antioksidan 2010 edit
TRANSCRIPT
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OKSIDAN &
ANTIOKSIDAN
Fathiyah SafithriDepartment of Pharmacology
Faculty of Medicine Muhammadiyah University
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Oksidan / Radikal bebas = atom / molekul ygmemiliki satu atau lebih elektron yg tdkberpasangan pd lapisanluarnya.
1 elektron bebas menjadi
mol sgt reaktif.
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Radikal bebas terbentuk dari :
1. Pemecahan 1 molk normal sec homolitik menjadi 2,mis. akibat pemanasan tinggi, radiasi ion, atau
sinar u.v A:B A° + °B2. Kehilangan satu elektron dari molk normal
A A+° + e-
3. Penambahan 1 elektron pada molk normal
A + e- A-°
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Sumber Radikal bebas
• Radikal bebas yang ada dlm tubuh manusia berasal dari 2 sumber :a. Endogen
Umunya dlm bent superoksida / ReactiveOxygen Species, free radical (ROS)
b. Eksogen
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-
Sumber endogen
1. Autoksidasi : – Merup produk dr proses metabolisme aerobik mis pd katekolamin,
hemoglobin, mioglobin, sitokrom C yang tereduksi dan thiol.
2. Oksidasi enzimatik
– xanthine oxidase, prostaglandin synthase, lipoxygenase, aldehydeoxidase, dan amino acid oxidase.
3. Respiratory burst – proses dimana sel fagositik menggunakan oksigen dlm jumlah >>>
selama fagositosis.
– Paparan thd bakteri yg diselimuti Ig, kompleks imun, komplemen 5a
atau leukotrienmengaktifkan enzim NADPH-oxidase membransel memproduksi superoksida
4. Subselluler organellakebocoran elektron yang terjadi dari rantai transport elektron, mis ygada dlm mitokondria dan endoplasma retikulum, molekul oksigenmenghasilkan superoksida
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- Transition metals ions
Iron & copper berperan dlm proses free radicals injury& memfasilitasi proses lipid peroxidation.
- Ischemia reperfusion injury
Selama ischemia tjd 2 factor yi : 1. produksi xanthine &xanthine oxidase . 2. Kehilangan antioxidants
superoxide dismutase & glutathione peroxidase.
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Sumber eksogen
1. Obat-obatan : – Pro oksidan : antibiotika kelomp quinoid atau
berikatan logam untuk aktifitasnya (nitrofurantoin),obat kanker seperti bleomycin, anthracyclines(adriamycin), dan methotrexate.
– fenilbutason, as fenamat dan aminosalisilat darisulfasalasinmenginaktifasi protease
– asam askorbat dlm jumlah >>> mempercepat peroksidasi lemak
2. Radiasi :
– Radioterapi Radiasi elektromagnetik (sinar X, sinar gamma) dan radiasi partikel (partikel elektron, photon,neutron, alfa, dan beta) radikal primer reaksisekunder bersama oksigen yg terurai atau bersamacairan seluler kerusakan jaringan
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3. Asap rokok :
• aldehida, epoxida, peroxida & radikal bebas lain
durasi panjang kerusakan alveoli.• nitrit oksida, radikal peroksil & radikal yg mengand
karbon ada dalam fase gas.
• radikal dalam fase tar (relatif stabil) meliputi semiquinone moieties dihasilkan dari bermacam-macamquinone dan hydroquinone.
• disposisi besi dalam jaringan paru pembentukanradikal hidroksil yang mematikan dari hidrogen peroksida perdarahan kecil berulang.
• netrofil sal napas bwh konsentrasi radikal bebas 4. Metal (aluminium, lead,arsenic dll)
5. Gas
6. Lain-Lain ( alcohol, halogenated hydrocarbon)
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• Produksi radikal bebas meningkat pd keadaan :
- sinar u.v
- polusi udara- asap rokok
- insektisida
- olah raga berat, stress dll
- Kontaminan dalam makanan
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Reaksi perusakan oleh radikal
bebas
• tekanan oksidatif (oxidative stress) = keadaandimana tingkat oksigen reaktif intermediate
(ROI) yg toksik melebihi pertahanan anti-oksidan endogen.
• kelebihan radikal bebas bereaksi dg
lemak, protein, as. nukleat seluler
kerusakan lokal & disfungsi organ tertentu.
• Lemak = biomolekul yg rentan thd serangan
radikal bebas.
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Oxidative Stress
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Oxidative Stress
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Reaksi perusakan oleh radikal
bebas
a. Peroksidasi lemak
– Membran sel = sumber poly unsaturated fatty acid (PUFA), mudahdirusak o/ bhn pengoksidasidisruption of hydrophobic nature of
membranes fragmentation and loss of membrane-bound
enzymatic activities.
b. Kerusakan protein
– Jarang, protein & asam nukleat lbh tahan thd radikal bebas dpPUFA , kecuali bila sangat ekstensif (Radikal terakumulasi atau
ada kerusakan yg terfokus pada daerah tertentu dalam protein
akibat ikatannya dengan ion logam transisi) affect enzyme /receptor.
c. Kerusakan DNA
– Sda protein, jarang terjadi
– Lesi pd susunan molekul, jk tidak dpt diatasi & tjd sebelum
replikasi leading to strand breaks mutations
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BIOMOLECULES
dangerous functionsactivated/reactive
biomolecules(reactive oxygen species,
free radicals)*
ANTIOXIDANTS
useful functions(oxidative phosphorylation,
photophosphorylation,
defense, biosynthesis, etc.)
membrane damage
proteindamag
e
DNAdamag
e
cell growth &maintenance premature
mutations
aging/degerative
diseasecancer
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Effect of Reactive Oxygen Species onDegenerative Diseases
Gastro intestinal• Hepatitis
• Liver injury
Eye• Cataractogenesis
• Retinal damage
Skin• Dermatitis
• Age pigment
Heart• Heart attack
Teeth
• Periodontis Reactive Oxygen Species
Joints
• Arthritis
Vessels
• Atherosclerosis
• Vasospasms
Multiorgan failure
• Cancer
Brain
• Trauma
• Stroke
Lung
• Asthma
• Hyperoxia
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Pertahanan tubuh terhadap radikal
bebas
Pengaruh buruk radikal bebas dapat
ditangkal oleh ANTIOKSIDAN
Antioksidan tdd :
o Antioksidan endogen, mis SOD, GSH
o Antioksidan eksogen , mis Vit C, Vit E, beta
karoten
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Oxidant : RO•, •O2-
AntioxidantsHO•, HOO•, H2O2
RO•, ·O2-
HO· HOO·
H2O2,
ROO•, 1O2,
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ROO• , 1O2
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Pertahanan tubuh terhadap radikal
bebas
1966 ditemukan enzimantioksigen endogen I,
yaitu superoxide
dismutase(SOD), serta
antioksidan eksogen yaituVit E, Vit C dan beta
karoten
Fungsi SOD :
menyingkirkan radikal bebas superoksida
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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 P t t bi l l i t ROS
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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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s
Antioxidants
Enzyme Antioxidant Role Remarks
Superoxide dismutase Dismutates Contains Manganese
(SOD)
Mitochondrial
Cytoplasmic
Extracellular
Catalase
Glutathione
O2·⁻ to H2O2
Dismutates
H2O2 to H2O
Removes
(Mn.SOD)
Contains Copper &
Zinc (CuZnSOD)
Contains Copper (CuSOD)
Selenoproteins peroxidase (GSH.Px) H2O2 and lipid (contains Se2+)
peroxides Primarily in the
cytosol also
mitochondria
Uses GSH
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s
Vitamin Alpha
tocopherol
Breaks lipid peroxidation
Lipid peroxide and O2·⁻ and
Fat soluble
vitamin
·OH scavenger
Beta
carotene
Ascorbic
acid
Scavenges ·OH, O2·⁻ and peroxy radicals
Prevents oxidation of
vitamin ABinds to transition metals
Directly scavenges O2·⁻,·OH, and H2O2
Neutralizes oxidants from
Fat soluble
vitamin
Water
soluble
vitamin
stimulated neutrophils
Contributes to regeneration
of vitamin E
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NAC
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Vitamin E
• tocopherols & tocotrienols
• tocotrienols less widely distributed thantocopherols - considered of less nutritional
importance
• 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)
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–
–
–
Vitamin E
• 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
• Excresi 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 Edeficiency by selenium
• Glutathione is:
– a tripeptide (g-glutamyl-cysteinyl-glycine)
– explanation for amelioration of vitamin Edeficiency by sulfur amino acids
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b-oxidation
Peroxide
PUFA(RH)
catalysis of peroxidation
Vitamin E
ROOH
ROH
GSH Peroxidase
(Se)
GSSG
GSH
GSH Reductase
(riboflavin)
NADPH
NADP
Peroxidation with
free radical
damage sulfur amino acids
Cellular
free radical
damage
)
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Deficiency Vit E
• Rare in humans • Fat malabsorption disorders can lead to deficiency
– adults: celiac disease, pancreatitis, biliary cirrhosis
– genetic diseases: cystic fibrosis, others
• 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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–
–
–
–
• 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
• 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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Carotene Groups
Caroteniods
carotenes xanthophylls
ά-carotene Β-carotene crypto-
xanthinlutein zeaxanthin
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Carotenoids
• Most familiar is yellow-orange pigments of carrots,b-carotene
• Two major groups: carotenes and xanthophylls
• 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
• To be metabolized to retinoids (ά-carotene Β-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 againstage-related cataract
• 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
• Toxicity – Megadosage treatment formation of kydney stone and rebound
scurvy
– Pro oxidant / acts as reductant to the iron (be aggravated indisease and traumatic injury)?
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Antioxidative Nutraceuticals
• Nutraceuticals are naturally derived, bioactive compounds that have healthpromoting, 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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Effects of plant phenol
• Scavenging alkoxyl and peroxyl radicals
• Chelation of metals
•. Oestrogenic effect / anti estrogen (isoflavones)
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Flavonoidsquercetin
Plant
ROOH
NAC
terpenoids
phenolic
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terpenoids
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Nutraceuticals in Orange
Hesperidin
TangeretinCH
3O
CH 3O
76
OCH 3
8A
5
O1
C4
1
3'
' B4'
OCH 3
OCH 3 O
OCH 3
NobiletinC H 3 O
C H 3 O
7
6
OCH
8
A5
3
O1
C4
1 '
3 'B 4 '
OCH 3
OCH 3 O
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Anthocyanin
Quercetin
Beta-Carotene
Lycopene
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Quercetin
Resveratrol
Lycopene
Hesperidin
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Broccoli
• Contains beta-carotene, lutein,
quercetins, sulphoraphane, and indoles
Beta-Carotene
Lycopene
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H
Soybean
Isoflavone
GenisteinGenistin
Daidzein
Daidzin
R2
R1
OHOH
H
R2
OHO-glucose
OH
O-glucose
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Tea
OH
OH OH
HO OOH
HO O OH
OH
OH
Epicatechin
OH
OH
Epigallocatechin