1. Vitamin E Fat soluble compounds, produced by plants to prevent lipid peroxidation in their cell membranes and oil droplets Tocopherols (, β, ,  ) Tocotrienols (, β, ,  )

2. Vitamin E natural compounds

3. Eight stereochemical isomers of -Tocopherol in synthetic Vitamin E Active Inactive RRR- SRR- RSR- SSR- RRS- SRS- RSS- SSS- Different arrangement of methyl groups in the side chain starting at chromanol ring

4. Vitamin E units 1 IU (International Unit) = 1 mg all rac--tocopheryl acetate = 0.67 mg RRR--tocopherol 1 mg RRR--tocopherol = 1.49 IU

5. Vitamin E activity units Used in food tables to calculate total intake: -Tocopherol Equivalent (-TE) = mg -tocopherol + (mg β-tocopherol x 0.5) + (mg -tocopherol x 0.1) + (mg -tocotrienol x 0.3) mg -tocopherol = mg -TE x 0.8

6. (1.49 IU/mg) o Major sources are vegetable oils, whole grains, seeds and nuts. Food Sources

7. Vitamin E Dietary Reference Intakes (2000) Life StageAge RDA (mg/day) Infants0-6 mo4 7-12 mo6 Children1-3 y6 4-8 y7 9-13 y11 Adults>13 y15 Pregnancy15 Lactation19

8. Vitamin E Tolerable Upper Intake Levels Life Stage -tocopherol (mg/d) 0 - 12 monthsNot determinable 1 – 3 y200 4 – 8 y300 9 – 13 y600 14 – 18 y800 >19 y1000 UL are referring to any form of supplementary of -tocopherol, and were set to prevent increased tendency to hemorrhage.

9. Vitamin E Deficiency Very rare in normal subjects AVED (ataxia and vitamin E deficiency) – defect in  -TTP gene Abetalipoproteinemia (inability to produce chylomicrons, LDL, VLDL) Cystic fibrosis (defective fat absorption) Cholestatic liver disease

10. Vitamin E deficiency symptoms Primary symptom – peripheral neuropathy (degeneration of large axons in sensory neurons) Ataxia Myopathy Hemolysis of RBC in vitro, using hydrogen peroxide, is indicative of low vitamin E status. Plasma level < 600 μg/dL

11. Absorption and transport of vitamin E All forms are absorbed with fat in the intestine, esters are hydrolyzed Liver binds only RRR--tocopherol to hepatic -tocopherol transfer protein (-TTP) RRR--tocopherol is preferentially secreted by liver to circulating lipoproteins (VLDL, HDL, LDL)

12. Antioxidant Function of Vitamin E Vitamin E is a free radical scavenger which halts the chain reaction of polyunsaturated fatty acid (PUFA) peroxidation. Oxidation is caused by highly reactive free radicals that contain one or more unpaired electrons and donate an electron (oxidize) to an electron acceptor. When PUFA react with free radicals, they form lipid radicals, which react with molecular oxygen to form lipid peroxyl radicals. When vitamin E intecepts a peroxyl radical, a relatively stable tocopheryl radical is formed. Vitamin E is regenerated by other antioxidants (vitamin C, ubiquinols, glutathione).

13. Oxidative damage Free radicals Quenched radical Vitamin E Function

14. Vitamin E may play a limited but significant role in the prevention or alleviation of certain diseases: Atherosclerosis (coronary heart disease) – by prevention of LDL oxidation Cancer (prostate and lung) – by prevention of DNA damage Cataract – by prevention of oxidative damage to lens proteins Alzheimer’s disease (slower progression) Tardive dyskinesia (less involuntary movements) Therapeutic Vitamin E

15. Vitamin E in Cardiovascular Disease Animal studies strongly support the prevention of CVD by vitamin E - inhibition of LDL oxidation, of smooth muscle proliferation, of platelet adhesion and aggregation - promotion of prostacyclin (vasodilator) in endothelium Epidemiological studies and human intervention trials were inconclusive

16. Adverse effects of high doses of Vitamin E Increase in prothrombin time Interruption of blood coagulation Inhibition of platelet aggregation and adhesion Hemorrhage - sepsis and necrotizing enterocolitis in premature infants, hemorrhagic stroke in adults

17. Vitamin K

18. Food sources Green leafy vegetables (kale, turnip greens, spinach, broccoli, cabbage, lettuce), 100 – 450 μg/100g Other vegetables and fruits (green beans, peas, avocados) Vegetable oils and margarine (50 – 200 μg/100g) Endogenous sources Colonic bacteria *Human milk is very low in vitamin K (2.5 μg/L) Vitamin K sources

19. Vitamin K Dietary Reference Intakes Adequate Intake (AI): 0 - 6 mo 2 μg 7 - 12 mo 2.5 μg 1 - 3 y 30 μg 4 - 8 y 55 ug 9 – 13 y 60 μg 14 -18 y 75 μg male > 18 y 120 μg female > 18 y 90 μg No Upper Tolerable Level Intake (UL) was established because no adverse effects of high intake were observed.

20. Vitamin K is a cofactor of  -carboxylation of glutamate in blood clotting factors (prothrombin – Factor II, Factors VII, IX, X) and in bone protein – osteocalcin. Vitamin K Function

22. Inhibit vitamin K-dependent  -glutamyl carboxylase: Prevent recycling of vitamin K epoxide to active vitamin form: ANTICOAGULANTS

23. Deficiencies are very rare in humans except in newborns due to: insufficient gut bacteria poor placental transport of vitamin K low prothrombin synthetic capacity of neonatal liver Newborns routinely receive vitamin K injection (0.5 -1 mg vitamin K) or 2 mg orally, because human milk is very low in vitamin K (2.5 μg/L). Bleeding episodes may occur in patients with low vitamin K status on long-term antibiotic treatment (loss of colonic bacteria). Vitamin K Deficiency

24. Hemorrhagic disease of the newborn GI Bleeding

25. Vitamin K Deficiency Subdural hematoma Hemorrhagic disease of the newborn

26. Vitamin K Deficiency or Excessive Anticoagulation Bruising Purpura

27. Vitamin D A hormone or a vitamin? Vitamin D is photosynthesized in skin and converted by liver and kidneys to its active form. It is the most important biological regulator of calcium homeostasis. Dietary intake of vitamin D precursors is required when sunlight exposure is limited.

28. Vitamin D: Endogenous Production UV exposure can be as little as 20 min 3 x per week Acetyl-CoA Cholesterol

29. Vitamin D: Endogenous Production Renal 1  hydroxylase is rate limiting enzyme Active form

31. Boston (42º N) 1h Boston (42º N) 3h Edmonton (52º N) 1h Los Angeles (34º N) 1h Puerto Rico (18º N) 1h

34. Vitamin D units 1 IU = 0.025 μg cholecalciferol (D3) = 0.005 μg 25(OH)D 1μg cholecalciferol = 40 IU 1μg 25(OH)D = 200 IU AI for 0-50 y old = 200 IU AI for 51-70y old = 400 IU AI for >70 y old = 600 IU

35. Special considerations Higher vitamin D intake (25 μg/day) may be required with some drugs: Glucocorticoids inhibit vitamin D dependent intestinal calcium absorption Seizure control (phenobarbital, dilantin) may alter vitamin D metabolism, resulting in osteomalacia

36. Functions of Vitamin D Vitamin D maintains blood calcium and phosphorus levels It enhances the efficiency of Ca and P absorption by promoting the synthesis of Ca and P binding proteins in the intestine. It mobilizes Ca from bones by stimulation of osteoclasts formation. It stimulates Ca reabsorption by kidneys.

37. Vitamin D deficiency Defective bone formation in children Rickets: Rickets: Overproduction and deficient calcification of osteoid tissue (bone matrix). Multiple skeletal abnormalities result from the soft bones. Adult bone diseases Osteomalacia: Osteomalacia: a gradual softening and bending of the bones due to poor calcification of osteoid tissue. Osteopenia : decreased bone density (porotic bones, fractures) Possible increase in risk of cancer (colon, breast, prostate )

38. Symptoms of Vitamin D deficiency Rickets in Children: Squared appearance of head (frontal bossing) Rachitic rosary (overgrowth of rib cartilage and osteoid tissue) Pigeon breast deformity (concave breast) Bowing of legs or knocked knees

39. Rachitic Rosary

40. Rickets

41. Pseudofracture

42. Vitamin D Toxicity Most toxic of all vitamins Hypercalcemia (increased Ca absorption, enhanced bone resorption) Calcification of soft tissues (heart, kidneys, lungs, blood vessels) Loss of appetite Increased calcium excretion (hypercalciuria) Excessive thirst and urination Irritability, depression Upper Tolerable Intake Level (UL) 0-12 mo 25 μg or 1000 IU >1 y 50 μg or 2000 IU

43. Serum 25(OH)D Primary indicator of vitamin D adequacy Normal range: 16-74 ng/ml Deficient children: <11 ng/ml African-Americans and Mexican-Americans have lower range due to lactose intolerance and melanin pigmentation.