for sure yet, but
a good bet is that there's a connection with reactive nitrogen
species.31 As we've already seen, chronic inflammation has
been linked to many different kinds of cancer,27 including
cancer of the prostate.36 A lot of inflammation's collateral
damage is inflicted directly by reactive nitrogen species ...
and gamma-tocopherol is an effective detoxifier of this
class of free radicals.

AOR Total E - 60 softgels
And there's more evidence linking nitrogen-based free
radicals to prostate cancer: the unique prostate-protecting
effects of the carotenoid lycopene. Carotenoids - such as
beta-carotene, lutein, and cryptoxanthin - are the plant
pigments that give many vegetables their colors. Numerous
studies have investigated the possibility that a diet rich in
carotenoids can protect a man from prostate cancer. When
this idea has been tested by looking at the dietary practices
of large populations of men, only lycopene has consistently
been found to be associated with reduced risk.37 And the
evidence is now building closer to a definitive conclusion, as
lycopene's prostate-protecting potency has now been
supported by preliminary controlled trials.38,39
Why only lycopene, and not its carotenoid cousins? Perhaps
it's because lycopene is much more effective against
reactive nitrogen species than are the other
carotenoids.22,40,41 If this is the key to lycopenes prostateprotecting
powers, then the promise of gamma-tocopherol
would be even greater, since even lycopene's ability to fight
off nitrogen-based free radicals is actually much weaker
than gamma-tocopherol's!22
The new information about prostate cancer, reactive
nitrogen species, and gamma-tocopherol may tie up the
loose ends in the vitamin E/prostate cancer story, giving
scientists an unified explanation of how low-dose alphatocopherol
could buffer the risk of prostate cancer,30 even
though high-dose alpha-tocopherol may possibly put men at
greater risk.31,32 Remember, while alpha-tocopherol alone is
almost impotent against the nitrogen-based free radical
assault,22-24 a small amount of alpha-tocopherol may help
keep gamma-tocopherol up and running, protecting you
against their onslaught.29 But a high intake of alphatocopherol
can force gamma-tocopherol out of your body,
denying you its protection altogether.2,5,6 So we would
expect that alpha-tocopherol would only be helpful against
prostate cancer at a dose low enough to allow gammatocopherol
levels to also be high - which is just what the
latest study found.33
But new research, published just before this article was
going to press, now suggests that there's more to the
protective power of gamma-tocopherol than its ability to
hose down reactive nitrogen species. In this new study,42
3
4 ADVANCES in orthomolecular research Vitamin E Special
scientists at the University of Bern's Institute of Biochemistry
and Molecular Biology investigated the ability the
tocopherols to prevent two different lines of prostate cancer
from advancing from the G1 ("Gap 1") phase (in which the
cancer cell increases its volume in preparation for
replicating its DNA) to the "S (Synthesis) phase" (in which
DNA is actually synthesized). The move from G1 phase to S
phase is a critical juncture in cancer cell proliferation:
slowing down this transition keeps the tumor from growing.
The differences were remarkable. In one cell line, gammatocopherol
slowed prostate cancer cell transition from G1 to
S by 86%, versus only 50% for alpha-tocopherol; the huge
efficacy gap was also seen in another prostate cancer line
(74% versus 48%), and also in a bone cancer cell line (13%
and 4%, respectively). By looking at the cells' production of
key proteins regulating the cell cycle, the scientists were
even able to track down this inhibition of growth to its
source: gamma-tocopherol significantly inhibited the cancer
cells' production of cyclins D1 and E - proteins that fuel
tumor growth by forcing cancer cells to undergo the G1-to-
S transition.42
This new research further reinforces the urgency of the
recommendations of the researchers who unraveled the
differing effects of the two tocopherols on mens' prostate
cancer risk: as they put it,33 "Since supplementation with
alpha-tocopherol may lower gamma-tocopherol
concentrations in plasma and tissues, consideration should
be given to supplementation with combined alpha- and
gamma-tocopherols in future prostate cancer prevention
trials."

AOR Total E - 60 softgels
Brain Smog Alzheimer's disease is now known to be a state
characterized by chronic inflammation: a slow flame that
gradually blackens the brain.28 Accordingly, people taking
anti-inflammatory drugs for more than two years have been
consistently found to have a dramatically lower risk of
developing the disease.43 Evidence has accumulated that, as
in other inflammatory disorders, much of the damage to the
brain of the Alzheimer victim is directly caused by nitrogenbased
free radicals generated by the inflammatory
process.44-46 The same appears to be true of several other
neurological disorders, including Parkinson's disease.45,46
The latest, strongest support for this hypothesis is a recent
study47 in which scientists looked at the amount of damage
in the brains of people with Alzheimer's disease that was
specifically caused by reactive nitrogen species. They found
that areas of the brain which degenerate in Alzheimer's
disease are riddled with the biochemical debris left over
when proteins are damaged by nitrogen-based free
radicals. In fact, these Alzheimer's-sensitive parts of the
brain had five to eight times as much of this kind of damage
as was found in areas of the brain which are less affected
by Alzheimer's pathology.
By tracing the smoky haze that clouds the brains of people
with Alzheimer's disease back to the flames of reactive
nitrogen, this study suggests that gamma-tocopherol might
be our first-line fire extinguisher. Scientists have just
released an ingenious study showing exactly that.48
As in a previous study,49 these investigators found that
alpha-tocopherol levels are the same in the brains of the
Alzheimer's victims as in the brains of people free from the
disease. But gamma-tocopherol levels are depleted
throughout the brains of people with Alzheimer's disease
compared to the brains of those without it, including a
significant decrease of over 50% in the cerebellum. These
depleted levels of gamma-tocopherol correspond with
increased levels of 5-NO2-gama-tocopherol - the leftover
husk of a molecule of gamma-tocopherol that has been
consumed in fighting nitrogen-based free radicals.48
What this shows is that there is a selective drain on gammatocopherol
in areas of the brain affected by Alzheimer's
disease, suggesting that this specific form of vitamin E is
being used up faster in the brains of people with the
disease than in healthy people. And you can almost hear the
second shoe dropping when researchers report that the
region-by-region pattern of used-up gamma-tocopherol
followed the pattern of nitrogen-based free radical
damage already established in the earlier study.47
To get a better idea of what gamma-tocopherol might
actually do to defend the cellular structures of the brain, the
same team tested gamma-tocopherol's capacity to protect
the enzyme alpha-ketoglutarate dehydrogenase complex
(KGDC) from damage by nitrogen-based free radicals,
comparing its power with alpha-tocopherol's performance.
KGDC is known to be destroyed by the nitrogen radical
peroxynitrite, and the brains of Alzheimer's patients have
50 to 75% less KGDC than do the brains of people who are
free of the disease. The researchers again confirmed the
protective power of gamma-tocopherol: as much as 55% of
the peroxynitrite damage to this Alzheimer's-sensitive
enzyme was prevented by gamma-tocopherol, while alphatocopherol
offered only a 15% reduction, even at the most
effective concentration.48
The implications of these detailed biochemical investigations
are supported by the results of recent studies comparing the
effectiveness of different sources of vitamin E in protecting
people against neurodegenerative diseases. In the last two
years, three separate studies of the risk of Alzheimer's
disease in large populations have found that high intakes of
the vitamin E in food - which is richest in gamma-tocopherol
- is associated with reduced risk of Alzheimer's disease,
while the use of alpha-tocopherol supplements provides no
protective benefits.50-52 A similar study of more general agerelated
cognitive decline reached the same conclusion.53
And the news keeps coming in, confirming that something
about food vitamin E is fundamentally different from the
vitamin E in supplements. As this article was approaching
press time, we were alerted to the results of a new study54
on the protective effects of "vitamin E" against Parkinson's
disease - a neurological disorder which, like Alzheimer's,
has been linked to reactive nitrogen species.45,46 In this
study,54 the diet and supplement habits of over 47 000 male
health professionals and nearly 80 000 nurses were
probed, and then their risk of Parkinson's was followed over
the course of the ensuing 12 to 14 years. Roughly one in five
of these health care workers was using a "vitamin E"
supplement (whether from alpha-tocopherol alone, or with
an cosmetic dash of "mixed tocopherols") - but these
supplements offered no protection. Yet those who got the
most of the vitamin E found in food, which is largely gamma
tocopherol, had their risk of Parkinson's disease knocked
down by one third.
The research all points in one direction. In fact, the scientists
who performed the landmark biochemical studies in
Alzheimer's patients' brains go further, suggesting that, since
"Dietary supplementation with alpha-tocopherol will
decrease plasma levels of gamma-tocopherol ... it is
conceivable that the beneficial effects of alpha-tocopherol
supplementation are confounded by a diminuition of
gamma-tocopherol pools in [Alzheimer's disease] ... A better
clinical paradigm might entail cosupplementation with
gamma-tocopherol [all emphasis ours]."48 As we've already
seen, these researchers are part of a growing chorus of
scientists calling for a fundamental shift in vitamin E
supplements: a shift away from alpha-tocopherol
hegemony, and toward a balance of E complex molecules,
giving preeminence to gamma-tocopherol.
Smoldering Arteries
Despite high hopes, many large-scale, double-blind,
placebo-controlled studies have now brought home an
inescapable conclusion: alpha-tocopherol supplements do
not give any protection against death from a heart attack
or other heart hazards in people at high risk, whether
alpha-tocopherol is taken alone (as in the HOPE,55 GISSI,56
CHAOS,57 Primary Prevention Project (PPP),58 and recent
VEAPS59 trials) or even in combination with other
antioxidants (as in the HATS60 and MRC/BHF Heart
Protection Studies61).
And late in 2004, the results of a new study combining these
and other trials into one "supertrial" (meta-analysis) made
the true impact of overdosing on alpha-tocopherol clear.62
The assembled trials showed no harmful effect from lowdose
(less than 50 IU per day) "vitamin E" supplements. In
fact, there even appeared to be a small benefit - but it's
hard to say, because most of these low-dose studies (the
Linxian, MIN.VIT.AOX., and SU.VI.MAX. trials) also included
selenium and other beneficial nutrients that might have been
responsible for the positive results. But the pooled results for
the "high dose" (>400 IU) trials were clear: people taking
400 IU or more of alpha-tocopherol a day are actually
increasing their risk of death!62
In contrast to the results of trials using alpha-tocopherol
supplements, studies of the health of large populations of
people consistently find that people getting plenty of the
"vitamin E" in food experience reduced risk of heart disease
and heart attacks.63-65 In fact, some studies64,65 have
specifically found that a high intake of the "vitamin E" in
food is protective against heart disease, but alphatocopherol
supplements are not.
Why the seeming paradox? Perhaps, again, the form of
"vitamin E" is to blame. Remember, the vitamin E in the diet
is fundamentally different from that in most so-called
"vitamin E" supplements. The vitamin E in food is a mixture
of the whole E complex, while most "vitamin E" supplements
are overloaded with alpha-tocopherol. And as we've
emphasized, supplements weighted toward alphatocopherol
deplete the body of other E vitamins, and can
even counteract their effects.2-6 So it may be that
conventional "vitamin E" supplements can't protect your
heart because of all of the vitamin E molecules that are
missing from, or drowned out in, such supplements.
Since gamma-tocopherol is the single largest component of
the vitamin E in the diet,9-13 it makes sense to look into the
role that this E-complex member might play in the protective
effect of the vitamin E family against heart disease. Such a
role would make sense in the context of our new
understanding of the key role played by inflammation in the
development and progression of heart disease,25,26 and of
reactive nitrogen species as one of the main ways that
inflammation can damage the body. And the connection
between reactive nitrogen and heart disease - and the
protective role of gamma-tocopherol - is much more than
just a reasonable-sounding theory. Plenty of studies have
found that people who have just suffered a heart attack66
Vitamin E Special AADDVVAANNCCEESS iinn oorrtthhoommoolleeccuullaarr rreesseeaarrcchh 5
6 ADVANCES in orthomolecular research Vitamin E Special
or who are afflicted with heart disease67-70 have low plasma
levels of gamma-tocopherol, while their alpha-tocopherol
levels are normal.
The question of just why heart patients' gamma-tocopherol
levels are so low may have been answered by a recent
study71 which measured the levels of 5-NO2-gamatocopherol
in such people. (You'll recall that the 5-NO2
marker is the telltale residue that's left over when gammatocopherol
detoxifies nitrogen-based free radicals. High
levels of this marker thus indicate that the body's gammatocopherol
is being used up in the fight against a brutal
onslaught of reactive nitrogen species). When scientists
measured levels of this waste product in the bodies of
people suffering with clogged-up arteries, they found that,
on top of having somewhat lower levels of gammatocopherol
itself, people with coronary heart disease have
three times more used-up gamma-tocopherol in their plasma
than do healthy people!71 Furthermore, these researchers
found similarly high levels of wasted gamma-tocopherol in
the atherosclerotic plaque itself, tying the suspect directly to
the scene of the crime.70
But other research shows us that gamma-tocopherol has
many heart-health benefits which reach beyond protecting
the body from reactive nitrogen species. For instance, a
study with experimental animals72 found that gammatocopherol
is superior to alpha-tocopherol in slowing down
the formation of potentially killer blood clots - clots which
can get stuck in a narrowed blood vessel and trigger a
stroke. The same study found gamma-tocopherol to be
better at preventing free radicals from making "bad" (LDL)
cholesterol more prone to form arteriosclerotic plaque
through oxidative modification, and at boosting levels of the
protective enzyme superoxide dismutase (SOD).
In another study,73 the same researchers tested the ability of
two different "vitamin E" preparations to protect heart cells
from the massive spike in free radicals that occurs when the
heart's oxygen supply is restored after a period of having
been cut off - a model of "reperfusion injury," which causes
much of the damage to the brain after a stroke, or to the
heart after a heart attack. One group of heart cells was
first pretreated with plain alpha-tocopherol. A second
group had its defenses bolstered with 62% gammatocopherol
blend (the remainder contained 25% deltatocopherol
and just 13% alpha-tocopherol). And a third
group was not given any protective E vitamins. Then, the
cells were subjected to the crisis of simulated reperfusion.
When heart cells are damaged by free radicals or various
other assaults, an enzyme called lactate dehydrogenase
(LDH) is leaked into the surrounding fluid at higher
concentrations than normal. This lets scientists use LDH levels
as a measure of damage to the heart after reperfusion
injury. In the unprotected cells, reperfusion savaged the cells,
causing levels of LDH in the surrounding medium to double.
As measured by the release of LDH, pretreatment with
alpha-tocopherol somewhat reduced the amount of
damage to the heart cells ... but in the cells given the highgamma-
tocopherol pretreatment, the injury was nearly
abolished (see Figure 2). The gamma-tocopherol blend also
provided superior protection against an aggravated
inflammatory response (as measured by the levels and
activity of the inflammatory enzyme inducible nitric oxide
synthase (iNOS)), and did a better job of keeping the
defensive SOD enzyme active (whereas reperfusion
normally forces its activity down).73
Figure 2: Gamma-tocopherol-rich mixture provides heart cells
with far more protection than alpha-tocopherol against
reperfusion injury, as measured by LDH. Redrawn from (73).
And there's more. While our attention has been focused on
its ability to protect the body from the downstream effects
of inflammation (by quenching reactive nitrogen species),
recent evidence shows that gamma-tocopherol can also
intervene in the inflammation process itself.
COX-2 Inhibitor
Cyclo-oxygenase (COX) is an enzyme involved in making a
class of cellular micro-hormones called prostanoids. There
are two varieties of this enzyme, called (reasonably
enough) COX-1 and COX-2. The prostanoids made by the
two forms of COX have very different effects on the body.
The prostanoids made by COX-1 are needed by cells to
perform essential, day-to-day "housekeeping functions"
such as producing mucin in the stomach, while the
prostanoids derived from COX-2 are involved in
inflammatory reactions. So when COX-2 is kept from
making its prostanoids, inflammation is blocked.
Many older anti-inflammatory drugs (such as aspirin and
Non-Steroidal Anti-inflammatory Drugs (NSAIDs) like
ibuprofen) work by inhibiting the inflammatory COX-2
enzyme. Unfortunately, these drugs also interfere with COX-
1, which prevents it from carrying out its important
n=5
*P<0.01 vs Control
†P<0.05 vs H-R
§P<0.05 vs a-T+H-R
Control
H-R
α-T+H-R
m-T+H-R
α-T+
Normoxia
m-T+
Normoxia
*
†
LDH Levels in Media (U/L)
40
20
0
† §
"housekeeping functions." It's this anti-COX-1 problem that
causes the ulcers, kidney damage, and other side effects
associated with these drugs. The new "COX-2" inhibitor
drugs (such as celecoxib (Celebrex(r)) and rofecoxib
(Vioxx(r))) put the damper on the fires of COX-2, but
without hampering the important activity of COX-1. This
allows them to provide the anti-inflammatory pain relief of
the NSAIDs with less risk to the kidneys and GI tract.
Now here's the vitamin E connection. Researchers have
recently reported that gamma-tocopherol, but not alphatocopherol,
is an effective COX-2 inhibitor.74 The discovery
was originally made in test tubes, but the anti-inflammatory
effect was confirmed in living organisms: the researchers
observed that "g[amma]T[ocopherol] supplementation
attenuated inflammation-induced damage in rats."
Does this mean that people suffering with chronic pain will
be able to ditch their pain medications in favor of gammatocopherol
supplements? Unfortunately, no: the effect of
gamma-tocopherol is much milder than is required to kill
pain or quench fevers in humans. But this research suggests
that gamma-tocopherol's ability to dampen the activity of
COX-2 might allow some people to use less of their
expensive, side-effect-causing anti-inflammatory drugs.
And it may have longer-term benefits as well. As we've
already noted, ongoing, low-level inflammation is
implicated in many age-related diseases. And COX-2
appears to be a key player in this process. COX-2 and the
prostanoids it makes are implicated in cancer,75 Alzheimer's
disease,76 and heart disease.77-79 There's even evidence
(including in some cases controlled clinical trials) that NSAIDs
and COX-2 inhibitors are protective against these
diseases.75-77,79 So it's possible that, over the long term,
gamma-tocopherol's mild COX-2 inhibitor capabilities may
provide an additional layer of protection against these
age-related assaults.
Gamma-Tocopherol in Aging
As we've seen, recent research has led to a new
understanding of the place of inflammation in age-related
diseases; of reactive nitrogen species as the key mediators
of inflammatory damage; and of gamma-tocopherol's
ability to protect against these smoggy internal pollutants.
So it's natural to find yourself asking whether, as we age,
even seemingly-healthy people's gamma-tocopherol stores
begin to fall, silently consumed by the unseen smudge-fires
of aging. Ironically, the question seems to have been
answered almost twenty years ago, before the importance
of reactive nitrogen was even understood - and the answer
is "yes."
In the mid-1980s, researchers at the Geriatric Research,
Education and Clinical Center of the Veterans
Administration Medical Center decided to see how aging
affected levels of all the tocopherols.80 Testing the blood of
volunteers ranging from 24 to 91 years of age, these
investigators found that, while concentrations of alphatocopherol
in plasma do not change significantly with age,
plasma gamma-tocopherol levels do drop off in correlation
with aging. With this study, an age-related loss of gammatocopherol
emerges as an invisible accelerator of the vicious
circle of aging, age-related disease, and inflammation.
The Fluid Regulator
Before going on to explore some of the exciting research on
tocotrienols, we'll briefly cover one last power of gammatocopherol
- a property which might protect the health of
your heart, and more. Ever since the 1960s, researchers
have been searching for the substance in the body which
allows the body to release excess extracellular fluid - the
water held in the space between your cells. Finding this
factor is not just a scientific curiosity, because retaining too
much extracellular fluid causes your blood pressure to shoot
up, as well as your risk of congestive heart failure, cardiac
fibrosis, and cirrhosis of the liver.81
The factor was finally identified in 1996: it's a substance
called LLU-alpha. LLU-alpha can only be made in the body
from gamma-tocopherol81 or gamma-tocotrienol:82 while
other E-complex members are metabolized in a similar
way,83 these metabolites do not regulate extracellular
fluid. This appears to be case of a biologically essential
"vitamin" activity - an activity for which other members of
the E family cannot substitute.
Tocotrienols
Fast-Strike Action
Tocotrienols, the "other half" of the E-complex, look a lot like
their tocopherol cousins - but with one crucial difference: the
"tails" of tocotrienol molecules have more unsaturated
bonds in them (see Figure 3). These unsaturated bonds make
tocotrienols more "fluid" molecules than the tocopherols, just
as the polyunsaturated fats found in most vegetable oils are
more fluid than saturated fats like butter.
Vitamin E Special ADVANCES in orthomolecular research 7
8 ADVANCES in orthomolecular research Vitamin E Special
Figure 3: Tocotrienols are more mobile because of their extra
double bonds.
Thanks to their extra fluidity, tocotrienols can slide around
more smoothly in cell membranes, allowing them to rush in
more rapidly to intercept incoming free radicals. And then,
having sacrificed themselves to protect your cell membranes
from the free radical threat, this same "lubrication" helps
tocotrienols get "recycled" more quickly into their active,
antioxidant form (for more on the critical "recycling"
interactions of E-complex molecules with the elite
Networking Antioxidant commando squad, see "Recycle
Your Antioxidants!" in an upcoming issue of Advances). As a
result of this "first-in, first-out" action, tocotrienols are forty
to sixty times more potent antioxidants than the
corresponding tocopherols in biological membranes.20
Tocotrienols Against Breast Cancer
Recently, Dr. Dawn Schwenke of the Wake Forest University
School of Medicine published an exhaustive review of the
evidence on vitamin E and breast cancer.84 She found that,
when studies of large populations of women have looked
for associations between "vitamin E" intake and risk of
breast cancer, the balance of evidence is that vitamin E in
food is associated with a lower risk of breast cancer. But she
found no evidence that the use of "vitamin E" supplements is
protective. Why the discrepancy?
Once again, the form of vitamin E in supplements may again
be to the key to the paradox. Remember, nearly all "vitamin
E" supplements are exclusively alpha-tocopherol, or are
heavily weighted toward this one E vitamer. By contrast, in
food, alpha-tocopherol is a minority ingredient in a
spectrum of E vitamins - a spectrum which is mostly gammatocopherol,
but which also includes other tocopherols and
tocotrienols in varying amounts.9-13 And five studies have
found that delta-tocopherol, as well as all four tocotrienols,
can slow the growth of breast cancer cells,85-87 and even
cause them to commit "cellular suicide"88,89 (apoptosis) in cell
culture. Critically, the same studies show that alphatocopherol
does not have this power.
Preliminary research also suggests that tocotrienols may
enhance the safety and effectiveness of tamoxifen, a drug
used to treat (and, in high-risk women, to prevent) breast
cancer. When tocotrienols are added to the medium bathing
breast cancer cells in culture, 75% to 95% less tamoxifen is
needed to stop the growth of half of the cells.87
Remarkably, swamping the cell with more estrogen does not
block this power of the tocotrienols. This would suggest that
a woman might be able to get the same anti-cancer effect
from a lower dose of tamoxifen plus tocotrienols as she
would using a higher dose of tamoxifen alone. If confirmed,
such an effect would slash the side-effects and toxicity of
the drug. By contrast, alpha-tocopherol treatment actually
results in more tamoxifen being needed to achieve the same
degree of growth inhibition!87
Clearly, further research is desperately needed to confirm
these powerful effects in human women. How much
tocotrienol might be used in such studies, based on the data
that science has accumulated to date? At first glance, it
might seem that very little would be required: tocotrienols
are rare in food compared with tocopherols, yet diets rich
in E-complex molecules are still associated with lower risk of
breast cancer. But for women at high risk, or who have
existing breast cancer, the results of the culture studies
suggest that higher dosages are well worth looking into. A
direct extrapolation would indicate that doses from 200 to
600 milligrams of total tocotrienols may be appropriate; on
the other hand, because tocotrienols tend to concentrate
themselves in fatty tissues like the breast, doses five to ten
times lower than this may be all that's needed to reach the
target concentrations.84 Fortunately, tocotrienols are
extremely safe, and any of these doses can be reached
using existing tocotrienol or complete E-complex
supplements.
Lipoprotein Balancers
As we've noted, studies in large populations of people living
their lives suggest that, while alpha-tocopherol supplements
do not protect you from heart disease, the equilibrated
mixture of different E-complex vitamins seen in food can
reduce your risk. We've already explored the many ways
that gamma-tocopherol may be contributing to this
protective effect. Now we'll explore the exciting research on
the role of the tocotrienols in heart health.
Numerous randomized, double-blind, placebo-controlled
trials have shown that, in combination with a diet low in
saturated fat, high doses (usually 200 milligrams),
tocotrienols lower total and LDL ("bad") cholesterol levels
over and above the effects of a heart-healthy diet
alone18,19,90,91-93 - typically by an additional 10 to 20%.
ADVANCES in orthomolecular research 9
Tocotrienols do this through a mechanism similar to - but not
the same as - the "statin" drugs (such as lovastatin
(Mevacor(r)) and simvastatin (Zocor(r))). The key to both
tocotrienols' and statins' effects on cholesterol lies in their
effects on an enzyme called hydroxymethylglutaryl CoA
reductase (or HMG-CoA reductase, if you don't have all
day to spit it out).
Despite what was once believed, most of the cholesterol in
the body is made by the body itself, and the cholesterol in
your food has only a very small impact on the amount of
cholesterol in your blood. The biosynthesis of cholesterol in
your cells takes place in several steps, and HMG-CoA
reductase occupies a critical place in the process. The
enzyme is called "HMG-CoA reductase" because it takes a
molecule of HMG-CoA and causes it to be biochemically
"reduced" into a molecule of mevalonic acid. Mevalonic
acid is then worked over by further enzymes, and the end
result is that a molecule of cholesterol is made. So if you can
somehow keep HMG-CoA from coming into contact with
HMG-CoA reductase, you can reduce the body's cholesterol
production.
"Statin" drugs work by preventing the enzyme from latching
onto HMG-CoA, so that it can't be turned into cholesterol.94
By contrast, tocotrienols simultaneously reduce the body's
production, and speed up the body's disposal, of the HMGCoA
reductase enzyme itself, so that there's less of the
enzyme available to work on HMG-CoA in the first place
(see Figure 4).95 Additionally, tocotrienols may help cells to
produce more "docking bays" for cholesterol,95 allowing
them to clear it out of the blood so that it doesn't build up
in the circulation and get "stuck" in blood vessels.
Tocotrienols may also reduce the formation of the protein
(apolipoprotein B) that carries cholesterol in the blood.96
By contrast, alpha-tocopherol is unable to favorably
modulate the HMG-CoA enzyme. And in fact, studies in
animals97,98 and humans99 have found that when tocotrienol
supplements contain more than one-third alpha tocopherol,
the cholesterol-balancing benefits of the tocotrienols are
lost!
In the most exciting test of tocotrienols' heart-health benefits
to date,100 fifty men and women with high cholesterol and
advanced atherosclerotic disease took either 240
milligrams of tocotrienols or a dummy pill for a year and a
half, without either the patients or their doctors knowing who
got what. Before starting the trial, and every six months
thereafter, scientists used ultrasound to monitor both groups'
disease status, measuring the thickening of the main artery
leading from the heart to the brain. As you might expect,
40% of the people taking the placebo got worse over the
course of the trial, and none improved. But astoundingly, not
only did only 8% of the tocotrienol group suffer any further
thickening, but 28% of the people taking the tocotrienol
supplement experienced an actual reversal of the
thickening of their arteries!
This is a far cry from the total failure of alpha-tocopherol
to protect heart health seen in previous studies. The
difference is most striking when you compare these results
with the recent VEPAS trial,59 which found that supplements
containing alpha-tocopherol alone may actually increase
the thickening of your arteries!
Stuck on You ...
Tocotrienols may have ways of keeping your arteries
plaque-free that extend beyond their ability to lower
cholesterol levels. One important mechanism may be the
tocotrienols' effect on adhesion molecules. When oxidized
LDL ("bad") cholesterol gets trapped in your arteries, the
arteries use adhesion molecules to call for help from a class
Vitamin E Special
8
7
6
5
0.30
0.27
0.24
0.21
0.18
0.15
mmol/L
HDL-chol / LDL-chol
I II III
Total Cholesterol
LDL-cholesterol
Figure 4: How Statin Drugs and Tocotrienols Affect Cholesterol
Synthesis.
Phase I = baseline
Phase II = American Heart Association (AHA) Step-1 diet
Phase III = AHA Step-1 diet + tocotrienol-rich fraction of rice
bran
10 ADVANCES in orthomolecular research Vitamin E Special
of immune cells called monocytes. The monocytes, once
activated, set about gorging themselves on rancid LDL,
desperately trying to clear the infiltrating toxin out of your
arteries. This might keep your arteries functional in the short
term, but the activated monocytes can't keep it up forever:
if LDL levels remain high, they will eventually stuff
themselves so full of the noxious gunk that they will literally
explode, filling your arterial tissue with toxic goo and their
own corpses, ultimately making the injury worse.26 So
preventing the arteries from attracting too many monocytes
is a key strategy in preventing the progression of
atherosclerotic disease.
Here's the tocotrienol connection. Using the cells that line the
inner layer of blood vessels, researchers compared the
ability of alpha-tocotrienol and alpha-tocopherol to
prevent both the production of several key adhesion
molecules (E-selectin, vascular cell adhesion molecule-1
(VCAM), and intercellular adhesion molecule-1), and the
actual adhesion of monocytes to the blood vessel cells.101
They found that alpha-tocotrienol cut the levels of key
adhesion molecules by 40 to 77%, and slashed monocyte
adhesion by 63%. Importantly, alpha-tocopherol was much
less effective.
Saving Brain Cells
Our brains have a love/hate relationship with a chemical
messenger known as glutamate. Glutamate is a stimulating
neurotransmitter which is essential to the formation of longterm
memories. Unfortunately, glutamate can be too
stimulating: excessive glutamate can lead to brain cell
death, and research suggests that abnormal glutamate
metabolism plays a major part in the loss of neurons in
neurological disorders such as Multiple Sclerosis (MS),102-104
Alzheimer's disease,105 Parkinson's disease,105 and Lou
Gehrig's disease (ALS).106,107 Glutamate excitotoxicity may
also play a role in damage to the neuroretinal system in
diabetics.108-110
Biochemists at the University of Berkeley's Packer Lab have
tested the ability of different members of the E complex to
shield brain cells exposed to glutamate in a test tube.
They've found that alpha-tocotrienol, but not alphatocopherol,
blocks brain cell death caused by glutamate.111
Interestingly, the effect was caused by an unique mechanism
involving cell signaling, and not by the molecules'
antioxidant properties.
The Lifespan Study
Japanese scientists recently reported that tocotrienols can
extend the average lifespan of the nematode
Caenorhabditis elegans by about 19% - while alphatocopherol
has no effect.112 Part of the reason for this lifeextending
effect may lie in the fact that tocotrienols, unlike
alpha-tocopherol, protect these animals against
carbonylation, a kind of free radical damage to the body's
proteins against which human research113 had already
proven alpha-tocopherol to be ineffective. In this study,112
tocotrienols cut carbonyl concentration by over 32%.
As part of the same study, the researchers exposed the
organisms to high-dose ultraviolet rays, and then treated
one group of nematodes with tocotrienols. While the
burning waves of UV reduced C. elegans' mean lifespan by
12%, animals bombarded by radiation and then given
tocotrienols lived longer than animals which had not been
subjected to radiation at all!112 What's especially
noteworthy about this finding is the fact that the scientists
only gave the organisms access to tocotrienols after they
had been assaulted by the damaging rays. So the longer
lives of these animals can't simply be the result of a
protective, antioxidant effect - after all, by the time the
animals received tocotrienols, the damage would have been
done. Instead, the suggestion is, tocotrienols somehow
helped the animals to recover from a free radical onslaught
they had already suffered.
It's a long way from a nematode to an aging human - but
perhaps not an insurmountable gulf. What might these
results bode for you and me?
How Much?
So let's say that you've decided that you want to take
advantage of this new research. Now that you know the
importance of getting a complete, balanced E-complex
formula, how much of the various vitamin E family members
should you take? The research on the place of the many Ecomplex
vitamers is still just a tiny exploratory expedition
into a vast, largely unexplored frontier, so the optimal
amounts and ratios of these molecules remain far from
nailed down. And different people, with different concerns
and priorities, will benefit from different E-complex
supplement plans. But we can gain some clues from the
research that's available to us.
First, obviously, to get the full benefits of the E-complex,
you'll want to ensure that your supplement contains the full
spectrum of eight E-complex vitamins: four tocopherols and
four tocotrienols, with no missing molecules. Second, because
of its depleting effect on other E-complex molecules, it's
important that the total amount of E-complex molecules
other than alpha-tocopherol should significantly exceed the
amount of alpha-tocopherol itself.
Vitamin E Special ADVANCES in orthomolecular research 11
In particular, based on what we know about the content of
different tocopherols in a healthy diet,9-13 and of the
depleting effects of excessive alpha-tocopherol,2-6 gammatocopherol
should make the single greatest contribution to
your E-complex fortification: there should be at least twice
as much gamma- as alpha-tocopherol in your total
supplement plan. Be sure to have a look at all of your
supplements. You may find that your multivitamin, your
antioxidant formula, or a supplement you take to address
some specific health concern are all laced with alphatocopherol.
You'll want to apply these rules on the sum of
your alpha-tocopherol intake, making sure that you're
getting enough of the rest of the E-complex to balance out
that "hidden" alpha.
But there will be people who are particularly concerned
with reaping the specific benefits of high-dose tocotrienols.
Such persons might include people looking to restore a
healthy lipoprotein pattern in their blood, or who are at
high risk of breast cancer, or who have existing heart
disease. If you're one of these people, the research suggests
you'll want to take considerably more tocotrienols than
would be felt necessary by basically healthy people who
are simply looking to preserve and enhance their overall
health. For people whose situations push them toward
tocotrienols, a separate, high-dose tocotrienol supplement is
an obvious solution. For such use, be sure that the amount of
alpha-tocopherol you're taking (in milligrams) does not
make up more than 30% of the sum of alpha-tocopherol
plus total tocotrienols combined, remembering to include the
alpha-tocopherol in all of your supplements in the equation.
Unfortunately, most multivitamin or antioxidant supplements
are formulated in ignorance of this research, with the result
that they often contain hundreds of IUs of alpha-tocopherol
and little to nothing of the rest of the complex. If you can,
it's probably best to avoid such products altogether; if you
can't, or choose not to, then you'll want to take extra
tocotrienols and gamma-tocopherol to meet the guidelines
we've discussed. (Since alpha-tocopherol is usually given in
IUs instead of milligrams, you'll need to multiply the IU value
of alpha-tocopherol by 0.66 to get the true number of
milligrams of alpha-tocopherol in these supplements).
The IU Lies!
And that brings up another point. People making the switch
from conventional alpha-tocopherol or "mixed tocopherol"
vitamin E formulas to a complete E-complex or tocotrienol
supplement often expect to see the "other" vitamin E
molecules in measured in the familiar international unit (IU).
But IUs are an inaccurate way to measure vitamin E activity.
The IU only measures one specific function of vitamin E: its
ability to prevent animals from spontaneously resorbing
their fetuses.
Alpha-tocopherol exerts the strongest influence on this
process, and thus is assigned the highest IU potency per
milligram. What the IU does not measure is the many unique
contributions to your health made by the other E-complex
molecules - contributions which go beyond the maintenance
of basic reproductive functions, which can be met in humans
by 15 milligrams of alpha-tocopherol per day. This means
that measuring vitamin E activity in IU distorts the
contributions made by different E molecules, exaggerating
the importance of alpha-tocopherol and downplaying the
contributions unique to the other E molecules. It's as if you
were asked to pay for works of sculpture by the pound,
irrespective of the subject or the sculptor: the real value is
obscured by an artificial common currency.

AOR Total E - 60 softgels
Vitamin E is an orchestra, and not just a talented tuba
player: eight molecules, not one. Make sure your E-team is
complete.
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AOR Total E - 60 softgels