Vitamin E Oxygen Society Education Program Traber 1 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 Fax: The Virtual Free Radical School

Vitamin E Oxygen Society Education Program Traber 2 CH 3 HH HO H3CH3C O RRR-  -Tocopherol 2R4’R8’R d-  -Tocopherol

CH 3 O HO H 3 C H 3 C CH H H H HH 3 C 3 3 HH 3 C H 3 C H H H 3 C H 3 O HO H 3 C H 3 C CH 3 3 O HO H 3 C H 3 C CH 3 3 O HO H 3 C H 3 C CH 3 RRR RSR RSS RRS O HO H 3 C CH H H 3 O HO H 3 C CH H 3 HH 3 C O HO H 3 C CH HH 3 C H 3 C H O HO H 3 C CH H H 3 C H SRR SSR SSS SRS Vitamin E Oxygen Society Education Program Traber 3 Synthetic vitamin E: all rac-  -tocopherol

Naturally Occurring Tocopherols  -tocopherol  -tocopherol  -tocopherol  -tocopherol CH 3 H H HO H3CH3C O CH 3 phytyl tail CH 3 HO O phytyl tail CH 3 HO H3CH3C O phytyl tail CH 3 HO O phytyl tail 2R2R4’R8’R Vitamin E Oxygen Society Education Program Traber 4

Naturally Occurring Tocotrienols  -tocotrienol  -tocotrienol  -tocotrienol  -tocotrienol CH 3 HO H3CH3C O CH 3 HO O tail CH 3 HO H3CH3C O tail CH 3 HO O tail CH 3 unsaturated tail CH 3 Vitamin E Oxygen Society Education Program Traber 5

Vitamin E Oxygen Society Education Program Traber 6 Vitamin E Functions Specific role in a required metabolic function has not been found Specific role in a required metabolic function has not been found Major function appears to be as a fat- soluble, “chain-breaking” antioxidant Major function appears to be as a fat- soluble, “chain-breaking” antioxidant è Peroxyl radical scavenger è Protects polyunsaturated fatty acids (PUFAs) within membranes and lipoproteins

Lipid Peroxidation HH = R-OO-H R-H ROO  Peroxyl Radical Initiation Propagation O2O2 Carbon-centered Free Radical Initiating Event RR Chain Reaction Lipid Hydroperoxide Polyunsaturated fat Burton & Traber. Annu. Rev. Nutr. 10: ; 1990 Vitamin E Oxygen Society Education Program Traber 7

Vitamin E Chain Breaking Antioxidant HH = R-OO-H R-H ROO  Peroxyl Radical Initiation Propagation Termination via Antioxidant O2O2 Carbon-centered Free Radical Initiating Event RR  TO   TOH Chain Reaction R-OO-H Lipid Hydroperoxide Polyunsaturated fat Burton & Traber Annu. Rev. Nutr. 10: ; 1990 Vitamin E Oxygen Society Education Program Traber 8

Vitamin E Oxygen Society Education Program Traber 9 Potential Cellular/Molecular Mechanisms of Vitamin E Endothelial cells Endothelial cells è Adhesion, NO production, superoxide production Smooth muscle cells Smooth muscle cells è Proliferation Macrophages Macrophages è Adhesion, invasion, signaling recruitment, ROS production Platelets Platelets è Adhesion, aggregation, clotting

Vitamin E Oxygen Society Education Program Traber 10 Vitamin E Biologic Activity in Humans Absorption & Chylomicron Catabolism Absorption & Chylomicron Catabolism è All forms absorbed and transported to liver Lipoprotein Transport Lipoprotein Transport è All lipoproteins transport vitamin E Liver Trafficking Liver Trafficking   -Tocopherol specifically secreted into plasma Metabolism Metabolism è Vitamin E metabolites are NOT oxidation products Brigelius-Flohe, R. and M.G. Traber. Faseb J. 13: , 1999.

Vitamin E Delivery to Tissues & Lipoproteins During Chylomicron Catabolism Traber, M.G 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 LPL Fatty acids & vitamin E to tissues Vitamin E Vit. E CIRCULATING LIPOPROTEINS Vitamin E CHYLOMICRON REMNANTS 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  Tocopherol in VLDL and Its Delivery to Tissues LIVER CHYLOMICRON REMNANTS Vitamin E VLDL LDLHDL  T Preferential Secretion Lipolysis Tissue Uptake RRR-  T Vitamin E BILE Traber, M.G 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 Vitamin E Oxygen Society Education Program Traber 12

Vitamin E Oxygen Society Education Program Traber 13 Regulation of Liver Vitamin E Kayden, H.J. and M.G. Traber. J. Lipid Res. 34: , Chylomicron Remnants lipoproteins  tocopherol other vitamin E Plasma  tocopherol { Bile Vit E  tocopherol transfer protein

Vitamin E Oxygen Society Education Program Traber 14 Traber, M.G 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. p Vitamin E Deficiency in Humans Malabsorption Syndromes Malabsorption Syndromes è Abetalipoproteinemia è Cholestatic Liver Disease è Cystic Fibrosis è Short Bowel Syndrome è Total Parenteral Nutrition Genetic Abnormalities in  -Tocopherol Transfer Protein Genetic Abnormalities in  -Tocopherol Transfer Protein è Familial Isolated Vitamin E Deficiency (FIVE) è Friedreich's Ataxia Variants (AVED)

Vitamin E Oxygen Society Education Program Traber 15 Traber, M.G 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. p Clinical Features and Associated Neuromuscular Lesions in Human Vitamin E Deficiency Loss of Position and Vibratory Sensation Loss of Position and Vibratory Sensation è Peripheral Nerve è Posterior Columns Ataxia Ataxia è Cerebellum è Spinocerebellar tracts Weakness Weakness è Skeletal Muscle

Vitamin E Oxygen Society Education Program Traber 16 Plasma deuterated  -tocopherol concentrations in controls and subject with ataxia with vitamin E deficiency (AVED) Time (hours)           [d 3 -SRR] [d 6 -RRR] AVED SUBJECT        CONTROLS nmol/ml Traber, M.G. et al. J Clin Invest. 85: , 1990.

Vitamin E Oxygen Society Education Program Traber 17 Vitamin E Definition Recommended intakes limited to the 2R– stereoisomer forms of  tocopherol 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) All forms of supplemental  tocopherol used to establish the UL(upper limit) Food and Nutrition Board and Institute of Medicine 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 Recommended Daily Allowance (RDAs) for  -Tocopherol (mg/day) Life StageEAR RDA 19+ yrs, M 19+ yrs, F Pregnancy Lactation Food and Nutrition Board and Institute of Medicine 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  -Tocopherol in Response to Vitamin E Supplements 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

 -tocopherol metabolite,  CEHC CH 3 HO H3CH3C O COOH  -tocopherol metabolite, LLU  CH 3 HO H3CH3C O COOH Vitamin E Metabolites 2,5,7,8-tetramethyl-2(2’-carboxy-ethyl)-6-hydroxychroman Schultz, M. et al. Am J. Clin. Nutr. 62: 1527S-1534S, ,7,8-trimethyl-2(2’-carboxy-ethyl)-6-hydroxychroman Wechter, W.J. et al. Proc. Natl. Acad. Sci. USA. 93: , 1996.

Vitamin E Oxygen Society Education Program Traber 21 Summary Vitamin E requirement in humans limited to  tocopherol Vitamin E requirement in humans limited to  tocopherol Liver controls plasma vitamin E concentrations Liver controls plasma vitamin E concentrations  TTP facilitates  tocopherol secretion into plasma Vitamin E deficiency results from genetic defects in  TTP Vitamin E deficiency results from genetic defects in  TTP Vitamin E metabolism may be important in regulating liver vitamin E Vitamin E metabolism may be important in regulating liver vitamin E