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GERIATRIC SYSTEM

BIOCHEMICAL CHANGE

**FREE RADICAL THEORY

**TELOMERE

Department of BiochemistryFaculty of Medicine.Hasanuddin Univ.

By Rosdiana Natzir


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Free Radicals andAntioxidants


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Free Radicals (FRs)

These are highly reactive chemical entities thathave a single unpaired electron in theiroutermost orbit.

Under certain conditions can be highly toxic to

the cells.

Generally unstable and try to become stable,either by accepting or donating an electron.


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Therefore if two FRs react, they neutralise eachother. However, if the FRs react with stable molecules,

there is generation of more free radicals.

This characteristic enables the FRs to participatein auto catalytic chain reactions,

Molecules with which they react are themselvesconverted to free radicals to propagate the chain ofdamages.

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Reactive Oxygen Species (ROS): -

These are free radicals derived initially fromoxygen. But as they do not contain unpaired

electrons in their outermost orbit, they do not

qualify as free radicals and so are referred to

separately as ROS.

Eg. - H2O2, HOCL, NO.

Free radicals are formed in side our body by bothPHYSIOLOGICAL (Natural) and PATHOLOGICALstimuli : -


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Physiological Stimuli that Form FRs

Normal respiration

O2 Superoxide, H2O2 Hydrogen Peroxide HOCL Hypochlorous acid

NO Nitric Oxide

Transition metals present inside our body whenare in free form behave as free radicals. Fe2+, Cu+


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Pathological Stimuli that Form FRs

RadiationBreaks the water inside our body:H2O =H+ + OH-

Metabolism of drugs CCl3

Transition Metals Cu+, Fe2+

Ultraviolet rays

Emotional stress


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Actions of FRs

Mechanism of Action: They act on the cell membranes and

membranes of different organelles of cells and

cause cell injury and death by oxidative

reactions.

So FRs are also called OXIDANTS.


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Actions of FRs

FRs cause lipid peroxidation. The PUFA of cell membrane are more vulnerable for this

injury. By lipid peroxidation FR increases the

permeability of cells, leading to calcium influx and

altered PH of the cell.

FRs alter the enzyme and receptor proteins. FRs cause cross-linking of proteins and

fragmentation of protein strands, oxidation of amino

acids like cystene, Methionine.

These alterations in the enzymes and receptoors inside

the cell lead to abnormal cell behaviour.


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Actions of FRs

FRs cause fracturing on the cell nucleusresulting in single strand DNA damage.

This oxidative injury may be. Lethal Leading to cell death and ultimately

removed by phagocytosis. Sub lethal - which may result in

Increased cell permeability.

Toxicity. Mutation of cells.


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FRs Induce Chain Reaction

During the process of oxidant damage resulting intissue destruction & degeneration, someelectrons may escape oxidation and become FRs

This chain reaction may produce diseases like:

Carcinogenesis. Myocardial reperfusion injury. Shock related injury. Arteriosclerosis. Rheumatoid arthritis.

Adult respiratory diseases. Diabetes. Obesity. Lipid abnormality. Etc.


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Antioxidants (AOs)

These are substances, derived fromoxygen.

In normal healthy state a balance ismaintained between FRs & AOs

The AO activity of serum is measured as -

% inhibition of lipid peroxidation in a

standardised brain homogenate.

Moreover we can as well supplement thesefrom outside (in vitro Antioxidants).


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In Vivo Antioxidants: -

I.EnzymesName Acts against Present in

SOD (Superoxide

dismutase)

Super oxide cytosol

mitochondria.

CATALASE H2 O2 Blood, bone marrow,

Mucus membrane

Kidney; Liver.GOP (Glutathion

peroxidase)

H2 O2, lipid

peroxidation

membranes of

lipids, Haemoglobin

and erythrocytes


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These are binding proteins. They keep thefree ions of plasma in a binding form, so

prevent oxidation injury. Eg.-Transferin for

Fe, Ceruloplasmin for Cu

II. Preventive AOs

III. Scavenger AOs

Also called chain breaking enzymes, they

break the catalytic chain propagated by FRs.


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In Vivo Antioxidants: - Source

Vitamin A, C & E,

Cystine, Glutathion, Melthionine,

Bioflavines, Se, Zn.

I. In the form of Medicines:

II. Food sources:

Green & yellow vegetables

Herbs: -Turmeric/kunyit, Garlic, Grape, Tea, Berries,Carrot, Spinach, Broccoli,

Red Meat, Kidney, Liver & Lipoic Acid


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Oxidative Stress: -

Under normal conditions body maintains anequilibrium between its own FRs and

Antioxidants.

When this equilibrium breaks, a state called

oxidation stress arises with in, due to FRformation or AO system.


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Example:

AO Status in Normal Pregnancy:

There is increased need for AOs as there is

increased production of FRs due to

Pregnancy being a stressful condition.

Because of the rapidly growing foetus there is increased

cellular activity.


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Thus AO activity during normal pregnancyprogressively increases as demonstrated by

Serum tocopherol. Activity of GOP(glutathione peroxidase) Serum ceruloplasmin & transferring level.

drugs that lead to FR formation must be avoided.

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AOs & Diabetic Embryopathy: -

Oxidative stress has been suggested tocontribute to the increased risk of foetalmalformations in poorly controlleddiabetics.

lipid peroxidation in cell membranes indiabetic pregnancies Periods of maternal hyperglycaemia &

hypoglycemia may cause marked changes inthe availability ofglucose to the foetus.

conc. of lipids, notably the ketone bodies andbranched chain amino acids in the maternalcirculation contribute to altered nutrition for theembryo.


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During later part of pregnancy

load of glucose in the mitochondria may acceleratethe flow of electrons through respiratory chainincluding mitochondrial leakage of free radicals.

This leads to production of FR in embryonic tissues tocause congenital malformations.


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Thus maintenance of normal concentrationof metabolites of all nutrient class may be

important for prevention of adverse foetaloutcome.

However, maintenance of blood glucose

level at euglycemic level is alwaysimportant for prevention of Diabeticembryopathy .

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AOs & Down Syndrome: -

Free radicals being the hallmark of aging, aregreatly increased with maternal age.

So FRs play a role in pathogenesis of Downs

syndrome.

Administration of AOs may help in preventing

this disease.

Increased activity of free radicals promote


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Increased activity of free radicals promotematernal uterine vascular malformations.

FRs are promoters of maternal vasoconstriction.

O2 , H2 O2 & NO2 in combinations

Inactivate the NO (a vasorelaxant) Causes PG synthatase activity. Produce peroxynitrate, a potent oxidant

Lipid peroxide in pre-eclamptic placenta is about 1.8times higher in comparison to normal placenta.

Severity of hypertension has been found to be inverselyproportional to concentration of Vit. E.


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Carcinogenesis: -

Basics of cancer formation: - A normal cell can undergo malignant

transformation in presence ofprocarcinogens

and carcinogens.

Without immune system detection a normal cell

is converted to malignant cell in stages>

Initiation Promotion Progression


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Free radicals are formed from stimulants like

Radiation- Xenobiotics

- Inflammatory cells- Respiration etc,

which act on cellular targets to cause

oxidant DNA damage in form ofmutagenesis.


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- which cause: - initiation of carcinogenesis by-

Activation of protooncogens. Inactivation or loss of tumour suppresser genes. Normal cell becomes initiated cell.

Procarcinogens are metabolically activated byFRs, which cause promotion and progressionof these initiated cells to cancer

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FRs & AOs in Carcinogenesis: -

Normal cell

Repair by AOsInitiation

Initiated Cell

Premalignant Cell

Malignant Cell

Repair by AOs

Repair by AOs

FRs Activation ofprocarcinogens &Carcinogens

Genetic Damage

Promotion

Progression

FRs

- Tumour promoters- Spontaneous

FRs

- Dysregulation

- Greater Cell autonomy

- Reduced Growth

Factor dependence

CLINICAL CANCER


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AOs in Cancer Prevention: -

DEFENCE: - enzymes with antioxidantproperty cause first line of defence by: - Protecting the lipids and enzymes against

oxidation Creating a balance of AOsagainst FRs in the body PREVENTS :

Cell pathology.

Metabolic disturbances.

Changes in cell permeability. Eormation of toxic products.

Prevention of initiation of Carcinogenesis


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INTERVENTION at promotion &progression stages: Local deactivation of genotoxins responsible

for further nuclear mutations

Inactivation of tumour promoters eg.- activationof granulocytes.

Simulate oxygen.

Maintenance of proper function of gap junction

communication. Maintenance of physical stability of membrane

& also within cells.


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Majority of epidemiological data suggestsupplementation with antioxidants

- Vit.- A, E, C;

- beta carotene & selenium, decreases the

incidence of various cancers.


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RECOMMENDED FOR CARCINOMA PREVENTION

Antioxidant RDA Recommende

d Dose

Possible

Toxicity

Level

Features Causing Req.Vitamin A 5000 IU 12,500 IU Chronic

intake of

125,000 IU

Smoking

Vitamin E 10-20 IU 200-800 IU >1,200 IU High PUFA

intake, Smoking

Vitamin C 60 mg 1000 mg Negligible / 1-2Gms Stress,OCP,Smoking

Selenium None 50-200 mg >200mg Aging, High PUFA

intake, Smoking,

Heavy metals


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Various studies have suggested Conc. ofMalondi-Aldehyde (MDA) is inversely

proportional to fertility in case of males.

In asthenospermic and oligoasthenospermic

males there is increased serum concentrationof MDA.

Even in normospermic males if there is

concentration of MDA there is reduced fertility. Addition of vitamin E causes decreased

concentration of MDA and improves fertility.


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FRs & AOs in Infertility - Female

FRs cause

Short luteal phase .

an arrest the cell growth (div) at 2, 4, 8 cell

stages Hamper the regulation of corpus luteum.

Addition of AOs improves the results.


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CONCLUSION

Oxidant generation is a part of human life.

Every O2 atom we breath in ,is converted to

water inside our body by addition of four

electrons sequentially.

When fourelectrons are added three FRs- O2,

H2 O2 & OH are formed along with water.

So where there is life there are oxidants.


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CONCLUSION

But when produced in excess, they can cause

any disease.

So our concern should be to FRs in systemiccirculation.

However, careful use of AOs and newerand

more accurate methods to measure oxidant

generation in humans , will go a long way to findout the exact contribution of oxidants in disease

processes and the role of AOs to prevent it.


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