VITAMIN ANTIOXIDANT

Nur Permatasari

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A vitamin may be broadly defined as a substance that is essential for the maintenance of normal metabolic functions but which is not synthesized by the body in sufficient quantity and, therefore, must be supplied from an exogenous source

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Oxidant : RO, O2-

Antioxidants

HO, HOO, H2O2 ROO , 1O2

RO, O2HO HOO H2O2,

1O , ROO, farm1 2

Effect of Reactive Oxygen Species on Degenerative Diseases

Gastro intestinal
Hepatitis Liver injury

Eye
Cataractogenesis Retinal damage

Skin
Dermatitis Age pigment

Heart
Heart attack

Teeth
Periodontis

Joints

Reactive Oxygen Species

Multiorgan failure
Cancer

Arthritis

Vessels
Atherosclerosis
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Brain
Trauma Stroke

Lung
Asthma

4 Hyperoxia

BIOMOLECULES

activated/reactive biomolecules

dangerous functions (reactive oxygen species, free radicals)*

useful functions (oxidative phosphorylation, photophosphorylation, defense, biosynthesis, etc.)

ANTIOXIDANTS

membrane damage

protein damage

DNA damage

cell growth & maintenance

mutations premature aging/degerative disease

cancer

Damaging reactions of free radicals

- Lipid peroxidation Cell membranes are a rich resource of PUFA, which are readily attacked by oxidising agents; a process that is called lipid peroxidation disruption of hydrophobic natu re of membranes fragmentation and loss of membranebound enzymatic activities Protein damage Proteins & nucleic acids seem to be less susceptible than PUFAs to free radicals affect enzyme, receptor - DNA damage
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Biologically significant reactive oxygen / nitrogen species

Reactive Oxygen Species O2 Superoxide radical
OH ROO H2O2 1O 2 NO ONOO HOCl
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Hydroxyl radical Peroxyl radical Hydrogen peroxide Singlet oxygen Nitric oxide Peroxynitrite Hypochlorous acid

Major Reactive Oxygen Species

Superoxide (O2*)
- formed when oxygen is reduced by the transfer of a single electron to its outer shells - the major source of superoxide in-vivo is the electron leakage that results from the electron transfer chain of the mitochondria - On its own it isn't particularly damaging. However, the superoxide radical anion appears to play a central role as other reactive intermediates are formed from it.
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Hydrogen peroxide (H2O2)

-2O2*+ 2H* H2O2 + O2 - not a free radical but falls in the category of reactive oxygen species. - It is an oxidising agent that is not particularly reactive but its main significance lies in that it is the main source of hydroxyl radicals in the presence of transition metal ions
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Hydroxyl radical (OH)

- Haber-Weiss reaction O2- + H2O2 O2 + OH + OH-

- Fenton reaction
H2O2 + Fe2+ OH + OH- + Fe3+ - is an extremely reactive oxidising radical that will react to most biomolecules
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Sources of free radicals (Endogenous sources)

- Autoxidation

Of the molecules that undergo autoxidation come catecholamines, haemoglobin, myoglobin, reduced cytochrome C and thiol
- Enzymatic oxidation

xanthine oxidase (activated in ischemia-reperfusion), prostaglandin synthase, lipoxygenase, aldehyde oxidase

- Respiratory burst

a term used to describe the process by which phagocytic cells consume large amounts of oxygen during phagocytosis ; between 70 and 90% of this oxygen consumption can be accounted for in farm1 11 terms of superoxide production

- Subcellular organelles Organelles such as mitochondria, chloroplasts, microsomes, peroxisomes and nuclei have been shown to generate O2* Mitochondria are the main cellular organelle for cellular oxidation reactions and the main source of reduced oxygen species in the cell.

The leaks in mitochondrial electron transport system allow O2 to accept a single electron forming O2* .
Superoxide production by the mitochondria increases in two conditions; either when the oxygen concentration is greatly increased or when the respiratory chain becomes fully reduced (as happens during ischemia). farm1 12

- Transition metals ions

Iron and copper play a major role in the generation of free radicals injury and the facilitation of lipid peroxidation.
- Ischemia reperfusion injury

During ischemia two factors occur, first the production of xanthine and xanthine oxidase are greatly enhanced. Second, there is a loss of both antioxidants superoxide dismutase and glutathione peroxidase.

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Sources of free radicals (Exogenous sources)

- Drugs (aminoglycoside, paracetamol etc)

- Radiation - Tobacco smoking - Metal (aluminium, lead,arsenic etc) - Gases

- Others ( alcohol, halogenated hydrocarbon)

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Mode of action of antioxidants

1. Catalycally remove ROS (enzymes) 2. Minimize the avaibility of pro oxidant ( transferin, metal chelation) 3. Protect biomolecules against ROS (heat shock protein) 4. Low-molecular-mass agents that scavenge ROS (gluthatione, uric acid,bilirubin ,vitamin)
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Antioxidants
Enzymes Antioxidant Superoxide dismutase (SOD) Mitochondrial Cytoplasmic Extracellular Catalase Role Dismutates O2 to H2O2 Remarks Contains Manganese (Mn.SOD) Contains Copper & Zinc (CuZnSOD) Contains Copper (CuSOD)

Dismutates H2O2 to H2O Removes H2O2 and lipid peroxides Selenoproteins (contains Se2+) Primarily in the cytosol also mitochondria 16 Uses GSH

Glutathione peroxidase (GSH.Px)

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Vitamins

Alpha tocopherol

Breaks lipid peroxidation Lipid peroxide and O2 and OH scavenger

Fat soluble vitamin

Beta carotene

Scavenges OH, O2 and peroxy radicals Prevents oxidation of vitamin A Binds to transition metals Directly scavenges O2, OH, and H2O2 Neutralizes oxidants from stimulated neutrophils Contributes to regeneration of vitamin E

Fat soluble vitamin

Ascorbic acid

Water soluble vitamin

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Vitamin E
Family of related compounds tocopherols & tocotrienols tocotrienols less widely distributed than tocopherols - considered of less nutritional importance 4 major forms based on # & position of methyl groups on ring - , , , all-rac -tocopherol

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CH 3 HO

2
H 3C CH 3 O CH 3

H 3C

H 3C

CH 3 CH 3

-Tocopherol

4'

8'

Activity roughly corresponds to number of methyl groups

Absorption &Transport
Absorbed in the lumen intestine Tocopherol in chylomicrons equilibrates with other lipoproteins Transport in lipoproteins Uptake in chylomicron remnants by liver Secreted in VLDL from liver (via tocopherol transfer protein) site of enrichment: vs , , distributes to tissues

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Uptake and Storage

Uptake into tissues - pathways in LDL via LDL receptors (apo B) lipoprotein lipase: hydrolysis of chylomicrons and VLDL other mechanisims? No specific storage site, but most vitamin E in adipose tissue, liver, and muscle

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Excretion
major - feces not absorbed, secreted from enterocytes, lost with enterocytes, biliary secretion

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Biochemical Function
Deficiency

in animals many symptoms species specific other compounds (e.g. Se, methionine) sometimes effective in relieving deficiency signs maintenance of membrane integrity lipid solubility -> direct protection of cell membranes
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Mysterious Interactions With Selenium Explained!

Selenium

is part of glutathione peroxidase

metabolizes lipid hydroperoxides explanation for amelioration of vitamin E deficiency by selenium

Glutathione

is:

a tripeptide (-glutamyl-cysteinyl-glycine) explanation for amelioration of vitamin E deficiency by sulfur amino acids
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-oxidation Peroxide catalysis of peroxidation

ROH

GSSG

NADPH

GSH Peroxidase Vitamin E PUFA (RH) Peroxidation with free radical damage ROOH (Se) GSH

GSH Reductase (riboflavin) NADP

sulfur amino acids

Cellular free radical damage

Deficiency
Rare in humans Fat malabsorption disorders can lead to deficiency adults: celiac disease, pancreatitis, biliary cirrhosis genetic diseases: cystic fibrosis, others

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Deficiency - 2

Deficiency signs neuropathological changes, esp. spinal cord degeneration swollen, distrophic axons accumulation of organelles, esp. mitochondria, neurofilaments reason unknown Incr risk for athersclerosis, cancer & cataract formation? Oral administration of vit E perday,the adult RDA :10mg/day (men), 8mg/day (women)

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Deficiency - 3

Premature infants susceptible to deficiency poor status hemolytic anemia: decreased RBC survival without increased production hypothesis: low vit. E increased hemolysis due to oxidative damage results of supplementation controversial

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Toxicity
one of least toxic vitamins known at extremely high levels, vitamin E may potentiate anticoagulation effect of drugs (Coumadin) & may decr platelet adhesion pro-oxidant

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Carotenoids

About 600 identified so far Most familiar is yellow-orange pigments of carrots, -carotene Two major groups: carotenes and xanthophylls

Carotene Groups
Caroteniods

carotenes
-carotene -carotene

xanthophylls
cryptoxanthin lutein zeaxanthin

Absorption &Transport
Absorbed in the lumen intestine depend on the presence of bile acid and absorbale fat Transported via lymphatics to the liver and circulate in association with lipoprotein

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Biochemical Function
To be metabolized to retinoids (-carotene carotene , cryptoxanthine) To acts as antioxidant ( protective against light-induced skin damage in patient with porphyria) Anti cancer effects? (in vitro yes, in vivo uncertain)

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Ascorbic acid (vitamin C)

Biochemical function: cofactor for at least eight enzymes At the tissue level, a major function collagen synthesis ( vit C deficiency can lead scurvy) The antioxidant properties protect NO, protect against age-related cataract

Absorption & Excretion

Absorbed in the lumen intestine via an energy dependent process (saturable) The daily intake > 100mg excreted, in adult RDA: 60 mg/daily The renal threshold for ascorbic acid : 1.5mg/dl. Urinary axcretion of oxalate and urate 1000mg

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Toxicity
Megadosage treatment formation of kydney stone and rebound scurvy Pro oxidant / acts as reductant to the iron (be aggravated in disease and traumatic injury)?

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Antioxidative Nutraceuticals

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 Nutraceuticals are naturally derived, bioactive compounds that have health promoting, disease preventing or medicinal properties. Nutraceuticals can be delivered in the form of food (functional foods) or as a dietary supplement or in both forms. Nutraceutical industry is a fast growing industry.
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Role of Nutraceuticals in Cancer

Oxidative Damage
Carotenoids, phenolics terpenes, tocopherols flavonoids Fibers, phytosterols, terpenes sulfides, phenolics, lignans triterpenoids, isoflavones cruciferous indoles

Carcinogens
Initiation Tumor Promotion

Steroid Hormones

Coumarins, flavonoids triterpenoids

Sulfides, isoflavones

Phenolics, salicylates flavonoids polyacetylenes sulfides

Prostaglandin (PGS)
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Antioxidative Nutraceuticals
Vitamin A, C, and E
Plant phenols (OH / two OH group attached to benzene ring) flavanol (epicatechin, catechin), flavanones (naringin, taxifolin), flavonols (kaempferol, quercetin), flavones/isoflavons (genistein, daidzein), anthocyanidins , phenylpropanoids (caffeic acis, p-coumaric acid) Thiol molecules Lipoic acid
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Effects of plant phenol

Scavenging alkoxyl and peroxyl radicals Chelation of metals

. Oestrogenic effect / anti estrogen (isoflavones)

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Nutraceuticals in Orange

Hesperidin
CH3O

OCH3
8 7 6

O
1

3' 4' 'B

OCH3

Tangeretin
CH3O

A
5

C
4

OCH3 O
OCH3

Nobiletin
CH3O
7 6

OCH3
8

3'

OCH3
4'

O
1

1'

A
5

C
4

CH3O
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OCH3 O

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Contain hesperidin, tangeretin, nobiletin, and limonene

Anthocyanin
Quercetin

Beta-Carotene

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Lycopene

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Quercetin Resveratrol

Lycopene

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Hesperidin

Broccoli
Contains

beta-carotene, lutein, quercetins, sulphoraphane, and indoles

Beta-Carotene

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Lycopene

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Soybean
R2

R1

OH

Isoflavone
Genistein Genistin

R1
OH OH

R2
OH O-glucose

Daidzein
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H
H

OH
O-glucose

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Daidzin

Herb and Spice

OH
HO HOOC CH3 CH3 HO O C O CH3 H3C CH3 CH3 OH CH3

H3C

Carnosoic Acid
HOOC O OH

Carnosol

OH

O
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HO
OH

Rosemarinic Acid

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Tea

OH OH OH

HO

O OH

HO

OH

OH OH OH

OH

Epicatechin
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Epigallocatechin
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Wine
Red wine decreases coronary heart disease mortality in some part of France. Please drink up to two glasses !!! The coumaric, cinnamic, caffeic, and ferulic acids catechin, epicatechin and quercetin in are good antioxidants.
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