INSIDER Webinar Series presents

Decoding the Elusive Vitamin E: Why

Tocotrienol Trumps Tocopherol
Sponsored by

To register for additional free Webinars,

visit NaturalProductsInsider.com
Today’s Webinar

 Today’s webinar will be available at

NaturalProductsInsider.com on Tuesday, Feb. 3

 To access this webinar, go to

NaturalProductsInsider.com, click on Webinars and
select today’s webinar title to view the presentation.
Today’s Presenter

Barrie Tan, Ph.D., earned his bachelor’s degree in

chemistry and doctorate in analytical chemistry at the
University of Otago, New Zealand, and later became a
professor of chemistry and food science/nutrition at the
University of Massachusetts, Amherst. His research
expertise included lipid-soluble materials such as
carotenoids, tocotrienols/tocopherols, CoQ10, omega-3s
and cholesterol. He was the first to introduce tocotrienol’s
benefits to our nutrition industry. He founded American
River Nutrition Inc. in 1998 and developed the first ever
tocopherol-free tocotrienol product derived from annatto
beans. Today, the focus of his research is on
phytonutrients that have an impact on chronic,
degenerative and cancer diseases.
 Decoding the Elusive Vitamin E:
© 1/09

Why Tocotrienol Trumps Tocopherol

Presented by
Barrie Tan, Ph.D.
American River Nutrition, Inc.©
January 27, 2009
 Vitamin E Perspective Today
© 1/09

• Superstar? Vitamin E – Antioxidant and Nothing More.1

• Under-dosing? Much higher doses of 3,200IU (2,100mg or
2.1g!) of Vitamin E needed to suppress oxidation
in humans.2
• Shocking! 95% of Americans do not even have enough
of the 12mg RDA, the proclaimed adequacy
to prevent a deficiency syndrome.3,4
• 5

1. Traber, M.G., and J. Atkinson. (2007) Vitamin E, antioxidant and nothing more. Free Rad Biol Med 43:4 -15.
2. Robert II, L.J., J.A. Oates, et al. (2007) The relationship between dose of vitamin E and suppression of oxidative stress in humans. Free Rad Biol Med 43(10):138 8-
93.
3. Maras, J.E., O.I. Bermudez, et al. (2004) Intake of alpha-tocopherol is limited among US adults. J Am Diet Assoc 104(4):567-575.
4. Traber, M.G. (2006) How much vitamin E?...Just enough! Am J Clin Nutr 84(5):959 -960.
5
5. Tocotrienols: Vitamin E beyond Tocopherols. 2008. Eds. R. Watson, V. Preedy. AOCS/CRC Press: Champaign, IL.
© 1/09

Vitamin E
Vitamin E Family ©1995-2003 by Michael W. Davidson

Tocopherol (T)
“Birth Vitamin” (1922)
RDA for Red Blood Cell
Function (1960)
Delta-T

Gamma-T

Beta-T

Alpha-T
Most common in vitamin
6
E supplements
© 1/09

Vitamin E
Vitamin E Family ©1995-2003 by Michael W. Davidson

Tocopherol (T) Tocotrienol (T3)

Delta-T Delta-T3

Gamma-T Gamma-T3

Beta-T Beta-T3

Alpha-T Desmethyl isomers - Alpha-T3

Most potent in
7
supporting heart health
© 1/09

Tocotrienol Trumps Tocopherol

• Both tocotrienol and

Chromanol nucleus

tocopherol are antioxidants

BUT….
• Only tocotrienol has

Tocotrienol
Tocopherol
been shown to:
– reduce cholesterol
– manage diabetes
– inhibit cancer Tocopherol
Tocopherol
Tocotrienol
Tocotrienol
Shorter farnesyl tail 8
© 1/09

Tail Discussion (1)

• Shorter tail = less anchor
= move faster = greater reach
to all membranes

• Trienol Tail
– Flip-flops less
– Waggles less
– Wobbles less

• Conclusion: Shorter tail moves

faster & better to protect a
much larger cell membrane
area (50x better)
9
9
© 1/09

Head Discussion (2)

• Less stuffed head (less
methyl groups) = smaller
head (desmethyl head) =
access to action

• Desmethyl Head
– Protracts (bobs and floats)
– Recharges faster
– Treat damage faster

• Conclusion: Smaller head

arrests/seals damaged
membrane efficiently
(50x better)
10
* Packer, L., S. U. Weber, et al. (2001). "Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling." J Nutr 131(2): 369S-73S.
* Atkinson, J., R. F. Epand, et al. (2008). "Tocopherols and tocotrienols in membranes: a critical review." Free Radic Biol Med 44(5): 739-64.
 Desmethyl Tocotrienols
© 1/09

• Desmethyl or less
methylated
(most potent; Mills-Nixon
Effect*)
– Delta-T3 and gamma-T3

• Fully or C-5 methylated

(less or non-potent)
– Alpha-T3 and beta-T3

δT3 γT3

11
* Behan, J.M., F.M. Dean, and R.A.W. Johnstone. 1976. Photoelectron spectra of cyclic aromatic ethers. Tetrahedron 32:167-171.
© 1/09

Interferences by Alpha-Tocopherol
• Blocks absorption of tocotrienols1
• Compromises tocotrienol’s ability to reduce
cholesterol2,5
• Induces breakdown of tocotrienols3
• Increases cholesterol in high doses4,5

1. Ikeda, S., et al. 2003. Dietary alpha-tocopherol decreases alpha-tocotrienol but not gamma-tocotrienol concentration in rats. J Nutr 133:428-434.
2. Qureshi, A. A., et al. 1996. Tocopherol attenuates the impact of gamma-tocotrienol on HMG-CoA reductase activity in chickens. J Nutr 126:389-394.
3. Sontag, T.J., and R.A. Parker. 2007. Comparative influence of major structural features of tocopherols and tocotrienols on kinetics of their ω -oxidation
by cellular and microsomal tocopherol-ω-hydroxylase. J Lip Res 48(5):1090-8.
4. Stocker, A. 2004. Molecular mechanisms of vitamin E transport. Ann NY Acad Sci 1031:44-59.
5. Khor, H. T. and T. T. Ng 2000. Effects of administration of alpha-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity. Int J
Food Sci Nutr 51 Suppl: S3-11.

12
© 1/09

Alpha-Tocopherol Attenuates Impact of

Desmethyl Tocotrienol
aT1
αT3 < 15%+and
< 15% gT3and
γT3 + dT3
δT3> 60%
> 60% HMGR Cholesterol

aT1
αT3 > 30%+and
> 30% gT3and
γT3 + dT3
δT3< 45%
< 45% HMGR? Cholesterol?

• Effective preparation for cholesterol reduction:

<15% α-tocopherol, >60% desmethyl tocotrienols
• Less effective or ineffective preparation:
>30% a-tocopherol, <45% desmethyl tocotrienols
• Shown in numerous animal studies (hamster, guinea pig, rat, chicken) with
alpha-T by itself or in combo with tocotrienols
* Qureshi, A. A., B. C. Pearce, R. M. Nor, A. Gapor, D. M. Peterson, and C. E. Elson. 1996. Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-
methylglutaryl coenzyme A reductase activity in chickens. J Nutr 126:389-94.
* Khor, H. T. and T. T. Ng 2000. Effects of administration of alpha-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity. Int J Food Sci Nutr 51 Suppl: S3-11.
* Khor, H.T. and D.Y. Chieng. 1997. Lipidemic effects of tocotrienols, tocopherols and squalene: studies in hamster. Asia Pac J Clin Nutr 6(1):36-40.
13
* Chen, H.W., C.K. Lii, et al. 1995. Dietary fat and vitamin E have differential effects on serum lipid levels. Nutr Res 15:1367-1376.
© 1/09

Diet and Supplement Vitamin E

Dietary Vitamin E Supplement Vitamin E

* Tan, B. 2005. Appropriate spectrum vitamin E and new perspectives on desmethyl tocopherols and tocotrienols. JANA 8(1):35-42. 14
* Eitenmiller, R. and J. Lee. 2004. Vitamin E: food chemistry, composition and analysis. New York, Marcel Dekker: 425-505.
© 1/09

Annatto Tocotrienols
Rice Palm Annatto

Tocopherol
Tocotrienol Tocopherol Tocotrienol
Tocotrienol

% Tocopherol
30 – 40% Des T3 50 - 55% Des T3 > 99% Des T3
Figure 1

100 100 100

80 80 80

60 60 60

40 40 40

20 20 20

0 0 0
Gamma Delta Gamma Delta Gamma Delta

• Only desmethyl Vitamin Es

• Exclusively delta-T3 and gamma-T3 Palm and rice have 150-300x
more tocopherols than
• Tocopherol-free annatto.
• All-natural 15
© 1/09
Bixa orellana: Annatto
• Natural source of
tocotrienols from
annatto beans

• 30-60x more potent

• The very best vitamin E tocotrienol nature makes!

16
© 1/09

Cholesterol Reduction Timeline (1)

1980 – Discovery of tocotrienol’s hypocholesterolemic activity
(U. Wisconsin/Madison)

1992 – Hypocholesterolemic Activity of Tocotrienols Specified

(Bristol-Myers Squibb)
• Delta- and gamma-tocotrienols are most active
• Alpha-tocotrienol is 5-30 times less active
• Alpha-tocopherol is inactive
• When combined, only delta-tocotrienol and gamma-tocotrienol
work best synergistically

1996 – Discovery of alpha-tocopherol’s interference with

tocotrienol’s cholesterol-lowering effects
17
© 1/09

Cholesterol Reduction Timeline (2)

2006 – Dose-Response Impact of Tocotrienols in Animals
• Which tocotrienol works better?
• Delta-tocotrienol worked best, followed by gamma-tocotrienol
• Potency of cholesterol-reduction is delta > gamma > TRF > alpha
• Alpha-tocopherol is inactive

2006 – Cholesterol-Reducing Mechanism of Tocotrienol Confirmed (U. Texas)

• Unequivocally confirms original Bristol-Myers Squibb study of 1992
• Tocotrienol blocks and degrades the HMGR enzyme protein
• Only delta- and gamma-tocotrienol decreases HMGR reductase
effectively, while alpha-tocotrienol is 10-fold less active
• Only delta-tocotrienol blocks HMGR
• Alpha-tocopherol does not work
• Endorsed/acknowledged by 1985 Nobel Prize winners for the
discovery of the LDL receptor, Goldstein & Brown 18
© 1/09
Mechanism of Action
Acetyl CoA

HMG CoA Reductase Statin

(HMGR) (targets HMGR)
Statin inhibits
entire IP
Isoprenoid Pool (IP)

Downregulates
Degrades

Geraniol

Farnesol

Geranylgeraniol
Cholesterol
Tocotrienol •Hypercholesterolemia 
(targets HMGR) •Lipidemia 

Proteins CoQ10
Protein  by statin may lead to: CoQ10  by statin may lead to:
•Global Myopathy •Congestive Heartfailure & Chronic Myopathy
•Anemia •Chronic Fatigue Syndrome & Energy/ATP 

*Pearce, B. C., R. A. Parker, M. E. Deason, A. A. Qureshi, and J. J. Wright. 1992. Hypocholesterolemic activity of synthetic and natural
tocotrienols. J Med Chem 35:3595-606.
*Song, B. L., and R. A. DeBose-Boyd. 2006. Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase
19
stimulated by delta- and gamma-tocotrienols. J Biol Chem 281:25054-61.
© 1/09

1992 Clinical – University of Wisconsin, Madison

Findings with TRF (200mg/day):
– Total cholesterol reduction: 15-22%
– LDL cholesterol reduction: 10-20%

– Of which 15% of patients did not respond to

supplementation

Additional supplementation
with 100mg/day delta- and
gamma-tocotrienol

Total cholesterol drop of 35 – 40% following

4 weeks supplementation
20
* Qureshi N., A. A. Qureshi. (1993). Tocotrienols, novel hypocholesterolemic agents with antioxidant properties. Vitamin E in Health and Disease. J. F. L. Packer. New York, Mercel Decker, Inc.:
247-267.
© 1/09

1993 Clinical – BMS-AMR 4-Week Internal Study

Findings with Delta- and Effects of Delta- and Gamma-tocotrienols

(100mg/day for 4 wks.) on Lipid Parameters
Gamma-Tocotrienol 20

Gamma-Tocotrienol
(100mg/day): 10 Delta-Tocotrienol

– Total cholesterol and LDL

% Change
0
reduction: 20-25%
– Triglyceride reduction:
-10

15-20% -20

– Delta-tocotrienol ≥ -30

Gamma-tocotrienol Serum
Cholesterol
LDL HDL TG

Lipid Parameters

21
© 1/09

2002 Clinical – Dose-Dependent Cholesterol-

Reduction by TRF in Hypercholesterolemic Humans
Findings of dose-
dependent study:
– Optimal dose is 75-
100mg/day
– Total cholesterol and
LDL reduction: 15-20%
– Triglyceride reduction:
7-10%

*Qureshi, A. A., S. A. Sami, W. A. Salser, and F. A. Khan. 2002. Dose-dependent suppression of serum cholesterol by tocotrienol-rich
fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis 161:199-207. 22
© 1/09

2004 Clinical – Lipid Profile of Hypercholesterolemic

Patients on Annatto Tocotrienols
Findings of Tocopherol-Free 10
Delta- and Gamma-
Tocotrienol (75mg/day): 0

%Change
– Total cholesterol & LDL: 15%↓
-10
– Triglyceride: 20-25%↓
– Cardiovascular risk (TC/HDL): -20
15-20%↓ Study A Study B
– Metabolic syndrome ratio -30
(TG/HDL): 20-30%↓ TC LDL HDL TG TC LDL HDL TG

– Plasma CoQ10: 20%↑ Lipid Parameters

(equi. to 30mg CoQ suppl.)

23
* Tan, B. and A. M. Mueller (2008). Tocotrienols in Cardiometabolic Diseases. Tocotrienols: Vitamin E beyond Tocopherol. R. Watson, V. Preedy, CRC/AOCS Press: 257-273.
© 1/09
Atherosclerosis
• Athere
(Gruel, thickening)
- stroke, heart attack

• Skleros
(Narrowing)
- high blood pressure,
small vessel problems

• Atherosclerosis
- hardening & blocking
of arteries, resulting
From Time: Your Body, A User’s Guide, 2008 in arterial dysfunction
24
© 1/09

Tocotrienol Reduces Plaque and Plaque Rupture

Atherogenic Diet Atherogenic Diet and Tocotrienol

Cholesterol Crystals Protruding cholesterol crystals at plaque

rupture site of human coronary artery
*Abela GS, and K Aziz. 2005. Cholesterol crystals cause mechanical damage to biological membranes: A proposed mechanism of plaque rupture and erosion leading to arterial thrombosis. Clin Cardiol 28:413-
420. 25
*Abela, G.S., and K. Aziz. 2006. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events – A novel insight into plaque rupture by SEM. Scanning 28(1):1-10.
* Black et al. 2000. Palm tocotrienols protect apoE +/- mice from diet-induced atheroma formation. J Nutr 130:2420-2426.
© 1/09
Tocotrienol Reduces Carotid
Atherosclerosis
• Tocotrienols regressed
carotid artery stenosis in
humans in a 4-year study
• With T3: 88% of subjects
either improved or
stabilized
• Without T3: 60% of
subjects deteriorated

26
* Kooyenga, D. K., T. R. Watson, et al. (2001). Antioxidants modulate the course of carotid atherosclerosis: A four-year report. Micronutrients and Health. K. Nesaretnam and L. Packer. Illinois,
AOCS Press: 366-375.
© 1/09

Tocotrienols Inhibit Atherosclerotic Lesions

Diets 0% DMT3† 71% DMT3 100% DMT3

(Months) (Alpha-T)
Low Fat 11% 42% 47%
(3.5 months)
High Fat (4.5 19% 28% 33%
months)
High Fat (6 23% 36% 57%
months)
†DMT3 = Delta- & gamma-tocotrienol
* Qureshi, AA, et al. 2001. Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 apoE-deficient mice. J Nutr 131:2606-2618. 27
* Black, T. M., P. Wang, et al. (2000). "Palm tocotrienols protect ApoE +/- mice from diet-induced atheroma formation." J Nutr 130: 2420-2426.
© 1/09

Dosage and Duration in Clinical Studies

Study (Source) Dosage (mg/d) Duration LDL ↓ (%) Triglyceride ↓ (%)
(months)
Hypercholesterolemia 500 1 15 13
(Palm)
Carotid Atherosclerosis 200-350 48 14 -
(Palm & Rice)
Hypercholesterolemia 200 1.5 0 -
(Palm*)
Hypercholesterolemia 100 1 20 8
(Rice†)
Dyslipidemia 100 1 20-25 15-20
(Pure Delta-T3, Gamma-T3)
Dyslipidemia 75 2 15 20-25
(Annatto)
* 33% alpha-tocopherol
† < 10% alpha-tocopherol and > 80% tocotrienols

1. Ajuluchukwu, J. N., N. U. Okubadejo, et al. (2007). "Comparative study of the effect of tocotrienols and -tocopherol on fasting serum lipid profiles in patients with mild hypercholesterolaemia: a preliminary report."
Niger Postgrad Med J 14(1): 30-3.
2. Kooyenga, D. K., T. R. Watson, et al. (2001). Antioxidants modulate the course of carotid atherosclerosis: A four-year report. Micronutrients and Health. K. Nesaretnam and L. Packer. Illinois, AOCS Press: 366-375.
3. Qureshi, A.A., D.A. Khan, et. Al. Interaction of alpha-tocopherol with palmvitee and lovastatin in cholesterol modulation in hypercholesterolemic human subjects. Manuscript in preparation.
4. Qureshi, A. A., S. A. Sami, W. A. Salser, and F. A. Khan. (2002). Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis
161:199-207.
5. BMS-AMR study (slide #19)
6. Tan, B. and A. M. Mueller (2008). Tocotrienols in Cardiometabolic Diseases. Tocotrienols: Vitamin E beyond Tocopherol. R. Watson, V. Preedy, AOCS/CRC Press: 257-273.
28
© 1/09
Effect of Tocopherol and Tocotrienol on Platelet
Aggregation (PA) in Stenosed Coronary Canine Artery

• Tocopherol-free tocotrienol (85% Delta & Gamma) significantly reduced PA in dogs with
induced coronary atherosclerosis
• Potency of PA Inhibition: DesT3 (Delta & Gamma) > Alpha-T3 > AlphaT
29
* Qureshi, A.A., C.W. Karpen, et al. (2009). “Tocotrienol-induced inhibition of platelet thrombus formation and platelet aggregation in a stenosed coronary artery canine model.” Manuscript in
preparation.
© 1/09

Diabetes by the Numbers

60 million
Pre-diabetics

27 million
Diabetics in 2005, about one quarter did not know

18.2 million
Diabetics in 2003
0 10 20 30 40 50 60 70

30
© 1/09

Complications of Diabetes

• 2-4 times higher risk of heart disease and stroke

• 75% of adults with diabetes have HBP
• 60-70% of people with diabetes have nerve-artery
damage
• Leading cause of blindness and kidney failure

31
© 1/09

AHA and NIH Metabolic Syndrome

Recommendations
• Metabolic syndrome is identified by presence
of three or more of these risk factors:
– Elevated waist circumference
– Elevated triglycerides
– Elevated blood pressure
– Elevated fasting glucose
– Reduced HDL cholesterol

32
© 1/09

Tocotrienol’s Effect in Type 2 Diabetes

• T3 decreases triglyceride
levels
• T3 reduces bad LDL and
increases good HDL
• The sum: Delta-T3 and
Gamma-T3 may help
manage diabetes and
prediabetes

• T3 reduces symptoms of
diabetes in animals: high blood
pressure, arterial integrity

33
33
© 1/09
2008 Leading Cancer Killers*
Women Men
Lung (71,030) Lung (90,810)

Breast (40,480) Prostate (28,660)

Colon & Rectum (25, 700) Colon and rectum (24,260)

Pancreas (16,790) Pancreas (17,500)

Ovary (15,520) Liver (12,570)

Non-Hodgkin lymphoma (9,370) Leukemia (12,460)

Leukemia (9,250) Esophagus (11,250)

Uterus (7,470) Bladder (9,950)

Liver (5,840) Non-Hodgkin Lymphoma (9,790)

80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000

34
*Source: American Cancer Society, Cancer Facts & Figures 2008.
© 1/09
2008 Leading Cancer Killers*
Women Men
Lung (71,030) Lung (90,810)

Breast (40,480) Prostate (28,660)

Colon & Rectum (25, 700) Colon and rectum (24,260)

Pancreas (16,790) Pancreas (17,500)

Ovary (15,520) Liver (12,570)

Non-Hodgkin lymphoma (9,370) Leukemia (12,460)

Leukemia (9,250) Esophagus (11,250)

Uterus (7,470) Bladder (9,950)

Liver (5,840) Non-Hodgkin Lymphoma (9,790)

80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000

35
*Source: American Cancer Society, Cancer Facts & Figures 2008.
© 1/09
Tocotrienols More Potent than Tocopherols
In Vivo and In Vitro
30 – 60x more potent

• Desmethyl tocotrienols dramatically increased bioavailability

• Inhibiting adhesion molecules, suppressing cancer growth, accumulating in tumors:
δT3 > γT3 > αT3 > δT > γT > αT
*Naito, Y., M. Shimozawa, M. Kuroda, N. Nakabe, H. Manabe, K. Katada, S. Kokura, H. Ichikawa, N. Yoshida, N. Noguchi, and T. Yoshikawa. 2005. Tocotrienols reduce 25-hydroxycholesterol-induced monocyte-
endothelial cell interaction by inhibiting the surface expression of adhesion molecules. Atherosclerosis 180:19-25. 36
*McIntyre, B. S., K. P. Briski, M. A. Tirmenstein, M. W. Fariss, A. Gapor, and P. W. Sylvester. 2000. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on normal mouse mammary epithelial cells.
Lipids 35:171-80.
* Hiura, Y., H. Tachibana, et al. 2008. Specific accumulation of gamma- and delta-tocotrienols in tumor and their antitumor effect in vivo. J Nutr Biochem. In press 2009.
© 1/09

Delta-Tocotrienol Treatment and Prevention of

Human Pancreatic Cancer*
• Apoptosis against pancreatic
cancer cells
– Delta-T3 >> gemcitabine, gamma-T3
– Delta-T3 is most potent Control

– Delta-T3 is non-toxic to non-

transformed cells

Delta-T3
• Preferred composition
– Delta-T3 and/or Gamma-T3
– Free of Alpha-T3, Beta-T3
– Free of tocopherol

37
* Malafa, M. P. and S. Sebti (2008). Delta-Tocotrienol Treatment and Prevention of Pancreatic Cancer. US, Lee Moffitt Cancer Center & Research Institute, University of South Florida (Tampa).
* Husain, K., R. Francois, et. Al. 2008. Delta-tocotrienol is the most bioactive natural tocotrienol in the prevention of pancreatic cancer transformation. Am Assoc Canc Res (April 12-16, 2008)
San Diego, Abstr 3826.
 © 1/09

Anti-Angiogenic Properties of Tocotrienols (1)

• Angiogenesis is important in
tumor growth, diabetic
retinopathy, rheumatoid
arthritis, and psoriasis
• Delta-T3 is most active;
without toxicity
• Alpha-T does not work
• May work better with omega-
3, resveratrol, EGCG, capsaicin
• Possible mechanisms:
– VEGF, FGF, EGF
– Telomerase
– Hypoxia

* Nakagawa, K., T. Eitsuka, et al. (2004). "DNA chip analysis of comprehensive food function: inhibition of angiogenesis and telomerase activity with unsaturated vitamin E, tocotrienol." Biofactors 21(1-4): 5-10.
* Mizushina, Y., K. Nakagawa, et al. (2006). "Inhibitory effect of tocotrienol on eukaryotic DNA polymerase lambda and angiogenesis." Biochem Biophys Res Commun 339(3): 949-55. 38
* Shibata, A., K. Nakagawa, et al. (2008). "Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1alpha." J Nutr 138(11): 2136-42.
© 1/09

Anti-Angiogenic Properties of Tocotrienols (2)

• In tumor-implanted mice:
(A) Without Delta-T3 –
Neovascularization
(B) With Delta-T3 – Inhibition of
neovessel formation

• Anti-angiogenic effect of Delta-T3 Neovascularization

attributable to
– Inhibition of growth factors
(e.g. vascular endothelial,
fibroblast, epidermal)
– Generation of ROS and apoptosis in
tumor

* Shibata, A., K. Nakagawa, et al. (2008). "Tumor anti-angiogenic effect and mechanism of action of delta-tocotrienol." Biochem Pharmacol 76(3): 330-9. 39
* Miyazawa, T., A. Shibata, et al. (2009). "Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol)." J Nutr Biochem 20(2): 79-86.
© 1/09
Delta-Tocotrienol Excels in Inducing Growth Inhibition of
Mammary Cancer Cells
>120uM
100

90
Potency to induce growth inhibition of
80 mammary tumor cells by 50%:
70
Treatment Dose to Induce IC 50 (uM)

δT3 > γT3 > αT3 > TRF > δT >> αT

60
Alpha-T

Alpha-T

50
Alpha-T

40
More invasive mammary cancer, more
Gamma-T3

30
responsive to tocotrienols:
Delta-T3

Gamma-T3

20
δT3 > γT3 > αT3 > TRF > δT >> αT
Delta-T3

Gamma-T3

10
TRF

Delta-T3

0
TRF

TRF

Preneoplastic
Neoplastic

Malignant
* McIntyre, B. S., K. P. Briski, et al. 2000. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary e pithelial cells. Proc Soc Exp
Biol Med 224(4): 292-301. 40
* Sylvester, P. W. and S. J. Shah. 2005. "Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells." Front Biosci 10: 699-709.
© 1/09
Interferences by Alpha-Tocopherol in
Mammary Cancer Cells
• Interferes with estrogen (+ve & –ve) cancer
• Antagonizes tamoxifen’s ability to block
estrogen +ve cancer by 1,000x
• Blocks completely the powerful effects of
tamoxifen on estrogen –ve cancer
• Argues for tocopherol-free desmethyl
tocotrienol (delta-T3 & gamma-T3) usage

1. Schwenke, D. C. (2002). "Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer?" J Nutr Biochem 13(1): 2-20.
2. Gundimeda, U., Z. H. Chen, et al. (1996). "Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells." J Biol Chem 271(23): 13504-14.
41
3. Guthrie, N., A. Gapor, et al. (1997). "Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and
tamoxifen, alone and in combination." J Nutr 127: 544S-548S.
© 1/09

Tocotrienol and Melanoma

• Desmethyl tocotrienols suppress
tumor growth in vitro and in vivo
100
• Via suppression of HMG CoA 90
reductase activity 80

• Tumor suppression: 70

T umor Weight (%)

Desmethyl isomers
– delta-T3: 50% 60

– delta-T3 + Lov: 60% 50

40
• Combo is nontoxic to animals at 30
tumor-suppressive doses with 20

T3:Lov of 5:1 10

• T3+Lov combo has already been 0

Control Alpha-T Gamma-T3 Delta-T3 Delta-T3 + Lov
successfully shown in 924 630
Blend

hypercholesterolemic patients u mol/kg

*He, L., H. Mo, S. Hadisusilo, A. A. Qureshi, and C. E. Elson. 1997. Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127:668-74.
*McAnally J.A., J. Gupta, S. Sodhani, L. Bravo, H. Mo. 2007. Tocotrienols potentiate lovastating-mediated growth suppression in vitro and in vivo. Exp Biol Med 232(4):523-31. 42
*Qureshi, A. A., S. A. Sami, et al. 2001. Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. J Nutr Biochem 12(6): 318-329.
© 1/09

Multifaceted Mechanisms of Tocotrienol

• Much higher cellular and tumor

bioavailability than tocopherol (50-
100x), especially delta-T3 and
gamma-T3
• HMG CoA reductase suppression
• Pro-apoptotic effects
• Anti-angiogenesis (growth factors,
hypoxia)
• Genetic regulations

Foundation for Cancer Research and Education

* Hiura, Y., H. Tachibana, et al. (2008). "Specific accumulation of gamma- and delta-tocotrienols in tumor and their antitumor effect in vivo." J Nutr Biochem. 43
* Mo, H. and C. E. Elson (2004). "Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention." Exp Biol Med (229): 567-585.
* Miyazawa, T., A. Shibata, et al. (2009). "Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol)." J Nutr Biochem 20(2): 79-86.
© 1/09 Antioxidant Values of Various Oils

DeltaGold® may be used as a food protectant (~500ppm) or as a super-antioxidant in

combination with EGCG and resveratrol.

* Kim, H. J. 2007. Oxidation mechanism of riboflavin destruction and antioxidant mechanism of tocotrienols. Food Science and Nutrition. Columbus, The Ohio State University. Ph.D.
*Qureshi, A. A., H. Mo, L. Packer, and D. M. Peterson. 2000. Isolation and identification of novel tocotrienols from rice bran with hypocholesterolemic, antioxidant, and antitumor properties. J Agric Food Chem 48:3130-
40.
*Chin, S.F., N.A. Hamid, et al. 2008. Reduction of DNA damage in older healthy adults by Tri E((R)) Tocotrienol supplementation. Nutrition 24(1):1-10. 44
*Yu, F. L., A. Gapor, and W. Bender. 2005. Evidence for the preventive effect of the polyunsaturated phytol side chain in tocotrienols on 17beta-estradiol epoxidation. Cancer Detect Prev 29:383-8.
 Antioxidation Action of Tocotrienol
© 1/09

• Oxidized LDL
• Advanced glycation
end (AGE) products
• Glycated hemoglobin
(HbAlc)
• Damaged DNAs
• Adhesion molecules
• Platelet aggregation
• Thromboxanes
• Leukotrienes
• CRP, TNF, NFkB
* Kim, H. J. 2007. Oxidation mechanism of riboflavin destruction and antioxidant mechanism of tocotrienols. Food Science and Nutrition. Columbus, The Ohio State University. Ph.D. 45
*Kim, H.J., and D.B. Min. 2007. Effects, quenching mechanisms, and kinetics of alpha-, beta-, gamma-, and delta-tocotrienol on chlorophyll photosynthesized oxidation of lard. Presented at IFT
Conference, July 2007.
 Product Concepts
© 1/09

1. T3 + (Sterol/RRY) 3. T3 + (EGCG/Resveratrol)
* Healthy lipids (cholesterol) * Healthy arteries
* Inside-Outside program (T3- * Healthy cells
Sterol) * Super lipid antioxidants
* One-Two punch (T3-RRY)
4. T3 + Lignans (Sesame/
2. T3 + Omega 3 Flaxseed)
* Healthy lipids (triglycerides) * Potentiate T3
* Healthy arteries * Increase blood levels
* Healthy RBCs
* Duncan, R.E., A. El-Sohemy, and M.C. Archer. 2005. Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA and DHA, alone and in combination with mevastatin. Cancer Letters 224:221-228.
* McAnally, J.A., J. Gupta, S. Shodhani, L. Bravo, and H.B. Mo. 2007. Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Exp Biol Med 232:523-531.
* Tan, B., and J. Llobrera. February 17, 2005. Annatto extract compositions including tocotrienols and tocopherols and methods of use. patent 2005003710 2. 46
© 1/09

Eye Formula
• Dry eye1
• Diabetic Retinopathy2
• Retinopathy of Prematurity3
• Glaucoma4
• Cornea (cataract)5
• T3 + Ω3 combo6,7
1. Rubin, B. Y., S. L. Anderson, et al. (2008). "Can the therapeutic efficacy of tocotrienols in neurodegenerative familial dysa utonomia patients be measured clinically?" Antioxid Redox Signal
10(4): 837-41.
2. Miyazawa, T., A. Shibata, et al. (2008). "Anti-angiogenic function of tocotrienol." Asia Pac J Clin Nutr 17 Suppl 1: 253-6.
3. Hittner, H., F.L. Kretzer. (1986). “Efficacy of Vitamin E in Retinopathy of Prematurity.” Retinopathy of Prematurity: Current Concenpts and Controversies. A.R. McPherson, H.M. Hittner, F.L.
Kretzer. B.C. Decker Inc: 89-103.
4. Meyenberg, A., D. Goldblum, et al. (2005). "Tocotrienol inhibits proliferation of human Tenon's fibroblasts in vitro: a compa rative study with vitamin E forms and mitomycin C." Graefes
Arch Clin Exp Ophthalmol 243(12): 1263-71.
5. Tanito, M., N. Itoh, et al. (2004). "Distribution of tocopherols and tocotrienols to rat ocular tissues after topical ophthal mic administration." Lipids 39(5): 469-74. 47
6. Miljanovic, B., K. A. Trivedi, et al. (2005). "Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women." Am J Clin Nutr 82(4): 887-93.
7. Rashid, S., Y. Jin, et al. (2008). "Topical omega-3 and omega-6 fatty acids for treatment of dry eye." Arch Ophthalmol 126(2): 219-25.
© 1/09

Tocotrienol-CoQ10 Formula
• CoQ10 and Systolic BP ↓ (6-18mm Hg)1-3
• CoQ10 and Diastolic BP ↓ (3-10 mm Hg)

• T3 and NOS ↑, Lipid Perox. ↓, SH ↓4-5

• T3 and Systolic BP ↓ (3-6 mm Hg)6
• T3 and arterial integrity ↑7

• Combo Concept per day:

100-200mg CoQ10
100mg Tocotrienol
1. Burke, B.E., et al. 2001. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J 94(11):1112-7.
2. Rosenfeldt, F.L., et al. 2007. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens 21:297-306.
3. Hodgson J.M., et al. 2002. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 56(11):1137-42.
4. Newaz, M. A., and N. N. Nawal. 1999. Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp
Hypertens 21:1297-313.
5. Newaz, M. A., Z. Yousefipour, N. Nawal, and N. Adeeb. 2003. Nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats: antioxidant protection by gamma-tocotrienol. J
Physiol Pharmacol 54:319-27.
6. Rasool, A.H.G., K.H. Yuen, K. Yusoff, A.R. Wong, and A.R.A. Rahman. 2006. Dosepdependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant
status, and lipid profile in healthy humans supplemented with tocotrienol -rich vitamin E. J Nutr Sci Vitaminol 52:473-478. 48
7. Rasool, A. H., A. R. Rahman, et al. 2008. Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E. Arch Pharm Res 31(9): 1212-7.
© 1/09

Conclusion
• DeltaGold® Annatto Tocotrienol is/has
– Multi-patent protection
– Tocopherol-free
– Exclusively Delta-T3 and Gamma-T3
– Best-in-Class Tocotrienol
– Made in the USA

• DeltaGold® Availability
– 50% Oil
– 35% Powder

49
© 1/09

First-Ever Tocotrienol Book!

This and more literature on

vitamin E tocotrienol available on
our website,

www.AmericanRiverNutrition.com

50
© 1/09

Contact Us!

DeltaGold® Tocotrienol
Your only source of tocopherol-free tocotrienol
arn@american-river.com
www.AmericanRiverNutrition.com
(413) 253-3449

American River Nutrition, Inc. ∙ 31 Campus Plaza Rd. ∙ Hadley, MA 01035

51