Transcript Free Radicals and Diseases

Free Radicals and Diseases
Jianzhong Sheng MD, PhD
Department of Pathology & Pathophysiology
School of Medicine, Zhejiang University
Email: [email protected]
Questions asked
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What are free radicals?
Types of free radicals
Sources of free radicals
Oxygen metabolism
What are free radicals?
• Any molecule containing
one or more unpaired
electrons.
• These unpaired electrons
readily form free radical
molecules which are
chemically reactive and
highly unstable.
Types of free radicals
1. Superoxide, O22. Hydrogen peroxide, H2O2
3. Hydroxyl radical, OH-
4. Singlet oxygen, 1O2
5. Hydroperoxy radical, HOO6. Lipid peroxide radical, ROO-
7. Nitric oxide, NO8. peroxynitrite, ONOO-
e-
O2
e-, 2H+
O2Superoxide
e-, H+
H2O2
Hydrogen H2O
peroxide
OH-
e-, H+
Hydroxyl
radical
H2O
Properties of free radicals
1.
2.
3.
4.
Highly reactive
Very short half-life
Generate new radicals by chain reaction
Cause damage to biomolecules, cells and tissues
Most free radicals in biological systems are
derivatives of oxygen (Reactive Oxygen Species, ROS),
but there are also derivatives of nitrogen (Reactive
Nitrogen Species, RNS), Reactive Metabolites or
Intermediates.
Reactive Oxygen Species (ROS)
• Superoxide (O2.-)
• Hydrogen Peroxide (H2O2)
• Hydroxyl Radical (OH.)
• Singlet oxygen, 1O2
• Reactive Oxygen Species is used in a broad
sense to collectively free radicals (O2.-, OH.)
and non-free radicals (H2O2, 1O2, which are
extremely reactive) of the biological system.
Generation of Free Radical
1. Cellular metabolism
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About 1-4% of oxygen taken up in the body is converted to
free radicals. They are constantly produced during the normal
oxidation of foodstuffs.
a) due to leaks in the electron transport chain in mitochondria.
b) Some enzymes such as xanthine oxidase and aldehyde
oxidase form superoxide anion radical or hydrogen peroxide.
c) Macrophage also produces NO from arginine by the enzyme
nitric oxide synthase. This is also an important anti-bacterial
mechanism.
Sources of oxygen free radicals
• In mitochondria:
- generation of energy - ATP
- glucose, fatty acids, amino acids
- O2
2H2O
4e-+4H+
- leakage of O2-. (superoxide)
H2O2 (hydrogen peroxide)
Generation of Free Radical
2. Environmental effects:
a) due to drug metabolism.
b) due to damages caused by UV or X-rays
c) cigarette or alcohol.
FREE RADICAL
FORMATION
FREE RADICALS : THE CAUSE
OF VIRTUALLY ALL DISEASES
Environmental pollution
Industrial pollution
Excessive
Alcohol &
smoking
Pesticides & herbicides
High fat
foods
Harmful effects of free radicals
A. Free Radical and biomolecules
1. Proteins
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Cause oxidation of sulfhydryl groups, and modification
of AA. ROS may damage protein by fragmentation,
aggregation results in the loss of biological activity of
proteins.
2. Lipids
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The polyunsaturated lipid molecules of cell
membranes are particularly susceptible to damaging
free radicals process and contribute to the
uncontrolled chain reaction (lipid peroxidation).
Lipid peroxidation
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Lipid peroxidation refers
to the oxidative
degradation of lipids.
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It is the process whereby
free radicals "steal"
electrons from the lipids in
cell membranes, resulting
in cell damage.
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This process proceeds by
a free radical chain
reaction mechanism. It
most often affects
polyunsaturated fatty
acids (PUFA).
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In addition, end products
of lipid peroxidation may
be mutagenic and
carcinogenic
Harmful effects of free radicals
A. Free Radical and biomolecules
3. Carbohydrates
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Glycation increases the susceptibility of proteins to
the attack by free radicals.
4. Nucleic acid
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cause DNA strand breaks, fragmentation of bases
and deoxyribose results in cytotoxicity and
mutations.
Oxidative Damage
Free Radicals
Proteins
(-SH)
Lipids
(R-OO.)
DNA/RNA
(-OH.)
Harmful effects of free radicals
B. Diseases
1. Cardiovascular diseases (CHD): ox-LDL, formed
by the action of free radicals, promote CHD and
atherosclerosis (AS).
2. Cancers: damage DNA and cause mutation and
cytotoxicity, play a key role in carcinogenesis.
3. Inflammatory diseases: damage on the extracellular
components such as collagen and hyaluronic acid, promote
glomerulonephritis and ulcerative colitis.
4. Respiratory diseases: destroy endothelium and
cause lung edema. Cigarette smoke contains free radicals
and promotes the production of more free radicals.
• Macrophage take up oxidized LDL, when
overload with lipid, become “foam cells”.
• Conglomerate of foam cells form fatty
streaks or yellow patches visible in the
arterial wall.
• Dying foam cells release lipid that form
lipid pool within the arterial wall.
Harmful effects of free radicals
B. Free Radical and diseases
5. Diabetes mellitus: Destruction of islets results in
pathogenesis.
6. Cataract
7. Male infertility: reduce sperm motility and
viability.
8. Aging process
9. Others: such as Parkingson’s disease, Alzheimer’s
disease, multiple sclerosis, liver cirrhosis, muscular
dystrophy.
Severity of Oxidative Stress &
Biological Consequences
Severity of
Oxidative Stress
Biological
Consequences
A. Low level & gradual
Aging
B. Medium level & rapid
C. Large level & rapid
Carcinogenesis
Mutagenesis
Death, Stroke,
Trauma, Ionizing
irradiation
Bacteria
Free Radicals
(Oxidants)
Anti-biotic
Anti-oxidants
Antioxidant
• The substance present in low concentrations
relative to the oxidizable substrate that
significantly delays or reduces oxidation of the
substrate.
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They reduce the effect of dangerous oxidants by
binding together with these harmful molecules,
decreasing their destructive power.
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They can also help repair damage already sustained
by cells.
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They may be considered as the scavengers of free
radicals.
• During this reaction the antioxidant sacrifices
itself by becoming oxidized.
• However, antioxidant supply is not unlimited as
one antioxidant molecule can only react with a
single free radical. Therefore, there is a constant
need to replenish antioxidant resources.
Antioxidants
• Prevents the transfer of electron
from O2 to organic molecules
• Stabilizes free radicals
• Terminates free radical reactions
Classification of antioxidant
Ⅰ. According to their location
a) Plasma antioxidants:
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ascorbic acid (Vitamin C), bilirubin, uric
acid, transferrin, ceruloplasmin, β-carotene;
b) Cell membrane antioxidants:
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α-tocopherol (Vitamin E)
c) Intracellular antioxidants:
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superoxide dismutase (SOD), catalase,
glutathione peroxidase (GPx)
Classification of antioxidant
Ⅱ. According to their nature and action
a) Enzymatic antioxidants:
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SOD, catalase, GPx, glutathione reductase
b) Non-enzymatic antioxidants:
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Nutrient antioxidants:
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β-carotene, α-tocopherol, ascorbic acid,
Metabolic antioxidants:
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bilirubin, uric acid, ceruloplasmin, ferritin,
transferrin, albumin, glutathione
Enzymatic antioxidant
1. superoxide dismutase (SOD)
2O2·⁻+ 2H+
SOD
H2O2 + O2
SOD is present in essentially every cell in the body
which actually represented by a group of metalloenzymes
with various prosthetic groups. SOD appears in three
forms:
a) Cu-Zn SOD: in the cytoplasm with two subunits
b) Mn-SOD: in the mitochondrion
c) Cu-SOD: extracellular SOD
This is the first line of defence to protect cells
from the injurious effects of superoxide.
Enzymatic antioxidant
2. catalase, CAT
2H2O2 catalase 2H2O + O2
Catalase, iron dependent
enzyme, is present in all body
organs being especially
concentrated in the liver and
erythrocytes. The brain, heart
and skeletal muscle contains
only low amounts.
Enzymatic antioxidant
3. glutathione peroxidase, GPx
GPx is a selenium-dependent enzyme.
The entire process is driven by energy production at
the cellular level, which involves proper thyroid hormone
levels, healthy mitochondrial function, and an active
pentose-phosphate metabolic pathway.
Nutrient antioxidant
1. α-tocopherol (vitamin E)
•The most important lipid-soluble antioxidant
•Present in all cellular membranes.
•Protect against lipid peroxidation.
1. Vitamin E was shown to be stored in adipose
tissue.
2. Vitamin E prevents the peroxidation of
membrane phospholipids and avoids cell
membrane damage through its antioxidant
action.
Nutrient antioxidant
2. ascorbic acid (vitamin C)
+ 2O2·⁻ + 2H+
H2O2 +
Dehydroascorbate, DHA
It is a water-soluble, antioxidant present in citrus
fruits, potatoes, tomatoes and green leafy vegetables.
It is a chain breaking antioxidant as a reducing agent
or electron donor. It scavenges free radicals and inhibits
lipid peroxidation. It also promotes the regeneration of αtocopherol.
Nutrient antioxidant
3. carotenoids
Carotenoids consist of C40 chains with conjugated
double bonds, they show strong light absorption and often
are brightly colored (red, orange). They occur as pigments
in bacteria, algae and higher plants.
β-carotene is the most important.
• It is composed of two molecules of
vitamin A (retinol) joined together.
• Dietary β-carotene is converted to
retinol at the level of the intestinal
mucosa. It can quench singlet oxygen.
– Quenching of singlet oxygen is
the basis for it's well known
therapeutic efficacy in
erythropoietic protoporphyria (a
photosensitivity disorder).
Lycopene is responsible for color
of certain fruits and vegetables like
tomato. It also possesses antioxidant
property.
Nutrient antioxidant
4. α-lipoic acids
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It is vitamin-like compound, produced in the
body, besides the supply from plant and animal
sources.
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It plays a key role in recycling other
important antioxidants such as ascorbic acid, αtocopherol and glutathione.
• Other important nutrient antioxidants
Antioxidant
1.Coenzyme Q10
2. Selenium
3. Proanthocyanidins
4. Catechins
5. Quercetin
6. Ellagic acid
Source
organ meats (best heart), beef, chicken
sea foods, meats, whole grains
grape seeds
green tea
onions, red wine, green tea
berries, walnuts, pomegranates
Metabolic antioxidant
1. glutathione, GSH
In addition to its role as a substrate in GSH
redox cycle, GSH is also a scavenger of hydroxyl
radicals and singlet oxygen. GSH also has an
important role in xenobiotic metabolism.
Metabolic antioxidant
1. Uric acid
scavenge singlet oxygen and hydroxy radical
2. Ceruloplasmin inhibit iron and copper dependent lipid peroxidation
3. Transferrin
4. Albumin
5. Bilirubin
6. Haptoglobin
prevents iron-catalyzed radical formation
scavenge radicals on its surface
protects albumin bound FFA from peroxidation
bind to free Hb and prevent the acceleration
of lipid peroxidation
Normally, cellular homeostasis is a delicate balance
between the production of free radicals and our
antioxidant defenses.
Chinese Saying --
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药补不如食补
“Supplementation with drugs is never
as good as supplemention with foods….”
GREEN TEA – A WONDERFUL
ANTIOXIDANT
Primarily consumed in China, Japan,
Middle East, North Africa & North America Rich in polyphenol – an antioxidant
• 200 times more powerful than Vitamin E
• Scavenges free radicals, high rate
• Reduce the risk of heart diseases
• Lowers LDL oxidation
• Prevents Red blood Cell breakdown
• Protects against digestive & respiratory
infections
• Prevents cancers of colon, pancreas &
stomach
FOR A HEALTHY TOMORROW…
What should you do?
Notice: Countering the Harmful
Effects of Free Radicals
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Don’t smoke – if you do then make it a point to quit
Don't overdo your exposure to the sun
Don’t over consume alcohol
Don’t consume foods containing trans fats or
hydrogenated oils
• Get your cardio exercise from sprinting or interval
training
• Do consume antioxidant rich foods and use a good
antioxidant formula
• Keep your stress levels down
Points
• Free radicals
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Definition, types and Properties
ROS, RNS
Generation of Free Radical
Harmful effects of free radicals
• Antioxidant
– Enzymatic antioxidants
• SOD, catalase, GPx, glutathione reductase
– Non-enzymatic antioxidants
• Nutrient antioxidants: β-carotene, α-tocopherol,
ascorbic acid,
• Metabolic antioxidants: glutathione (GSH)