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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+ + e3. 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 kebocoran elektron yang terjadi dari rantai transport elektron, mis yg ada dlm mitokondria dan endoplasma retikulum, molekul oksigen menghasilkan superoksida

4. Subselluler organella

- 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 antioksidan 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

activated/reactive biomolecules

dangerous functions (reactive oxygen species, free radicals)*


ANTIOXIDANTS

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

membran e damage

protein damag e

DNA damag e mutations

cell growth & maintenance

premature aging/degerative disease

cancer

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

Reactive Oxygen Species

Joints
Arthritis

Vessels
Atherosclerosis
Vasospasms

Multiorgan failure
Cancer

Brain
Trauma
Stroke

Lung
Asthma
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, O2HO, HOO, H2O2 ROO , 1O2

Antioxidants

RO, O2HO HOO H2O2, ROO, 1O2,

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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

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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)

Antioxidants
Enzyme s Antioxidant Role Remarks Contains Manganese (Mn.SOD) Contains Copper & Zinc (CuZnSOD) Contains Copper (CuSOD) Superoxide dismutase Dismutates (SOD) O2 to H2O2 Mitochondrial Cytoplasmic Extracellular Catalase Dismutates H2O2 to H2O Removes Selenoproteins H2O2 and lipid (contains Se2+) peroxides Primarily in the cytosol also mitochondria Uses GSH

Glutathione peroxidase (GSH.Px)

Vitamin s

Alpha tocopherol

Breaks lipid peroxidation Lipid peroxide and O2 and OH scavenger 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

Beta carotene

Fat soluble vitamin

Ascorbic acid

Water soluble vitamin

NAC

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 peroxidation

ROH

GSSG

NADPH

Vitamin E PUFA (RH) Peroxidation with free radical damage

GSH Peroxidase (Se)

GSH Reductase (riboflavin) GSH

ROOH

NADP

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
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Carotene Groups
Caroteniods

carotenes -carotene -carotene

xanthophylls cryptoxanthin lutein 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 (-carotene carotene , cryptoxanthine) To acts as antioxidant ( protective against lightinduced 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 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)?

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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.

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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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Flavonoids quercetin

terpenoids

NAC

ROOH

Plant phenolic

terpenoids

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Nutraceuticals in Orange

Hesperidin
CH 3O

OCH 3
8 7 6

3'

OCH 3
4'

O
1

1' B

Tangeretin
CH 3O

A
5

C
4

OCH 3 O
OCH
3

Nobiletin
C H 3O
7 6

OCH
8

3'

OCH
4'

O
1

1'

A
5

C
4

C H 3O

OCH

Contain hesperidin, tangeretin, nobiletin, and limonene


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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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Soybean

R2

Isoflavone Genistein Genistin Daidzein Daidzin

R1
OH OH

R2 OH O-glucose OH O-glucose

H
H

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Tea

OH OH HO O OH

OH OH

HO

O OH OH

OH

OH

Epicatechin

Epigallocatechin

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