Role of Free Radicals in Health and Disease

8/4/2019 Role of Free Radicals in Health and Disease

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Role of free

radicals in

health and

disease


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Introduction

Free radical is defined as an atom or molecule that

contains one or more unpaired electrons.

Mitochondria are the major source of intracellularfree radicals.

Free radicals can be anionic , cationic or neutral.

The first organic free radical identifiedwas triphenylmethyl radical, by Moses Gomberg in

1900 at the University of Michigan.


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Formation of Free Radical

Free radicals are produced during the homolyticfission of a covalent bond.

Excessive free radical formation can be caused by

environmental radiation, cigarette smoking,myocardial reperfusion, infection, hyperglycemia,

hypoxia, chemical pollutants and certain drugs.


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Reactive Oxygen Species

Molecular oxygen is completely reduced to water.The partial reduction of oxygen are highly reactiveand create havoc in the living systems. Hence theyare called Reactive oxygen species or ROS.

ROS are ions or very small molecules that includeoxygen ions, free radicals and peroxides, bothinorganic and organic.

ROSs form a natural byproduct of the normalmetabolism of oxygen and have important roles incell signaling.


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Reactive oxygen species are formed by several

different mechanisms.

The interaction of ionizing radiation with biological

molecules.

Byproduct of cellular respiration. Some electronspassing down the electron transport chain leak away

from the main path and go directly to reduce oxygen

molecules to the superoxide anion

Synthesized by an enzymes in phagocytic cells like

neutrophils and macrophages

NADPH oxidase (in both type of phagocytes)

Myeloperoxidase (in neutrophils only)


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ROS (reactive oxygen species)

Free radicals

Superoxide, O2 -

Hydroxyl radical, OH

Peroxyl, ROO

Alkoxyl, RO

Hydroperoxyl, HO2

Particals, which are not

free radicals

Hydrogen peroxide, H2O2Hypochlorous acid, HClO

ozone, O3

Singlet oxygen,1

O2


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RNS (reactive nitrogen species)

Free radicals

Nitrogen(II) oxide, NO .

Nitrogen(IV) oxide, NO2.

Particals, which are not free

radicals

Nitrosyl, NO+

Nitrous acid, HONO

Nitogen(III) oxide, N2O3

peroxynitrite, ONOO -

Alkylperoxinitrite, ROONO


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Main sources of free radicals

Membranes enzymes and/or coenzymes with

flavine structures, hem coenzymes, enzymes

containing Cu atom in an active site.

1.Respiratory chain mitochondria : Mainly

superoxide and then H2O2

Approx 1- 4% O2

enters into respiratory chain

(mainly complexes I and III)


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2.Endoplasmic reticulum

Superoxide creation by cytochrome P- 450

3. Special cells (leukocytes)Superoxide creation by NADP-oxidase

4.Hemoglobin to methemoglobinoxidation

Erytrocyte is full of antioxidants


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Free Radical Scavenger System

Superoxide Dismutase (SOD)to get rid of superoxide produced from electron

transport chain, the product is hydrogen peroxide.

MnSOD (mitochondria).

CuZn SOD (cytosol).

Non-heme protein

2O2 + 2H H2O2 + O2


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Glutathione

GSH is a tripeptide, -glutamyl-

cysteinyl-glycine

The sulfur atom of the cysteine moietyis the reactive site which provides

electrons

GSH is stable because the bond inglutamyl-cysteine (not the a peptide

bond) is resistant to cellular peptidases


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Glutathione

GSH is the most abundant non-protein thiol inmammalian cells

GSH is a substrate for two enzymes that are

responsible for detoxification and antioxidation. Other physiological roles including cysteine

storage and transport, prostaglandin metabolism,

immune function, cell proliferation and redoxbalance


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Glutathione Synthesis

Protein

Methionine

CysteineGlutamate

g-GlutamylcysteineGlycine


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Glutathione Peroxidase (GSH PX)

To get rid of hydrogen peroxide (H2O2) and

some lipid peroxide.- It requires reduced glutathione (GSH) as

substrate and produces oxidized glutathione

(GSSG) as product. A cytosolic enzyme.

H2O2 + 2 G-SH G-S-S-G + 2H2O


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Glutathione reductase (GSR or GR) Reduces glutathione disulfide (GSSG) to

the sulfhydryl form GSH, which is an importantcellular antioxidant.

GSSG +NADPH +H+

2GSH +NADP The activity of glutathione reductase is used as

indicator for oxidative stress

The activity can be monitored by

the NADPH consumption In the case of erythrocytes, if the PPP is non-functional,

then the oxidative stress in the cell will lead tocell lysis and anemia.


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CatalaseTo get rid of hydrogen peroxide produced inperoxisome.

2 H2O2 2 H2O + O2

Tetramer with Fe, needs NADPH


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Oxidative stress

Oxidative stress represents an imbalance

between the production and manifestation

of reactive oxygen species and a biological

system's ability to readily detoxify the reactive

intermediates or to repair the resulting damage.

Be carefull - this equilibrium can be disbalance

in both sides


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Oxidative damage to lipids

Damage

Unsaturated bonds loss

Arising of reactive

metabolites (aldehydes)

Sequel

Changes in fluidity and

permeability ofmembranes

Membranes integral

enzymes are influenced


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Lipid Peroxidation

A free radical prefers to steal electrons from the

lipid membrane of a cell, initiating a free radical

attack on the cell known as lipid peroxidation.

A deficiency in glucose 6-phosphatedehydrogenase produces hemolytic anemia.

This enzyme is the only source of NADPH in the

red blood cells (they lack mitochondria). With noNADPH, glutathione in the red blood cells cannot

be maintained in its reduced form.


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Stages of Lipid Peroxidation


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Oxidative damage to proteins

Damage

Agregation,fragmentation andcleveage

Reaction with hem iron

ion Functional group

modification

Sequel

Changes in: enzymesactivity, ions transport

Proteolysis


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Oxidative damage to DNA

Damage

Saccharide ring

cleveage

Bases modification

Chain breakeage

Sequal

Mutation

Translation mistakes

Proteosynthesis

inhibition


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Oxidative stress markers

Lipoperoxidation markers:

Malondialdehyde (MDA), conjugated diens,

isoprostanes

Oxidative damage to protein markers :

Protein hydroperoxides

Oxidative damage to DNA :Modified nucleosides


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Various DiseasesKidney

GlomerulonephritisChronic Renal Failure

Joints

ArthritisRheumatism

Fetus

Pre-eclampsiaIU growth

restriction

Multi Organ

Cancer

Aging

Diabetes

Inflammation

Infection

Heart-vessels

ArtherosclerosisHypertension

Ischemia

Cardiomyopathy

Heart failure

Brain

Alzheimers

Parkinsons

Memory loss

Depression

Stroke

Eyes

Cataract

Retinal diseases

Lungs

AsthmaChronic

bronchitis


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Biochemistry of Aging

Reactive oxygen species play a vitol role in thedegenerative brain disorders such as

Parkinsonism, Alzheimers dementia and

multiple sclerosis The increasing accumulation of lipofuscin in

cells, like heart, muscle, nerve, ganglia and

nerve cells demarcates aging.


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Brown pigment granules compound of lipid

containing residues of lysosomal digestion.

It is one of the aging wear and tear pigments.

Age- dependent accumulation of lipofuscin in

brain cells is one of the most consistent

features of aging.


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Centrophenoxine cleans out LF in the cells in

the body and brain, improving their function

and their longevity.

Concentration of carnosine in muscles

correlates with maximum life span, a fact that

makes it a promising bio-marker of aging.

It prevents lipid peroxidation within the cell

membrane.


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Antioxidants

Is a substance neutralizes free radicals by donating an

electron to an unpaired electron of free radical beforeit causes damage to the cell.

Prevents the transfer of electron from O2 to organicmolecules.

Stabilizes free radicals.

Terminates free radical reactions.


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High-molecular endogennous

antioxidants Transferrin- iron transport protein

Ferritin -iron storage protein

Haptoglobin Hemopexin

Albumin


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Low-molecule endogennous antioxidants

Ascorbate (vitamin C)

Collagen synthesis

Dopamine to epinephrine

conversion

Reduction agent

Fe absorption

Antioxidant = reduction O2

- OH , ROO, HO2 Prooxidant

Alfa-tocopherol a vitamin ELocalise in membranes

Produces hydroperoxides,

which are changes by

GSHPx


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Ubiquinone (coenzyme Q)

Electron carrier in respisratory chain

Co-operates with tocopheryl

Carotenoides,-carotene

Removing the radicals from lipids


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Glutathione (GSH, GSSG)

In all mammalian cells (1-10 mmol/l)

Important redox buffer2 GSH GSSG + 2e- + 2H+

ROS elimination, stabilisation in reduction form

( SH- groups, tocopheryl and ascorbate regeneration)Substrate ofglutathione peroxidases


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Low-molecule endogennous antioxidats

Lipoic acid (lipoate)

PDH cofactortocopheryl and ascorbate regeneration

MelatoninLipophilic ; hydroxyl radicals scavenger

Uric acid (urates)

Bilirubin

Flavonoids


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Trace elements influence to Free

Radical metabolism

Selenium

Influence to vitamin E resorption, part of

selenoproteins of Se = insufficient immune response,

erythrocytes hemolysis, methemoglobin

synthesis

Zinc

Cell membrane stabilisation

Fe antagonist


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Defending Against Cancer

Cancers occur when cellular DNA is damagecausing mutations.

Sometimes this damage is caused by free-radicalattacks.

Antioxidants may reduce cancer risk byprotecting DNA from oxidative damage.

Lower cancer rates among people whoconsume abundant fruits and vegetables richin antioxidants.


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Diets rich in vitamin C correlated with lowercancer rates, especially cancer of the mouth,

larynx, esophagus, and stomach.

Such correlations reflect the benefit of

consuming a diet rich in fruits and vegetablesand low in fat, but it does not necessarilysupport taking vitamin C supplements to treator prevent cancer.


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Protective effect of vitamin E against canceris less consistent than that for vitamin C.However, people with low vitamin E bloodlevels have higher rates of certain types ofcancer.

Several studies also report a cancer protectiveeffect of fruits and vegetables rich in beta-

carotene and the other carotenoids.


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Defending Against Heart Disease

High LDL cholesterol is a major risk factorfor cardiovascular disease.

One way LDL cholesterol increases the risk

of cardiovascular disease is that free radicalsin the arteries oxidize LDL cholesterol.

Oxidized LDL cholesterol accelerates the

formation of artery-clogging plaques.


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Free radicals also oxidize polyunsaturated

fatty acids in cell membranes, initiating

additional changes in artery walls which

decrease blood flow.

Oxidative damage in artery walls is increased

by a diet high in saturated fat or cigarette

smoke.


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On the other hand, diets high in fruits andvegetables, especially in combination with

low saturated fat, increase antioxidant action

against LDL cholesterol oxidation which can

help decreases the development of

atherosclerosis.


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Antioxidants, especially vitamin E, mayprotect against the development of

cardiovascular disease.

Epidemiological studies have reported thatpeople who consume diets rich in vitamin E

have lower rates of death from cardiovascular

disease.


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Some studies also suggest that vitamin Cprotects against LDL cholesterol oxidation,

raises HDL, lowers total cholesterol, and

improves blood pressure.

Vitamin C may also decrease free radical

oxidation in the artery wall that typically

follows a high-fat meal.


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Carotenoids

Carotenoids are a group of red,

orange and yellow pigments

found in plant foods,particularly fruits and

vegetables.

Some carotenoids like b-carotene act as a precursor of

vitamin A; others do not.


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Rheumatoid Arthrities

Diseases like rheumatoid arthrities is self-

propagated by the free radicals released by

the neutrophils. Drugs like corticosteroids and NSAIDs

interfere with the formation of free radicals

and thus provides relief


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Thank you

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Role of Free Radicals in Health and Disease

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