1. Vitamin E and Selenium Nov 6, 2013

2. Forms of vitamin E: alpha-tocopherol is the most active

3. 1.Tremendous hype as “wonder vitamin” – “prevents aging, heart disease, cancer, improves sex life, promotes wound healing”. Virtually none of this has been rigorously substantiated, but the vitamin pushers work hard to keep the myth alive. (Dr. Handelman’s judgement!). 2.Only defined role: protects polyunsaturated fatty acids (PUFA) from peroxidation. Since the CNS, and the membranes of the mitochondria, and are very rich in PUFA, vitamin E deficiency first attacks the central nervous system and muscles. All forms of vitamin E work pretty well, but only the a-tocopherol form is tenaciously retained by the body (see below).

4. 3.Deficiency in humans takes many years to develop, since we store several grams in our fat tissues. First tissue to be damaged is the retina, since the retina is very rich in fatty acids with 6 double bonds. 4.Long-term deficiency leads to spinal cord degeneration and muscle atrophy. 5.If your diet is high in PUFA, such as from fish, you more vitamin E in your diet. However, since vitamin E is plentiful in whole grains, vegetable oils, and green vegetables, even people who eat a lot of seafood get enough for health, and they don’t need supplemental vitamin E.

5. 6.Since vitamin E is NOT water-soluble, it is transported in the bloodstream in the lipoprotein particles (LDL and HDL). The diagram in the handout shows why only form, RRR-alpha-tocopherol, is conserved in the tissues. PEOPLE WHO LACK THIS BINDING PROTEIN require high daily doses of a-tocopherol to avoid being deficient. 7.Since 1990, there have been 4 large trials of vitamin E supplements to prevent heart disease – none has been effective, but other interventions (aspirin, ACE inhibitors, drugs to lower cholesterol) have been quite effective!

6. INITIAL FORMATION OF A PEROXYL RADICAL FROM UNSATURATED FATTY ACID

7. IF THESE EVENTS OCCUR IN THE MEMBRANE, THERE CAN BE SUBSTANTIAL DISTURBANCE TO THE STRUCTURE OF THE BILAYER, AS THE DAMAGED FATTY ACID “STICKS OUT”.

8. THIS TRIGLYCERIDE HAS TWO SATURATED FATTY ACIDS, AND ONE POLYUNSATURATED FATTY ACID

9. PALMITIC ACID: SATURATED FAT OLEIC ACID (1 DOUBLE BOND): MONOUNSATURATED FAT These fatty acids do not peroxidize. Which foods contain a lot of these fatty acids?

10. THESE ARE TWO IMPORTANT POLYUNSATURATED FATTY ACIDS. THEY HAVE A VERY POWERFUL IMPACT ON NUTRITION. BOTH OF THESE FATTY ACIDS PEROXIDIZE

11. THESE ARE TWO IMPORTANT POLYUNSATURATED FATTY ACIDS. THEY HAVE A VERY POWERFUL IMPACT ON NUTRITION.

12. THESE FATTY ACIDS ARE OBTAINED FROM SEAFOOD, IN ADDITION TO BEING MADE IN YOUR TISSUES. THEY ARE MAJOR COMPONENTS OF THE CNS AND RETINA. THEY PEROXIDIZE VERY FAST, WHICH IS WHY FISH DOES NOT KEEP WELL.

13. THE VERY HIGH ABUNDANCE OF EPA AND DHA IN THE BRAIN AND RETINA EXPLAINS: WHY THE MAJOR LESIONS OF VITAMIN E DEFICIENCY IN HUMANS OCCUR IN THE CNS.

14. INITIAL FORMATION OF A PEROXYL RADICAL FROM UNSATURATED FATTY ACID

15. THIS RADICAL ATTACKS ANOTHER FATTY ACID WITH MANY DOUBLE BONDS

16. Once an initial radical attack is made on a fatty acid – The first fatty acid radical will attack ANOTHER unsaturated fatty acid. Then another, and another. The first radical attack can lead to the destruction of hundreds of polyunsaturated fatty acids. VITAMIN E TO THE RESCUE!

17. In this scenario, the methyl radical reacts directly with vitamin E, to form methane, and the harmless tocopheroxy radical.

18. MORE TYPICALLY, VITAMIN E REACTS WITH LIPID-OO RADICALS

19. TOCOPHEROL DONATES HERE TO CREATE THE LIPID PEROXIDE PRODUCT.

20. VITAMIN E CONVERTS THE VERY DANGEROUS ROO INTO THE LESS DANGEROUS ROOH (lipid hydroperoxide). IT IS NOW UP TO Glutathione peroxidase TO REMOVE THE ROOH. VITAMIN E AND GLUTATHIONE PEROXIDASE WORK TOGETHER IN THE CELL.

21. Glutathione peroxidase (abbreviated, “GSH-Px” is a Selenium-Dependent ENZYME that converts peroxides to alcohols. The electrons for this reduction come from glutathione (GSH).

22. + GSH-Px (active enzyme) H Product is ~harmless alcohol of fatty acid + GSH-Px (inactive enzyme)

23. GSH-Px (active) GSH-Px (inactive) + 2 GSH + GSSG GSSG + NADPH 2 GSH + NADP + The enzyme is then reactivated by glutathione. Glutathione reductase enzyme Finally, all the GSSG is converted back to GSH

24. H GSH GSH-disulfide (or GSSG)

25. 1)Fatty-acid-OOH + GSH-Px (active) Fatty-acid-OH +GSH-Px (inactive) 2)GSH-Px (inactive) + 2 GSH GSH-Px (active) + GSSH 3)GSSG + NADPH 2 GSH + NADP + THE GLUTATHIONE PEROXIDASE PATHWAY. The first step requires selenium.

26. CONSERVATION OF RRR-alpha-TOCOPHEROL BY THE HEPATIC BINDING PROTEIN LIVER DIET: Many forms of vitamin E RRR-alpha-tocopherol other isomers of alpha-T gamma-tocopherol delta-tocopherol tocotrienols Intestinal lumen Lymph chylomicrons Bloodstream Chylomicron remnants, containing all different forms of vitamin E RRR-a- tocopherol Binding protein grabs alpha-T VLDL Bloodstream (mostly, alpha-T) LDL Others forms of vitamin E BILE: Largely gamma-T

27. A-TOCOPHEROL IS RAPIDLY EXCRETED IF THE BINDING PROTEIN IS DEFECTIVE LIVER DIET: Many forms of vitamin E RRR-alpha-tocopherol other isomers of alpha-T gamma-tocopherol delta-tocopherol tocotrienols Intestinal lumen Lymph chylomicrons Bloodstream Chylomicron remnants, containing all different forms of vitamin E RRR-a- tocopherol Binding protein grabs alpha-T VLDL Bloodstream (mostly, alpha-T) LDL Others forms of vitamin E BILE: alpha-T and gamma-T