Vitamin E Oxygen Society Education Program Traber 1

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Regulation of Vitamin E, a Nutritional
Antioxidant
The Virtual Free Radical School

• 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 [phone]
• Email maret.traber_at_oregonstate.edu

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RRR-?-Tocopherol
CH3
HO
CH3
O
H3C
CH3
CH3
H
H
CH3
CH3
CH3
2R
4R
8R
d-?-Tocopherol
3
Synthetic vitamin E all rac-a-tocopherol
H
H
H
H
HO
RRR
O
SRR
O
HO
H
H
H
H
HO
O
SSR
O
RSR
HO
H
H
H
CH
3
H
O
HO
SRS
O
RRS
HO
H
H
H
H
HO
O
SSS
O
RSS
HO
Vitamin E Oxygen
Society Education Program
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Naturally Occurring Tocopherols
Vitamin E Oxygen
Society Education Program
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Naturally Occurring Tocotrienols
Vitamin E Oxygen
Society Education Program
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Vitamin E Functions

• Specific role in a required metabolic function
  has not been found
• Major function appears to be as a fat-soluble,
  chain-breaking antioxidant
• Peroxyl radical scavenger
• Protects polyunsaturated fatty acids (PUFAs)
  within membranes and lipoproteins

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Lipid Peroxidation
Initiating Event
Initiation
Carbon-centered Free Radical
O2
R?
R-OO-H
Chain Reaction
Lipid Hydroperoxide
Propagation
ROO?
R-H

Peroxyl Radical
H
H

Polyunsaturated fat
Burton Traber. Annu. Rev. Nutr. 10 357-382
1990
Vitamin E Oxygen
Society Education Program
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Vitamin E Chain Breaking Antioxidant
Initiating Event
Initiation
Carbon-centered Free Radical
O2
R?
R-OO-H
Chain Reaction
Lipid Hydroperoxide
Propagation
ROO?
R-H

??TOH
Peroxyl Radical
Termination via Antioxidant
H
H
??TO?

R-OO-H
Polyunsaturated fat
Burton Traber Annu. Rev. Nutr. 10 357-382 1990
Lipid Hydroperoxide
Vitamin E Oxygen
Society Education Program
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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, aggregation, clotting

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Vitamin E Biologic Activity in Humans

• Absorption Chylomicron Catabolism
• All forms absorbed and transported to liver
• Lipoprotein Transport
• All lipoproteins transport vitamin E
• Liver Trafficking
• a-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.
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Circulation
Vitamin E Delivery to Tissues Lipoproteins
During Chylomicron Catabolism
Vitamin E
Intestine
CHYLOMICRONS
Fatty acids vitamin E to tissues
CHYLOMICRON REMNANTS
CIRCULATING LIPOPROTEINS
HDL
Vitamin E
Vitamin E
Vit. E
Tissue Vitamin E Uptake
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
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Preferential Secretion of ??Tocopherol in VLDL
and Its Delivery to Tissues
Vitamin E
BILE
Preferential Secretion
CHYLOMICRON REMNANTS
RRR- ??T
??T
VLDL
LDL
HDL
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.
Tissue Uptake
Vitamin E Oxygen
Society Education Program
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Regulation of Liver Vitamin E
Kayden, H.J. and M.G. Traber. J. Lipid Res. 34
343-358, 1993.
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Vitamin E Deficiency in Humans

• Malabsorption Syndromes
• Abetalipoproteinemia
• Cholestatic Liver Disease
• Cystic Fibrosis
• Short Bowel Syndrome
• Total Parenteral Nutrition
• Genetic Abnormalities in a-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.
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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
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Plasma deuterated ?-tocopherol concentrations in
controls and subject withataxia with vitamin E
deficiency (AVED)
Time (hours)
Traber, M.G. et al. J Clin Invest. 85 397-407,
1990.
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Vitamin E Definition

• Recommended intakes limited to the
  2Rstereoisomer forms of a-tocopherol
• RRR-a-tocopherol
• Half of the stereoisomers in all rac-a-tocopherol
• No other forms such as gtocopherol or
  tocotrienols meet vitamin E requirement
• All forms of supplemental a-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.
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Estimated Average Requirement (EAR) and
Recommended Daily Allowance (RDAs) for
a-Tocopherol (mg/day)
Life Stage
EAR
RDA

19 yrs, M
12
15
19 yrs, F
15
12
Pregnancy
12
15
Lactation
16
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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.
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Plasma a-Tocopherol in Response to Vitamin E
Supplements
100
a-tocopherol (a -T) and a-tocopheryl acetate (a
-TAC) from supplements 1 IU RRR-a-TAC divided by
1.36 equals mg RRR-a -TAC 1 IU all rac a -TAc
divided by 2 equals mg 2R-a-TAC 400 IU Vitamin
E 294 mg RRR-a-TAc or 268 mg RRR- a -T 200
mg 2R- - a TAc Or 182 mg 2R- a -T Devaraj et
al. Arterio Thromb Vasc Biol 172273, 1997
80
Plasma a-tocopherol µM
60
40
all rac-
20
RRR-
0
0
200
400
600
800
a-tocopherol (mg/day)
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Vitamin E Metabolites
2,5,7,8-tetramethyl-2(2-carboxy-ethyl)-6-hydroxyc
hroman
2,7,8-trimethyl-2(2-carboxy-ethyl)-6-hydroxychrom
an
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.
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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