Antioksidan 2010 Edit

7/16/2019 Antioksidan 2010 Edit

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OKSIDAN &

ANTIOKSIDAN

Fathiyah SafithriDepartment of Pharmacology

Faculty of Medicine Muhammadiyah University



Oksidan / Radikal bebas = atom / molekul ygmemiliki satu atau lebih elektron yg tdkberpasangan pd lapisanluarnya.

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° + °B2. 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 / ReactiveOxygen 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, 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



- 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 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



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)



• 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) = 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.



Oxidative Stress



Oxidative Stress



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



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



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



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-

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






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



3. Protect biomolecules against ROS

(heat shock protein)

4. Low-molecular-mass agents that

scavenge ROS (gluthatione, uric acid,

bilirubin ,vitamin)





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



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



NAC



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)



–

–

–

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 Edeficiency by selenium

• Glutathione is:

– a tripeptide (g-glutamyl-cysteinyl-glycine)

– explanation for amelioration of vitamin Edeficiency by sulfur amino acids



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

)



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-

xanthinlutein zeaxanthin






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 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)?






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.






Effects of plant phenol

• Scavenging alkoxyl and peroxyl radicals

• Chelation of metals

•. Oestrogenic effect / anti estrogen (isoflavones)






Flavonoidsquercetin

Plant

ROOH

NAC

terpenoids

phenolic


terpenoids





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






Quercetin

Resveratrol

Lycopene

Hesperidin






Broccoli

• Contains beta-carotene, lutein,

quercetins, sulphoraphane, and indoles

Beta-Carotene

Lycopene






H

Soybean

Isoflavone

GenisteinGenistin

Daidzein

Daidzin

R2

R1

OHOH

H

R2

OHO-glucose

OH

O-glucose






Tea

OH

OH OH

HO OOH

HO O OH

OH

OH

Epicatechin

OH

OH

Epigallocatechin

Antioksidan 2010 Edit

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