In the future tocotrienols in different varieties are promising treatments for cancer and other
diseases. Alfa-tocotrienol is a potent agent on prevention of strokes and gamma- and deltatocotrienols
hold promise in holistic cancer treatment.

Health effects of tocotrienols – a scientific review
Christer Sundqvist, PhD, biology and biochemistry
christer.sundqvist@ravintokirja.fi
June 27th, 2017
The tocotrienols are prestigious members (isomers) of the essential fat-soluble vitamin E family.
Four tocopherols and four tocotrienols make up the active isomers of this family. This review is
focusing on the shockingly concealed health effects of the tocotrienol quartet: α- (alfa), β- (beta), γ-
(gamma) and δ- (delta) tocotrienol. The tocotrienols differ from the tocopherols only by the
presence of three conjugated double bonds in their phytyl side chains (Combs and McClung, 2017).



A brief history of tocotrienols
In the year of 1922 the American physician Herbert Evans and anatomy scientist Katherine Bishop
of University of California, while analyzing green vegetables, discovered something they called
”the mysterious substance X” (Evans ja Bishop, 1922). In 1924 ”substance X” was given the name
vitamin E. Later the American multitalented biochemist Elmer McCollum confirmed these
observations as he found vitamin E also from animal sources (egg yolk, lard and butter). Although
vitamin E is present in most plants, only plant oils are rich sources, and most people consume less
than recommended levels (Maras et al, 2004). The richest food sources are rice bran oil, in which
tocotrienols comprise most of the vitamin E isomers, and palm oil, in which tocotrienols
comprise 70% of total vitamin E isomers.
However, the tocotrienols were yet to enter the scene. The history of tocotrienols is commencing as
late as 1964 with the publication in the scientific journal Biochemical and Biophysical Research
Communications describing the detection of four tocotrienols in palm oil (Pennock et al, 1964). The
final assurity was due to the isolation of these four isomers of vitamin E from the rubber tree
(Hevea brasiliensis): α- (alfa), β- (beta), γ- (gamma) and δ- (delta) tocotrienols (Horvath et al,
2006). Herbert Evans wrote in 1962 that he was assisted in the coining of the name for vitamin E by
George M. Calhoun, Professor of Greek, and a colleague at the University of California. It was
professor Calhoun who suggested the Greek roots of this now-familiar name (Combs and McClung,
2017).
Around 1966 scientists started believing that vitamin E is essential for human health and research
focused on the health effects of principally alfa-tocopherol. This isomer is usually found in

commercial vitamin E supplements. Even today it is quite rare to find other isomers of vitamin E on
the market. The whole world together with scientists fell in love with alfa-tocopherol and
tocotrienols were merely forgotten. There were instances in vitamin consulting when nobody spoke
of vitamin E. The word used was tocopherol.
Let me cite a few lines from a tocotrienol book (Tan B, Watson RS, Preedy VR. Tocotrienols -
Vitamin E Beyond Tocopherols. CRC Press, 2013): ”Vitamin E was erroneously named tocopherol,
an error that remained uncorrected for 30 years - appearing as such in the Merck Index as recently
as 1996 - until eventually changed in 2001.”
Gradually interest towards tocotrienols arose, and several research groups began studying this
vitamin E isomer in greater detail.


Tocotrienols bring down cholesterol
Modern tocotrienol research pin-pointed their importance in preventing cholesterol synthesis and
especially their capacity to lower ”the bad” LDL-cholesterol. (Qureshi et al, 1986). The importance
of this finding was evident after the clarification of the biochemical mechanisms in detail and the
eminent researchers Joseph Goldstein and Michael Brown were awarded the Nobel Prize of
Medicine in 1985. Five years later the research group of Qureshi published their findings of
lowering the cholesterol with the aid of tocotrienols in palm oil. Finally the cholesterol lowering
mechanism was described by the research group of Bristol-Myers Squibb, a biomedical company, in
1992 and all the details were confirmed almost 15 years later in University of Texas (Song et al,
2006). The main message is: Delta-tocotrienol and gamma-tocotrienol are potent HMG CoA
reductase inhibitors, and the otherwise so important alfa-tocopherol has no effect on cholesterol
synthesis. 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting
enzyme of the mevalonate pathway.
Dr. Sundqvist is speculating that the surprisingly bad reputation of the palm oil and the heavily
marketed cholesterol-lowering statins have hindered distribution of proper information about the
health effects of tocotrienols. It seems like tocotrienols are nature's own way to correct disturbances
in lipid metabolism.
Specifically the antioxidative tocotrienols of palm oil were found beneficial in treating high levels
of serum lipids and atherosclerosis (Kooyenga et al, 1997). By virtue of the phenolic hydrogen on
the C-6 ring hydroxyl group, the vitamin E isomers have antioxidant activities. Kooyenga et al.
(2001) conducted a 4 year clinical study to investigate the effect of supplementation with an extract
from palm oil on carotid atherosclerosis. There were no reports of side effects (headache, intestinal
upset, muscle weakness, persistent liver function abnormalities etc.) in the 50 subjects studied.
Clinical studies are tricky as no statistically significant improvement in blood lipids was observed
during the first 36 months, although blood flow appeared to improve. Decreases in serum
cholesterol, LDL, and triglyceride levels and an increase in HDL occurred from month 36–48
during a period of consumption of rice bran oil containing tocotrienols. Eight of the subjects who
consumed the supplement moved to a lower category of stenosis, two subjects moved two
categories lower, three subjects increased in progression of disease, and the remaining subjects
showed no difference in disease progression. On offer is a lowering of cholesterol without any
statin-induced side effects. Tocotrienols produce significant (-28%) reductions in circulating
triglyceride levels by reducing the upstream regulators of lipid homeostasis genes (Zaiden et al,
2010).

More clinical studies are necessary. In one study the augmentation index (this index is interpreting
the flexibility of blood vessels) of healthy men was 5.3% better when ingesting 160 mg tocotrienols
daily for two months (Rasool et al, 2006). No change in lipid parameters was seen in Rasool's study.
Prevention of oxidation of LDL cholesterol is the reason for vitamin E's protection against heart
disease. The major role of vitamin E is as an antioxidant in body lipids. It's an essential component
of all cell membranes where it performs this vital function. Since the lipids in the cell membrane are
mostly polyunsaturated and more susceptible to peroxidation, vitamin E sits in the cell membrane
and stops oxidation by grabbing the free radicals before they can spread damage (Reinhard, 1998).
The way antioxidants work is that they themselves become oxidized, sort of sacrificing themselves
for the good of the body. And they are rewarded by an ingenious system of teamwork with the other
antioxidant nutrients.


Who is the winner?
Tocotrienols and tocopherols have been compared in many studies. Which isomer is better? Many
investigators claim that tocopherols (particularly the alfa-isomer) have been emphasized too much
on the behalf of tocotrienols. Tocotrienols are thought to have more potent antioxidant potential
than tocopherols, as their unsaturated side chains facilitate their more efficient penetration into
tissues containing saturated fatty layers, e.g., brain, liver (Combs and McClung, 2017).
The effects of tocotrienols would appear to be related to the fact that, because they are inefficiently
removed from the liver, they can stimulate stress responses including induction of detoxification
and antioxidant genes. These effects appear to be greatest for the undermethylated forms (γ- and δ-)
and in hypoxic cells, e.g., tumor cells (Combs and McClung, 2017).
Tocotrienols are prefered as more efficient and direct antioxidants than tocopherols in in vitro
-studies (Kamal-Eldin ja Appelqvist, 1996 ; Serbinova et al, 1991). Also indirect antioxidant
potential via selenium is better in tocotrienols (Ong et al, 1993). The comparison favors
tocotrienols also in promotion of apoptosis and cancer protection (Yu et al, 1999 ; McIntyre et al,
2000). Tocotrienols are also better neuroprotectors (Mazlan et al, 2006 ; Sen et al, 2000). In animal
studies the superiority of tocotrienols in prevention of cancer prevention has been found
(Komiyama et al, 1989), antioxidant potential is better (Serbinova et al, 1991 ; Ahmad et al, 2005),
protection against inflammations is expedited (Gu et al, 1999) and tocotrienols offer also better
protection against osteoporosis than tocopherols (Ahmad et al, 2005 ; Norazlina et al, 2007 ;
Hermizi et al, 2009 ; Mehat et al, 2010 ; Shuid et al, 2010). In tissue studies alfa-tocopherol has
been shown to increase allergy (mast cells lose their effectiveness) and tocotrienols have a
beneficial effect on allergy (Hemmerling et al, 2010 ; Komai-Koma et al, 2012). There are too few
clinical studies, but scientists assume that tocotrienols have the same effect in humans as in animal
and in vitro studies.
Tocotrienols tend to be less stable to high temperatures than tocopherols (Combs and McClung,
2017). Baking and frying tends to destroy them selectively.


Cancer and tocotrienols
The attractiveness of tocotrienols has emerged a large amount of scientific studies (Constantinou et
al, 2008; Ju et al, 2010). In 1994 international attention was drawn into the observation that
tocotrienols of palm oil decreased the growth of certain cancer types in vitro (Goh et al, 1994).
Many cancer types are dependable on the development of angiogenesis or the regeneration of small
blood vessels. Research has shown that delta-tocotrienol prevents the occurrence of angiogenesis
and the cancer is possibly stopped from growing (Shibata et al, 2008).
Gamma-tocotrienol appears to prevent colon cancer in tissue cultures (Yang et al, 2010). The
possible mechanisms could be prevention of angiogenesis, accelerated cell death (apoptosis) and
prevention of telomere growth in dividing cancer cells (Shibata et al, 2010; Eitsuka et al, 2006;
McIntyre et al, 2000). There is an urgent need for clinical trials in order to exploit the usefulness of
this observation in cancer treatment (Nesaretnam et al, 2010, 2011; Springett et al, 2011).
The research scenario is extremely challenging since alfa-tocopherol is possibly enhancing cancer
growth and gamma- as well as delta-tocotrienols prevent it from growing. This means there is no
easy solution available. No ”vitamin E protects you from cancer” is possible. Most likely there is a
need for exact tocotrienol dosage and much more reaserch in order to gain full understanding of this
type of cancer therapy.
In treatment of prostatic cancer tocotrienols are gaining popularity as smart solutions. Animal
studies have been performed with so called TRAMP mice (transgenic) and it sure looks good
(Barve et al, 2010). Tocotrienols given as food additives restrain the growth of prostatic cancer.
Dietary mixed tocotrienols reduce the levels of high-grade prostatic intraepithelial neoplasia as well
as the incidence of tumor formation compared to controls.
In the experiments the animals have been delivered a variety of different tocotrienols and alfatocopherol
has been totally eliminated from the dosage as there is evidence for possible stimulation
of cancer growth (Barve et al, 2010). Clinical studies are on its way. Humans are possibly best
treated with approx. 3 g/day of a mixture of tocotrienols in the form of a capsule. Researchers are
welcoming cooperation from developers of tocotrienol capsules and have a strong demand for
funding of clinical studies.
The effect of tocotrienols on breast cancer has been vividly studied for decades, but the output of
these studies have not been on a desirable level. A great majority of the injected tocotrienols have
not reached their target. Large doses of tocotrienols are also poisonous for healthy as well as cancer
cells. The most recent approach is to utilize nanotechnology, which means that tocotrienols are
capsulated inside small lipid droplets (Fu et al, 2011). This enhances the delivery of tocotrienols
into the cancerous tissue and prevents excess accumulation into healthy cells.
It is also possible to make transferrin protein coated vesicles (Dufès et al, 2013). This technique is
increasing the vitamin absorption of cancerous cells. Cancer cells have been found to depend on
large amounts of iron in order to continue dividing. Transferrin receptors are found on the surface of
cancer cells. They attract transferrin and the iron which is transported. This is an efficient way to
transport tocotrienols into the cancerous tissue, says the leading scientist doctor Christine Dufés.
New ways of transporting vitamins are developed at the laboratory of doctor Dufès (Karim et al,
2017). A better understanding on effects of tocotrienols on genes is emerging (Kannappan et al,
2010 & 2012)

As you can see, there has been promising cell culture tests of exact treatment of breast and lung
cancer (Nesaretnam et al, 2000 ; Pierpaoli et al, 2010). Unfortunately clinical tests have just started
(Nesaretnam et al, 2010). In a clinical trial lasting five years the tocotrienol group had a little bit
better survival rate than the controls. The tocotrienol group showed a 60% lower mortality in breast
cancer, but due to the small sample size the statistical significance was too low (Nesaretnam et al,
2010).
The biochemist and cancer reasearcher Bharat B. Aggarwal from university of Texas has for a long
time been accounting on tocotrienols in cancer therapy.