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OKSIDAN &

ANTIOKSIDAN

Fathiyah Safithri
Department of Pharmacology
Faculty of Medicine Muhammadiyah University
Oksidan / Radikal bebas =
atom / molekul yg memiliki
satu atau lebih elektron yg
tdk berpasangan pd lapisan
luarnya.
1 elektron bebas menjadi
mol sgt reaktif.
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° + °B
2. Kehilangan satu elektron dari molk normal
A  A+° + e-
3. Penambahan 1 elektron pada molk normal
A + e-  A-°
Sumber Radikal bebas
• Radikal bebas yang ada dlm tubuh manusia
berasal dari 2 sumber :
a. Endogen
 Umunya dlm bent superoksida / Reactive
Oxygen Species, free radical (ROS)

b. Eksogen
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, aldehyde
oxidase, 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 leukotrien mengaktifkan enzim NADPH-oxidase  membran
sel memproduksi superoksida
4. Subselluler organella
- kebocoran elektron yang terjadi dari rantai transport elektron, mis yg
ada dlm mitokondria dan endoplasma retikulum, molekul oksigen
menghasilkan superoksida
- 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.
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 dari
sulfasalasin menginaktifasi 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  reaksi
sekunder bersama oksigen yg terurai atau bersama
cairan seluler  kerusakan jaringan
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-macam
quinone dan hydroquinone.
• disposisi besi dalam jaringan paru  pembentukan
radikal 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)
• Produksi radikal bebas meningkat pd keadaan :
- sinar u.v
- polusi udara
- asap rokok
- insektisida
- olah raga berat, stress dll
- Kontaminan dalam makanan
Reaksi perusakan oleh radikal
bebas

• tekanan oksidatif (oxidative stress) = keadaan


dimana 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.
Oxidative Stress
Oxidative Stress
Reaksi perusakan oleh radikal
bebas
a. Peroksidasi lemak
– Membran sel = sumber poly unsaturated fatty acid (PUFA), mudah
dirusak o/ bhn pengoksidasi disruption 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 dp
PUFA , 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
BIOMOLECULES

dangerous functions
activated/reactive (reactive oxygen species,
biomolecules free radicals)*

ANTIOXIDANTS
useful functions
(oxidative phosphorylation, membrane protein DNA
photophosphorylation, defense, damage damage damage
biosynthesis, etc.)

cell growth & mutations


maintenance premature
aging/degerative cancer
disease
Effect of Reactive Oxygen Species on
Degenerative Diseases

Gastro intestinal Eye Skin Heart


• Hepatitis • Cataractogenesis • Dermatitis • Heart attack
• Liver injury • Retinal damage • Age pigment

Teeth Joints
Reactive Oxygen Species
• Periodontis • Arthritis

Vessels Multiorgan failure Brain Lung


• Atherosclerosis • Cancer • Trauma • Asthma
• Vasospasms • Stroke • Hyperoxia
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
Oxidant : RO•, •O2-
Antioxidants HO•, HOO•, H2O2
ROO• , 1O2

RO•, ·O2-
HO· HOO·
H2O2,
ROO•, 1O2,
Pertahanan tubuh terhadap radikal
bebas

1966 ditemukan enzim


antioksigen endogen I,
yaitu superoxide
dismutase(SOD), serta
antioksidan eksogen yaitu
Vit E, Vit C dan beta
karoten

Fungsi SOD :
menyingkirkan radikal
bebas superoksida
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)
Antioxidants
Enzyme Antioxidant Role Remarks
s
Superoxide dismutase Dismutates Contains Manganese
(SOD) O2·⁻ to H2O2 (Mn.SOD)
Mitochondrial Contains Copper &
Cytoplasmic Zinc (CuZnSOD)
Extracellular Contains Copper
(CuSOD)
Catalase Dismutates
H2O2 to H2O

Glutathione Removes Selenoproteins


peroxidase (GSH.Px) H2O2 and lipid (contains Se2+)
peroxides Primarily in the
cytosol also
mitochondria
Uses GSH
Vitamin Alpha Breaks lipid peroxidation Fat soluble
s tocopherol Lipid peroxide and O2·⁻ and vitamin
·OH scavenger

Beta Scavenges ·OH, O2·⁻ and Fat soluble


carotene peroxy radicals vitamin
Prevents oxidation of
vitamin A
Binds to transition metals

Ascorbic Directly scavenges O2·⁻, Water


acid ·OH, and H2O2 soluble
Neutralizes oxidants from vitamin
stimulated neutrophils
Contributes to regeneration
of vitamin E
Vitamin E

• tocopherols & tocotrienols


• tocotrienols less widely distributed than
tocopherols - 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)
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
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
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 (g-glutamyl-cysteinyl-glycine)
– explanation for amelioration of vitamin E
deficiency by sulfur amino acids
b-oxidation

Peroxide
catalysis of
ROH GSSG
peroxidation NADPH

GSH Peroxidase GSH Reductase


(Se) (riboflavin)
Vitamin E
PUFA ROOH GSH
(RH) NADP

Peroxidation with
free radical
damage sulfur amino acids

Cellular
free radical
damage
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)
• 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
Carotene Groups

Caroteniods

carotenes xanthophylls

ά-carotene Β-carotene crypto- lutein zeaxanthin


xanthin
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)
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
• 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 in
disease and traumatic injury)?
Antioxidative Nutraceuticals

• 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.
Effects of plant phenol

• Scavenging alkoxyl and peroxyl radicals


• Chelation of metals
•. Oestrogenic effect / anti estrogen (isoflavones)
Flavonoids terpenoids
quercetin

NAC

ROOH

Plant
phenolic terpenoids
Nutraceuticals in Orange

OCH3
Hesperidin OCH3 3'
B 4'
CH3O O 1'
8 1
7
Tangeretin 6
A C
5 4
CH3O
OCH3 O

OCH3
Nobiletin OCH3 3'
OCH3
B 4'
CH3O O 1'
8 1
7
6
A C
5 4
CH3O
OCH3 O

Contain hesperidin, tangeretin, nobiletin, and limonene


Anthocyanin
Quercetin

Beta-Carotene

Lycopene
Quercetin
Resveratrol

Lycopene

Hesperidin
Broccoli
• Contains beta-carotene, lutein,
quercetins, sulphoraphane, and indoles

Beta-Carotene

Lycopene
Soybean

R2
Isoflavone R1 R2
Genistein OH OH
Genistin OH O-glucose
Daidzein H OH
Daidzin H O-glucose
Tea

OH

OH
OH

O HO O
HO OH
OH

OH
OH
OH
OH

Epicatechin Epigallocatechin

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