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Free Radicals and Vitamin E
- 1. FREE RADICALS AND VITAMINE BY: DR. MAYUR MAKADIA RESIDENT, BIOCHEMISTRY DEPARTMENT PRAMUKHSWAMI MEDICAL COLLEGE KARAMSAD
- 2. Definition • A freeradical is a molcule or molecular fragment that contains one or more unpaired electrons in its outer orbital. • Represented by a superscript dot, (R˙)
- 4. ROS • Normally, 4e-are transferred to complete reduction of O2 to form H2O. • O2 + 4H⁺ + 4e- ―› 2 H2O • The products of partial reduction of O2 are highly reactive and called Reactive Oxygen Species(ROS), Reactive Oxygen Intermediates, Oxygen free radicals(OFR).
- 5. ROS (reactive oxygenspecies) Free radicals Superoxide =O2 · Hydroxyl radical =OH · Lipid peroxyl =ROO · Hydroperoxyl =HOO· Particals, which are not free radicals Hydrogen peroxide (H2O2) Hypochlorous acid(HClO) Ozone (O3) Singlet oxygen (1 O2)
- 6. Reactive Oxygen Intermediates •Superoxide Radical: single electron reduction product of oxygen • Hydrogen Peroxide: two-electron reduction product of oxygen Dismutation • Hydroxy Radical: three-electron reduction product of oxygen Fenton Reaction Haber- Weiss Reaction
- 8. Transition Metals • Ferrousiron, and Cuprous copper can react with hydrogen peroxide to yield the hydroxy radical. • They are referred to as the Transition Metals. • They never occur in free, unbound form in the body.
- 9. Generation of OxygenFree Radicals • 1) Electron Leakage: major source Constantly produced due to leaks in ETC. There is production of superoxide radicals from interaction between CoQ and O2 in ETC.
- 10. Generation of OxygenFree Radicals • 2) Normal Oxidation- Reduction Reaction • Auto-oxidation of certain compound: Adrenaline, thiols, ascorbic acid • Falvin coenzymes present in peroxisomes are specially active in generating H2O2. • Enzymes: xanthine oxidase, aldehyde oxidase.
- 11. Generation of OxygenFree Radicals • 3) Exogenous Agents: • Toxic compound, such as CCl4 • Ionizing Radiation • Light of appropriate wavelengths • Cigarette smoke • Inhalation of air pollutants
- 13. Generation of OxygenFree Radicals • 4) Respiratory Burst: • Free radical production is sometimes required in biological systems.
- 15. Damage Produced byFree Radicals • Extremely reactive • Half life is only a few milliseconds • Almost all biological macromolecule are damaged • Protein: fragmentation of proteins. • Oxidation of sulfhydryl group containing enzymes, loss of function. • DNA: damaged by strand breaks, directly cause inhibition of protein and enzyme synthesis and indirectly cell death, mutation & carcinogenesis.
- 17. Lipid Peroxidation • Lipidsare most susceptible • PUFA present in cell membrane especially prone to damage. • Initiation phase: • Primary event is production of R˙ by interaction of a PUFA with free radicals generated by other means. • RH + OH˙ ―› R˙ + H2O
- 18. Lipid Peroxidation • Propagationphase: • R˙ rapidly react with molecular O2 forming a Peroxyl radical (ROO˙) which can attack another PUFA. • R˙ + O2 ―› ROO˙ • ROO˙ + RH ―› ROOH + R˙ • Net result is the conversion of R˙ to ROOH (Hydroperoxide). • But simultaneous conversion of R˙ to ROO˙ which lead to continuous production of Hydroperoxide. • Chain reaction • “Death kiss” by free radicals.
- 19. Lipid Peroxidation • Terminationphase: • The chain reaction continue untill a peroxyl radical react with another peroxyl radical to form inactive products. • ROO˙ + ROO˙ ―› RO-OR + O2 • R˙ + R˙ ―› R-R • ROO˙ + R˙ ―› RO-OR
- 21. Free radical scavengersystems • Also called Antioxidant defence mechanism
- 22. Free radical scavengersystems • A) Preventive mechanism: Prevent the generation of free radicals • B) Interceptive mechanism: Destroy the free radicals that are generated
- 23. Preventive mechanism • Theefficacy of ETC • Sequestration of transition metals • Peroxide decomposing enzymes – Glutathion peroxidase – Catalase
- 24. Interceptive mechanism • A)Enzyme: Superoxide dismutase (SOD) • Only enzyme that take a free radical as its substrate. • Different isoenzymes • 1) mitochondrial SOD: Mg++ dependant • 2)cytosoplasmic SOD: copper-zinc dependant
- 26. Interceptive mechanism • B)Non- enzyme substance: • Vitamin E • Retinoids • Ascorbate • Ceruloplasmin • Uric acid
- 27. Vitamin E asantioxidant • Most effective naturally occurring chain breaking antioxidant in tissue. • Alpha tocopherol (T-OH) intercept the peroxyl free radical • T-OH + ROO˙―› TO˙+ ROOH • The tocoperoxyl radical formed is stable and will not propagate the cycle any further • TO˙+ ROO˙ ―› inactive products
- 28. Vitamin E • Onlytraces of tocopherol are required to protect considerable amounts of PUFA. • 1 tocopherol per 1000 lipid molecule • But as antioxidant, alpha tocopherol is consumed, so it has to be replenished by dietary supply
- 29. Vitamin E • Isolatedfrom wheat germ oil • Earlier known as Anti-Sterility Vitamin • Other name “tocopherol” derived from greek word tokos (childbirth), pheros (to bear) and ol(alcohol) • Eight naturallly occurring tocophrols • Most Important: Alpha tocopherol
- 30. Vitamin E • Chemicalstructure: • A chromane ring(tocol), with an isoprenoid side chain
- 31. Vitamin E • Absorption: along with other fats and need bile salts • Transport : as chylomicrons • Store : adipose tissue • Plasma concentration : 0.5-1 mg/dL • Excretion : in feces via hepato-biliary route, after chromane ring oxidation followed by conjugation with glucuronic acid
- 32. Function of VitaminE • Most powerful natural antioxidant
- 34. Function of VitaminE • Reduce risk of Atherosclerosis by reducing oxidation of LDL • Boost immune response • Protect RBC from haemolysis • Keeps structural and functional integrity of all cells • Slows ageing process • Protection against Alzheimer’s disease • Act synergistically with Selenium to minimise lipid peroxidation
- 35. Deficiency of VitaminE • Uncommon, due to adequate level in average diet. • Deficiency seen in : – Cannot absorb dietary fat – In premature infants – In abetalipoproteinemia – Mutation in the gene for tocopherol trasfer protein
- 36. RDA • Male :10 mg/day • Females : 8 mg/day • Pregnancy : 10 mg/day • Lactation: 12 mg/day • 15 mg Vit. E = 33 IU • Requirement increase with higher intake of PUFA • Pharmacological dose= 200-400 IU/day • Hypervitaminosis E: rarely occur • Cause tendency to hemorrhage, bcz it is mild anti- coagulant
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