• Provides key nutrients needed by the body to neutralize free radicals.

• Helps protect against cellular damage. May exhibit anti-aging benefits.

• Super ORAC (Primary) Antioxidants are the body’s own natural defense against free radicals.

• They scavenge or ‘mop’ them up before they have a chance to harm cells.

Slow or prevent damage to body cells May improve immune function and

lower risk for infection and cancer Carotenoids – beta carotene (familiar) Vitamin C Vitamin E Found in colorful fruits/veggies and

grains

Stroke

Lung Cancer

Prostate Cancer

Macular Degeneration & Cataracts

Osteoarthritis

Rheumatoid Arthritis

Skin Cancer &Melanoma

Photo-aging (wrinkles)

Alzheimer’sParkinson’s

PeriodontitisEmphysema

Coronary Heart Disease

Alcohol &Viral Liver Diseases

Diabetes

Hypertension &Chronic Kidney Disease

Colo-rectal CancerPeripheral Vascular Disease

Free Radical Diseases

The free radical diseases

•Cancer initiation and promotion is associated with chromosomal defects and oncogene activation. It is possible that endogenous free radical reactions, like those initiated by ionizing radiation, may result in tumour formation.

The free radical diseases

•Atherosclerosis may be due to free radical reactions involving diet-derived lipids in the arterial wall and serum to yield peroxides and other substances. These compounds induce endothelial cell injury and produce changes in the arterial walls .

Antioxidants•vitamin E

•vitamin C

•carotenoids

vitamin E

•Vitamin E is a fat-soluble substance present in all cellular membranes and is mainly stored in adipose tissue, the liver and muscle. Vitamin E is a principal antioxidant in the body and protects polyunsaturated fatty acids in cell membranes from peroxidation.

Vitamin E and cancer

•Besides being a free radical scavenger, vitamin E at high intakes enhances the body's immune responses. Vitamin E also inhibits the conversion of nitrites in the stomach to nitrosamines, which are cancer promoters.

Vitamin E and cardiovascular disease

•Vitamin E intakes are associated with lowered risk of angina and mortality from heart disease.

Vitamin E and neurological disorders

•Supplementation with vitamin C and E might be of benefit in slowing the progression of Parkinson's disease.

Vitamin C

•Vitamin C, or ascorbic acid, is a water-soluble vitamin. This vitamin is a free radical scavenger, it is considered to be one of the most important antioxidants in extra cellular fluids. Its protective effects extend to cancer, coronary artery disease, arthritis and aging.

Vitamin C and cancer

•Vitamin C is effective in protecting tissues against oxidative damage. It suppresses the formation of carcinogens. Numerous studies have reported the protective effect of fruit and vegetable consumption on incidence of cancer . This is mainly attributed to the protective effect of vitamin C against cancer.

Vitamin C and cardiovascular disease

•Vitamin C may lower total cholesterol in the blood, thus reducing the risk of cardiovascular disease. Coronary heart disease mortality is higher in those with blood vitamin C levels that are near or in the deficient range.

Vitamin C and cataracts

•High intake of fruits and vegetables which are rich sources of ascorbic acid appear to be protective too. In several studies, cataract patients were shown to have low vitamin C and E intakes and low plasma vitamin C levels.

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.

Superoxide Dismutase (SOD) is essential for the body and is:

A metalloprotein – containing several sub units organised around a metallic group

An enzyme – the antioxidant enzyme SOD eliminates, in a continuous way, superoxide radicals, precursors of other oxygen reactive

forms (secondary free radicals)

And most importantly

SOD acts at the source. It is the first and one of the major components of the body’s antioxidant system.

SOD is a powerful and efficient antioxidant:• 1 iu SOD eliminates 1μmol superoxide/min and SOD has an active lifespan of several days!• In the end, billions of superoxide molecules destroyed

SOD is a primary antioxidant and possibly our most important one

Reactive oxygen species:formation of secondary free radicals

Hydroxyl radical induces the formation of secondary free radicals:

• Secondary free radicals or organic peroxides are very toxic

• They increase oxidative reactions which are propagated from one to the next

• They are directly responsible for cell alterations and destruction

• They indirectly participate in the inflammation process

Pro-Oxidants(Reactive Oxygen Species Free Radicals)

Antioxidants

OXIDATIVE STRESSCell & Tissue Damage

Protection / Tissue Repair

Antioxidants

Cell / Tissue Damage

Oxidants

Antioxidant systems:the primary antioxidants

The primary antioxidants:• are endogenous molecules• act at the source (where free radicals are

created)• are enzymes which continuously

eliminate the free radicals just formed:- SOD eliminates the superoxide ion- catalase and the glutathione peroxidase

eliminate hydrogen peroxide

Antioxidant systems:the secondary antioxidants

The secondary antioxidants• are exogenous molecules, carried by

food (vitamins A, C, E, polyphenols…)• they scavenge the secondary free

radicals• one molecule of a secondary antioxidant

traps one free radical molecule – a 1:1 relationship

Oxidants and antioxidants in the body

Under normal circumstances and conditions, the body’s endogenous antioxidant systems are able to neutralize the oxidant (free radical) molecules

Therefore → no oxidative stress means

→ no cell damage

Oxidative stress…

…is the result of an imbalance between oxidant and antioxidant

production

increase of free radicals → antioxidant systems overpowered

Oxidative stress: consequences

A break in the equilibrium caused by…• UVA and B• Stress, overwork, diet• Pollution, chemicals, cigarettes• Chronic inflammation

… puts the body into oxidative stress:

→ attacks on cell constituents (cell membranes, protein, lipids DNA)

Only solution: we must combat free radicals

O2

UV lightheme FeCoQ

1O2

NADPHor CoQ

O2-

H2O2

H+

H+

HOO

Lipid(LH)

L

H2O

O2

LOO

OH

Fe2+

H2O, H+

Figure 5. Pathways for the formation of reactive oxygen species

Superoxide dismutase

Haber-Weiss reaction; Fenton reaction

Singlet oxygen

Superoxide radical anion

Peroxyl radical lipid radical

lipid peroxyl radical

The fight against secondary free radicals…

…occurs with the secondary antioxidants (vitamins A,C, E, polyphenols etc)

BUT antioxidants (acting 1 against 1) are

quickly outnumbered and cannot eliminate a continuous and strong

production of free radicals

Secondary antioxidants are vital but just slow down the oxidative

stress

– we need to do something extra…

Functions of Pentose Phosphate Pathway

1) NADPH for biosynthetic pathways (e.g., synthesis of fatty acids and cholesterol);

2) NADPH for maintaining glutathione in its reduced state .

3) Pentose sugar for synthesis of nucleic acids

Table 1. Reactive Oxygen Species and Antioxidants that Reduce Them

Reactive Species Antioxidant

Singlet oxygen 1O2 Vitamin A, vitamin E

Superoxide radical (O2-) superoxide dismutase, vitamin C

Hydrogen peroxide (H2O2)

Catalase; glutathione peroxidase

Peroxyl radical (ROO) Vitamin C, vitamin E

Lipid peroxyl radical (LOO) Vitamin E

Hydroxyl radical (OH) Vitamin C

H2O2 glutathioneperoxidase

2 H2O

2 GSH

GSSGglutathionereductase

NADPH + H+NADP+

pentose pathway

Figure 6. Reactions of glutathione reduction and oxidation

SUMMARY OF ANTI-OXIDANT ENZYMES

Glutathione peroxidase: 2 GSH + H2O2 GSSG + 2 H2O

Uses selenium as a cofactor

Catalase : 2 H2O2 H2O + O2

Superoxide dismutase: 2 O2- + 2H+ H2O2 + O2

Mitochondrial - Mn2+ cofactor

Cytoplasmic – Cu2+-Zn2+ cofactors; mutations associated with familial amyotrophic lateral sclerosis (FALS)

Lipid Peroxidase: removes LOOH

selenocysteine in glutathione peroxidase intake may be related to lower cancer mortality

• cancer patients have lower plasma Se levels• risk may be higher in those with low Se intake• AZCC study – reduced incidence of prostate, colon, lung cancers

toxicity (> 1 mg/day) results in hair loss, GI upset, nerve damage

NUTRITIONAL CORRELATE: SELENIUM

Vit EredVIT Eox

Vit CredVIT Cox

LOOHlipid peroxyl radical LOO

Glutathionered

(GSH)

NADP+

NADPH + H+

Glucose-6-P Ribulose-5-P

Pentose phosphate pathway (rxn 8)

+ROOH

rxn 2

Glutathioneox

(GSSG)

H2O2

2H2O

hydroxyl radical (OH) superoxide radical (O2

-)

reduced products

Figure 7. Antioxidant cascade Reduced forms/reductionOxidized forms/oxidation

rxn 9

rxn 7

rxn 1

rxn 6

rxn 5

rxn 4

Medical Scenario:

If the antioxidant protective system in the red blood cell becomes defective, hemolytic anemia occurs; that is red blood cells undergo hemolysis and their concentration in the blood decreases. Such is the case if glucose 6-phosphate dehydrogenase is defective in the pentose phosphate pathway. In individuals whose glucose 6-phosphate dehydrogenase is defective, there is insufficient NADPH produced in red blood cells to maintain the ratio of reduced glutathione to oxidized glutathione at its normal value of well over 100. Hence, peroxides destroy the red cell membrane because of the limited protective mechanism in these cells.