The Virtual Free Radical School Regulation of Vitamin

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

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 CH 3 HO CH 3 O H 3 C CH 3 2

RRR- -Tocopherol CH 3 HO CH 3 O H 3 C CH 3 2 R CH 3 H 4’R 8’R CH 3 d- -Tocopherol Vitamin E Oxygen Society Education Program Traber 2

Synthetic vitamin E: all rac- -tocopherol CH 3 H 3 C H CH 3

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

Naturally Occurring Tocopherols CH 3 -tocopherol phytyl tail HO CH 3 O H 3

Naturally Occurring Tocopherols CH 3 -tocopherol phytyl tail HO CH 3 O H 3 C CH 3 2 R CH 3 -tocopherol H CH 3 4’R H CH 3 8’R HO phytyl tail O CH 3 HO -tocopherol H 3 C phytyl tail O CH 3 HO phytyl tail -tocopherol O CH 3 Vitamin EE CH 3 Oxygen Society Education Program Traber 44

Naturally Occurring Tocotrienols unsaturated tail CH 3 -tocotrienol HO CH 3 O H 3

Naturally Occurring Tocotrienols unsaturated tail CH 3 -tocotrienol HO CH 3 O H 3 C CH 3 CH 3 -tocotrienol HO tail O CH 3 HO -tocotrienol H 3 C tail O CH 3 HO tail -tocotrienol O CH 3 Vitamin E CH 3 Oxygen Society Education Program Traber 5

Vitamin E Functions Specific role in a required metabolic function has not been found

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 è Peroxyl radical scavenger è 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 O 2 Chain

Lipid Peroxidation Initiating Event R R-OO-H Lipid Hydroperoxide Carbon-centered Free Radical O 2 Chain Reaction R-H Initiation Propagation ROO Peroxyl Radical H H = Polyunsaturated fat Vitamin EE Burton & Traber. Annu. Rev. Nutr. 10: 357 -382; 1990 Oxygen Society Education Program Traber 77

Vitamin E Initiating Chain Breaking Event Antioxidant Carbon-centered R R-OO-H Lipid Hydroperoxide Free Radical

Vitamin E Initiating Chain Breaking Event Antioxidant Carbon-centered R R-OO-H Lipid Hydroperoxide Free Radical Initiation O 2 Chain Propagation Reaction R-H ROO Peroxyl Radical H H TO = Polyunsaturated fat TOH R-OO-H Lipid Hydroperoxide Vitamin E E Oxygen Society Education Program Termination via Antioxidant Burton & Traber Annu. Rev. Nutr. 10: 357 -382; 1990 Traber 8 8

Potential Cellular/Molecular Mechanisms of Vitamin E Endothelial cells è Adhesion, NO production, superoxide production

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

Vitamin E Biologic Activity in Humans Absorption & Chylomicron Catabolism è All Lipoprotein Transport

Vitamin E Biologic Activity in Humans Absorption & Chylomicron Catabolism è All Lipoprotein Transport è All forms absorbed and transported to liver lipoproteins transport vitamin E Liver Trafficking è -Tocopherol specifically secreted into plasma Metabolism è 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 Vit. E

Vitamin E Delivery to Tissues & Lipoproteins During Chylomicron Catabolism Circulation Intestine Vit. E CIRCULATING LIPOPROTEINS Tissue Vitamin E Uptake Vitamin E LPL Fatty acids & vitamin E to tissues CHYLOMICRON REMNANTS HDL Vit. E CHYLOMICRONS 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 E Oxygen Society Education Program Traber 11 11

Preferential Secretion of Tocopherol in VLDL and Its Delivery to Tissues LIVER Vitamin E

Preferential Secretion of Tocopherol in VLDL and Its Delivery to Tissues LIVER Vitamin E CHYLOMICRON REMNANTS Preferential Secretion Lipolysis T T LDL HDL Tissue Uptake Vitamin E E 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 12

Regulation of Liver Vitamin E Chylomicron Remnants lipoproteins Vit E { Bile Vit E

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 è Abetalipoproteinemia è Cholestatic Liver Disease è

Vitamin E Deficiency in Humans 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 è Familial Isolated Vitamin E Deficiency (FIVE) è 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. p 347 -362. Vitamin E Oxygen Society Education Program Traber 14

Clinical Features and Associated Neuromuscular Lesions in Human Vitamin E Deficiency Loss of Position

Clinical Features and Associated Neuromuscular Lesions in Human Vitamin E Deficiency Loss of Position and Vibratory Sensation è Peripheral Nerve è Posterior Columns Ataxia è Cerebellum è Spinocerebellar tracts Weakness è 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. p 347 -362. Vitamin E E Oxygen Society Education Program Traber 15 15

Plasma deuterated -tocopherol concentrations in controls and subject with ataxia with vitamin E deficiency

Plasma deuterated -tocopherol concentrations in controls and subject with ataxia with vitamin E deficiency (AVED) 10 10 1 nmol/ml 0. 1 [d 3 -SRR] [d 6 -RRR] CONTROLS 1 0. 1 AVED SUBJECT 0. 01 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 2 R– stereoisomer forms of tocopherol

Vitamin E Definition Recommended intakes limited to the 2 R– stereoisomer forms of tocopherol è RRR- -tocopherol è Half of the stereoisomers in all rac- -tocopherol è No other forms such as g–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

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

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 2 R- -TAC 80 Plasma 60 -tocopherol µM 40 20 0 400 IU Vitamin E = 294 mg RRR- -TAc or 268 mg RRR- -T all rac. RRR 0 200 400 600 800 200 mg 2 R- - TAc -tocopherol (mg/day) Vitamin E Or 182 mg 2 R- -T Devaraj et al. Arterio Thromb Vasc Biol 17: 2273, 1997 Oxygen Society Education Program Traber 19

Vitamin E Metabolites -tocopherol metabolite, CEHC CH 3 HO COOH O H 3 C

Vitamin E Metabolites -tocopherol metabolite, CEHC CH 3 HO COOH O H 3 C CH 3 2, 5, 7, 8 -tetramethyl-2(2’-carboxy-ethyl)-6 -hydroxychroman -tocopherol metabolite, LLU HO COOH O H 3 C CH 3 2, 7, 8 -trimethyl-2(2’-carboxy-ethyl)-6 -hydroxychroman Schultz, M. et al. Am J. Clin. Nutr. 62: 1527 S-1534 S, 1995. Wechter, W. J. et al. Proc. Natl. Acad. Sci. USA. 93: 6002 -6007, 1996. Vitamin E Oxygen Society Education Program Traber 20

Summary Vitamin E requirement in humans limited to tocopherol Liver controls plasma vitamin E

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