vitamin e oxygen society education program traber 1 regulation of vitamin e, a nutritional...

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


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


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


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 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 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



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 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


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.



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


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)


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


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 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.


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.


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.


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

vitamin e oxygen society education program traber 1 regulation of vitamin e, a nutritional...

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