vitamin e oxygen society education program traber 1 regulation of vitamin e, a nutritional...
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Vitamin E Oxygen Society Education Program Traber 1
Regulation of Vitamin E, a Nutritional Antioxidant
Maret G. Traber, Ph.D.Department of Nutrition & Food ManagementDepartment of Nutrition & Food Management
Linus Pauling InstituteLinus Pauling Institute
571 Weniger Hall571 Weniger Hall
Oregon State UniversityOregon State University
Corvallis, OregonCorvallis, Oregon
541-737-7977541-737-7977
Fax: 541-737-5077Fax: 541-737-5077
Email: [email protected]: [email protected]
The Virtual Free Radical School
Vitamin E Oxygen Society Education Program Traber 2
CH3
CH3
CH3
CH3 CH3HHCH3 CH3
HO
H3CO
RRRRRR---Tocopherol-Tocopherol
2R 4’R 8’R
d--Tocopherol
CH3O
HO
H3C
H3C CH3
CH3
CH3CH3
CH3
HH
CH3
CH3
CH3HHH3C
CH3
CH3
HH3C H3C H
H CH3CH3
CH3
H3C H
CH3O
HO
H3C
H3C CH3
CH3O
HO
H3C
H3C CH3
CH3O
HO
H3C
H3C CH3
RRR
RSR
RSS
RRS
O
HO
H3C
CH3
CH3
CH3
CH3CH3
CH3
H
H
CH3
O
HO
H3C
CH3
CH3
CH3
CH3
CH3H
CH3
HH3C
O
HO
H3C
CH3
CH3
CH3
CH3
CH3
HH3CH3C H
O
HO
H3C
CH3
CH3
CH3H CH3
CH3
CH3
H3C H
SRR
SSR
SSS
SRS
Vitamin E Oxygen Society Education Program Traber 3
Synthetic vitamin E: all rac--tocopherol
Naturally Occurring TocopherolsNaturally Occurring Tocopherols
-tocopherol
-tocopherol
-tocopherol
-tocopherol
CH3
CH3
CH3
H CH3CH3CH3CH3H
HO
H3CO
CH3
phytyl tail
CH3CH3
CH3
HO
O
phytyl tail
CH3
HO
H3CO
phytyl tail
CH3CH3
HO
O
phytyl tail
2R 4’R 8’R
Vitamin E Oxygen Society Education Program Traber 4
Naturally Occurring TocotrienolsNaturally Occurring Tocotrienols
-tocotrienol
-tocotrienol
-tocotrienol
-tocotrienol
CH3
CH3CH3
HO
H3CO
CH3
CH3CH3
CH3
HO
O
tail
CH3
HO
H3CO
tail
CH3CH3
HO
O
tail
CH3
unsaturated tail
CH3
CH3CH3
Vitamin E Oxygen Society Education Program Traber 5
Vitamin E Oxygen Society Education Program Traber 6
Vitamin E FunctionsVitamin E Functions
Specific role in a required metabolic Specific role in a required metabolic function has not been foundfunction has not been found
Major function appears to be as a fat-Major function appears to be as a fat-soluble, “chain-breaking” antioxidantsoluble, “chain-breaking” antioxidant Peroxyl radical scavenger Protects polyunsaturated fatty acids
(PUFAs) within membranes and lipoproteins
Lipid Lipid PeroxidationPeroxidation
HH
=
R-OO-H
R-H ROO
Peroxyl Radical
Initiation
Propagation
O2
Carbon-centeredFree Radical
InitiatingEvent
R
Chain
Reaction
Lipid Hydroperoxide
Polyunsaturated fat Burton & Traber. Annu. Rev. Nutr. 10: 357-382; 1990
Vitamin E Oxygen Society Education Program Traber 7
Vitamin E Vitamin E Chain Breaking Chain Breaking
AntioxidantAntioxidant
HH
=
R-OO-H
R-H ROO
Peroxyl Radical
Initiation
Propagation
Termination viaAntioxidant
O2
Carbon-centeredFree Radical
InitiatingEvent
R
TO
TOH
Chain
Reaction
R-OO-H
Lipid Hydroperoxide
Lipid HydroperoxidePolyunsaturated fat
Burton & Traber Annu. Rev. Nutr. 10: 357-382; 1990
Vitamin E Oxygen Society Education Program Traber 8
Vitamin E Oxygen Society Education Program Traber 9
Potential Cellular/Molecular Potential Cellular/Molecular Mechanisms of Vitamin E Mechanisms of Vitamin E
Endothelial cellsEndothelial cells Adhesion, NO production, superoxide
production
Smooth muscle cellsSmooth muscle cells Proliferation
MacrophagesMacrophages Adhesion, invasion, signaling recruitment, ROS
production
PlateletsPlatelets Adhesion, aggregation, clotting
Vitamin E Oxygen Society Education Program Traber 10
Vitamin E Biologic Activity Vitamin E Biologic Activity in Humansin Humans
Absorption & Chylomicron CatabolismAbsorption & Chylomicron Catabolism All forms absorbed and transported to liver
Lipoprotein TransportLipoprotein Transport All lipoproteins transport vitamin E
Liver TraffickingLiver Trafficking -Tocopherol specifically secreted into plasma
MetabolismMetabolism Vitamin E metabolites are NOT oxidation products
Brigelius-Flohe, R. and M.G. Traber. Faseb J. 13: 1145-1155, 1999.
Vitamin E Vitamin E Delivery to Delivery to Tissues & Tissues &
Lipoproteins Lipoproteins During During
Chylomicron Chylomicron CatabolismCatabolism
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.
LPL
Fatty acids & vitamin Eto tissues
Vitamin
E
Vit.E
CIRCULATING LIPOPROTEINS
Vitamin E
CHYLOMICRONREMNANTS
Liver Uptake
Vitamin E
Vit.E
HDL
Tissue Vitamin E
Uptake
CHYLOMICRONS
Vitamin E Oxygen Society Education Program Traber 11
Intestine
Circulation
Preferential Secretion of Preferential Secretion of Tocopherol in Tocopherol in VLDL and Its Delivery to TissuesVLDL and Its Delivery to Tissues
LIVER
CHYLOMICRONREMNANTS
Vitamin E
VLDL
LDL HDL
TT
PreferentialSecretion
Lipolysis
Tissue Uptake
RRR-T
Vitamin E
BILE
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 12
Vitamin E Oxygen Society Education Program Traber 13
Regulation of Liver Vitamin ERegulation of Liver Vitamin E
Kayden, H.J. and M.G. Traber. J. Lipid Res. 34: 343-358, 1993.
ChylomicronRemnants
lipoproteins
tocopherolother vitamin E
Plasmatocopherol
{
Bile
Vit E Vit E
tocopherol transfer protein
Vitamin E Oxygen Society Education Program Traber 14
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 Deficiency in HumansVitamin E Deficiency in Humans Malabsorption Syndromes Malabsorption Syndromes
Abetalipoproteinemia Cholestatic Liver Disease Cystic Fibrosis Short Bowel Syndrome Total Parenteral Nutrition
Genetic Abnormalities in Genetic Abnormalities in -Tocopherol Transfer -Tocopherol Transfer ProteinProtein Familial Isolated Vitamin E Deficiency (FIVE) Friedreich's Ataxia Variants (AVED)
Vitamin E Oxygen Society Education Program Traber 15
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.
Clinical Features and Associated Clinical Features and Associated Neuromuscular Lesions Neuromuscular Lesions
in Human Vitamin E Deficiencyin Human Vitamin E Deficiency
Loss of Position and Vibratory SensationLoss of Position and Vibratory Sensation Peripheral Nerve Posterior Columns
AtaxiaAtaxia Cerebellum Spinocerebellar tracts
WeaknessWeakness Skeletal Muscle
Vitamin E Oxygen Society Education Program Traber 16
Plasma deuterated Plasma deuterated -tocopherol -tocopherol concentrations in controls and subject withconcentrations in controls and subject with
ataxia with vitamin E deficiency (AVED)ataxia with vitamin E deficiency (AVED)
Time (hours)
0.01
0.1
1
10
0 12 24 36 48 60 72
[d3-SRR]
[d6-RRR]
AVED SUBJECT
0.01
0.1
1
10
0 12 24 36 48 60 72
CONTROLS
nmol/ml
Traber, M.G. et al. J Clin Invest. 85: 397-407, 1990.
Vitamin E Oxygen Society Education Program Traber 17
Vitamin E DefinitionVitamin E Definition
Recommended intakes limited to the 2Recommended intakes limited to the 2RR––stereoisomer forms of stereoisomer forms of tocopheroltocopherol 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 All forms of supplemental tocopherol used to tocopherol used to establish the UL(upper limit)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 18
Estimated Average Requirement (EAR) and Estimated Average Requirement (EAR) and Recommended Daily Allowance (RDAs) for Recommended Daily Allowance (RDAs) for
-Tocopherol (mg/day)-Tocopherol (mg/day)
Life Stage EAR RDA
19+ yrs, M19+ yrs, F
PregnancyLactation
1212
1216
1515
1519
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 19
Plasma Plasma -Tocopherol in Response -Tocopherol in Response to Vitamin E Supplementsto Vitamin E Supplements
0
20
40
60
80
100
0 200 400 600 800
Plasma -tocopherol
µM
-tocopherol (mg/day)
all rac-
RRR-
-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
400 IU Vitamin E = 294 mg RRR--TAc or 268 mg RRR- -T
200 mg 2R- - TAc Or 182 mg 2R- -T Devaraj et al. Arterio Thromb Vasc Biol 17:2273, 1997
-tocopherolmetabolite,CEHC
CH3
CH3CH3
HO
H3CO
COOH
-tocopherol metabolite,LLU
CH3
CH3
HO
H3CO
COOH
Vitamin E MetabolitesVitamin E Metabolites
2,5,7,8-tetramethyl-2(2’-carboxy-ethyl)-6-hydroxychroman
Schultz, M. et al. Am J. Clin. Nutr. 62: 1527S-1534S, 1995.
2,7,8-trimethyl-2(2’-carboxy-ethyl)-6-hydroxychroman
Wechter, W.J. et al. Proc. Natl. Acad. Sci. USA. 93: 6002-6007, 1996.
Vitamin E Oxygen Society Education Program Traber 21
SummarySummary
Vitamin E requirement in humans limited to Vitamin E requirement in humans limited to tocopherol tocopherol
Liver controls plasma vitamin E concentrationsLiver controls plasma vitamin E concentrationsTTP facilitates tocopherol secretion into plasma
Vitamin E deficiency results from genetic Vitamin E deficiency results from genetic defects in defects in TTPTTP
Vitamin E metabolism may be important in Vitamin E metabolism may be important in regulating liver vitamin Eregulating liver vitamin E