The Virtual Free Radical School
Regulation of Vitamin E,
a Nutritional Antioxidant
Maret G. Traber, Ph.D.
Department of Nutrition & Food Management
Linus Pauling Institute
571 Weniger Hall
Oregon State University
Corvallis, Oregon
541-737-7977
Fax: 541-737-5077
Email: maret.traber@oregonstate.edu
Vitamin E
Oxygen Society Education Program
Traber 1
RRR--Tocopherol
CH3
HO
CH3
O
H3C
CH3
CH3
2R
CH3 H
CH3 H
4’R
8’R
CH3
d--Tocopherol
Vitamin E
Oxygen Society Education Program
Traber 2
Synthetic vitamin E: all rac--tocopherol
CH3
H
H3C
H
CH3
HO
O
H3C
CH3
CH3
H
CH3
RRR
CH3
H
H3C
CH3
O
HO
CH3
CH3
H3C
H
H
CH3
CH3
SRR
CH3
CH3
H3C
CH3
H3C
CH3
H
H
CH3
CH3
CH3
CH3
CH3
HO
O
H3C
H3C
CH3
O
SSR
RSR
HO
CH3
CH3
CH3
H3C
H3C
H
H
CH3
CH3
CH3
HO
O
H3C
CH3
RRS
CH3
H3C
H
CH3
CH3
H3C
H3C
H
H3C
HO
O
CH3
CH3
SRS
H3C
H3C
H
CH3
CH3
O
HO
CH3
H3C
CH3
H
RSS
H3C
CH3
CH3
CH3
H
H
CH3
CH3
H3C
O
HO
SSS
CH3
CH3
Vitamin E
Oxygen Society Education Program
Traber 3
Naturally Occurring Tocopherols
CH3
-tocopherol
phytyl tail
HO
CH3
O
H3C
CH3
CH3
2R
CH3
-tocopherol
H
CH3
4’R
H CH3
CH3
8’R
HO
phytyl tail
O
CH3
CH3
HO
phytyl tail
-tocopherol
O
H3C
CH3
CH3
HO
phytyl tail
-tocopherol
O
CH3
Vitamin E
CH3
Oxygen Society Education Program
Traber 4
Naturally Occurring Tocotrienols
unsaturated tail
CH3
-tocotrienol
HO
CH3
O
H3C
CH3
CH3
CH3
CH3
CH3
CH3
-tocotrienol
HO
tail
O
CH3
CH3
HO
tail
-tocotrienol
O
H3C
CH3
CH3
HO
tail
-tocotrienol
O
CH3
Vitamin E
CH3
Oxygen Society Education Program
Traber 5
Vitamin E Functions


Specific role in a required metabolic
function has not been found
Major function appears to be as a fatsoluble, “chain-breaking” antioxidant
 Peroxyl
radical scavenger
 Protects polyunsaturated fatty acids
(PUFAs) within membranes and lipoproteins
Vitamin E
Oxygen Society Education Program
Traber 6
Lipid
Peroxidation
Initiating
Event
R
R-OO-H
Lipid Hydroperoxide
Carbon-centered
Free Radical
O2
Chain
Reaction
R-H
Initiation
Propagation
ROO
Peroxyl Radical
H H
=
Polyunsaturated fat
Vitamin E
Burton & Traber. Annu. Rev. Nutr. 10: 357-382; 1990
Oxygen Society Education Program
Traber 7
Vitamin E
Initiating
Chain Breaking Event
Antioxidant
Carbon-centered
R
R-OO-H
Lipid Hydroperoxide
Free Radical
Initiation
O2
Chain
Propagation
Reaction
R-H
ROO
Peroxyl Radical
H H
TO
=
Polyunsaturated fat
TOH
R-OO-H
Lipid Hydroperoxide
Vitamin E
Oxygen Society Education Program
Termination
via
Antioxidant
Burton & Traber Annu. Rev.
Nutr. 10: 357-382; 1990
Traber 8
Potential Cellular/Molecular
Mechanisms of Vitamin E

Endothelial cells
 Adhesion,
NO production, superoxide
production

Smooth muscle cells
 Proliferation

Macrophages
 Adhesion,
invasion, signaling recruitment,
ROS production

Platelets
 Adhesion,
Vitamin E
aggregation, clotting
Oxygen Society Education Program
Traber 9
Vitamin E Biologic Activity
in Humans

Absorption & Chylomicron Catabolism
 All

Lipoprotein Transport
 All

forms absorbed and transported to liver
lipoproteins transport vitamin E
Liver Trafficking
 -Tocopherol

specifically secreted into plasma
Metabolism
 Vitamin
E metabolites are NOT oxidation products
Brigelius-Flohe, R. and M.G. Traber. Faseb J. 13: 1145-1155, 1999.
Vitamin E
Oxygen Society Education Program
Traber 10
Vitamin E
Delivery to
Tissues &
Lipoproteins
During
Chylomicron
Catabolism
Circulation
Intestine
Vitamin
E
Vit.
E
CIRCULATING
LIPOPROTEINS
Tissue
Vitamin E
Uptake
Vitamin
E
LPL
CHYLOMICRONS
Fatty acids
& vitamin E
to tissues
CHYLOMICRON
REMNANTS
HDL
Vit.
E
Vitamin
E
Liver
Uptake
Traber, M.G. 1999. Vitamin E. In Modern Nutrition in Health and
Disease. M. E. Shils, J. A. Olson, M. Shike, and A. C. Ross, eds.
Williams & Wilkins. Baltimore. 347-362.
Vitamin E
Oxygen Society Education Program
Traber 11
Preferential Secretion of Tocopherol in
VLDL and Its Delivery to Tissues
Vitamin E
LIVER
Vitamin
E
CHYLOMICRON
REMNANTS
Preferential
Secretion
Lipolysis
T
T
LDL
HDL
Tissue Uptake
Vitamin E
BILE
RRRT
VLDL
Traber, M.G. 1999. Vitamin E. In Modern
Nutrition in Health and Disease. M. E. Shils,
J. A. Olson, M. Shike, and A. C. Ross, eds.
Williams & Wilkins. Baltimore. 347-362.
Oxygen Society Education Program
Traber 12
Regulation of Liver Vitamin E
Chylomicron
Remnants
lipoproteins
Vit E
{
Bile
Vit E
 tocopherol
other vitamin E
tocopherol
transfer protein
Plasma
tocopherol
Kayden, H.J. and M.G. Traber. J. Lipid Res. 34: 343-358, 1993.
Vitamin E
Oxygen Society Education Program
Traber 13
Vitamin E Deficiency in Humans

Malabsorption Syndromes
 Abetalipoproteinemia
 Cholestatic
Liver Disease
 Cystic Fibrosis
 Short Bowel Syndrome
 Total Parenteral Nutrition

Genetic Abnormalities in -Tocopherol
Transfer Protein
 Familial
Isolated Vitamin E Deficiency (FIVE)
 Friedreich's Ataxia Variants (AVED)
Traber, M.G. 1999. Vitamin E. In Modern Nutrition in Health and Disease. M. E. Shils, J. A. Olson, M.
Shike, and A. C. Ross, eds. Williams & Wilkins. Baltimore. p347-362.
Vitamin E
Oxygen Society Education Program
Traber 14
Clinical Features and Associated
Neuromuscular Lesions
in Human Vitamin E Deficiency

Loss of Position and Vibratory Sensation
 Peripheral
Nerve
 Posterior Columns

Ataxia
 Cerebellum
 Spinocerebellar

tracts
Weakness
 Skeletal
Muscle
Traber, M.G. 1999. Vitamin E. In Modern Nutrition in Health and Disease. M. E. Shils, J. A. Olson, M.
Shike, and A. C. Ross, eds. Williams & Wilkins. Baltimore. p347-362.
Vitamin E
Oxygen Society Education Program
Traber 15
Plasma deuterated -tocopherol
concentrations in controls and subject with
ataxia with vitamin E deficiency (AVED)
10
10

1 


nmol/ml



0.1








[d3-SRR]

[d6-RRR]


 
 


1

 0.1
CONTROLS
AVED SUBJECT
0.01
0.01
0
12 24 36 48 60 72
0
12 24 36 48 60 72
Time (hours)
Traber, M.G. et al. J Clin Invest. 85: 397-407, 1990.
Vitamin E
Oxygen Society Education Program
Traber 16
Vitamin E Definition

Recommended intakes limited to the 2R–
stereoisomer forms of tocopherol
 RRR--tocopherol
 Half
of the stereoisomers in all rac--tocopherol
 No other forms such as –tocopherol or tocotrienols
meet vitamin E requirement

All forms of supplemental tocopherol used to
establish the UL(upper limit)
Food and Nutrition Board and Institute of Medicine. 2000. Dietary Reference Intakes for
Vitamin C, Vitamin E, Selenium, and Carotenoids. National Academy Press. Washington, DC.
Vitamin E
Oxygen Society Education Program
Traber 17
Estimated Average Requirement (EAR) and
Recommended Daily Allowance (RDAs) for
-Tocopherol (mg/day)
Life Stage
EAR
RDA
19+ yrs, M
19+ yrs, F
12
12
15
15
Pregnancy
Lactation
12
16
15
19
Food and Nutrition Board and Institute of Medicine. 2000. Dietary Reference Intakes for Vitamin C,
Vitamin E, Selenium, and Carotenoids. National Academy Press. Washington, DC.
Vitamin E
Oxygen Society Education Program
Traber 18
Plasma -Tocopherol in Response
to Vitamin E Supplements
100
-tocopherol ( -T) and tocopheryl acetate ( -TAC)
from supplements:
1 IU RRR--TAC divided by
1.36 equals mg RRR- -TAC
1 IU all rac  -TAc divided by
2 equals mg 2R--TAC
80
Plasma 60
-tocopherol
µM
40
400 IU Vitamin E =
294 mg RRR--TAc
or 268 mg RRR-  -T
all rac-
20
RRR0
0
200
400
600
800 200 mg 2R- -  TAc
-tocopherol (mg/day)
Vitamin E
Or 182 mg 2R-  -T
Devaraj et al. Arterio Thromb Vasc
Biol 17:2273, 1997
Oxygen Society Education Program
Traber 19
Vitamin E Metabolites
-tocopherol
metabolite,
CEHC
CH3
HO
COOH
O
H3C
CH3
CH3
2,5,7,8-tetramethyl-2(2’-carboxy-ethyl)-6-hydroxychroman
-tocopherol
metabolite,
LLU
HO
COOH
O
H3C
CH3
CH3
2,7,8-trimethyl-2(2’-carboxy-ethyl)-6-hydroxychroman
Schultz, M. et al. Am J. Clin. Nutr. 62: 1527S-1534S, 1995.
Wechter, W.J. et al. Proc. Natl. Acad. Sci. USA. 93: 6002-6007, 1996.
Summary


Vitamin E requirement in humans limited to
tocopherol
Liver controls plasma vitamin E concentrations
TTP facilitates tocopherol secretion into plasma


Vitamin E deficiency results from genetic
defects in TTP
Vitamin E metabolism may be important in
regulating liver vitamin E
Vitamin E
Oxygen Society Education Program
Traber 21