Antioxidant Free Radicals

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Copyright 2006, The Johns Hopkins University and Benjamin Caballero. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.

Antioxidant Nutrients

Benjamin Caballero, MD, PhDJohns Hopkins University

Section A

Antioxidant Nutrients

4

Antioxidant Nutrients

Ascorbic acidAlpha-tocopherolBeta-caroteneSeleniumManganese

5

Oxidants and Antioxidants

AntioxidantsFree radical scavengers:−Extracellular/

circulating−Cellular

CytosolicMembrane-bound

Pro-OxidantsSubstrate oxidationAntimicrobial defenseRadiationSunlightIonized compoundsAgingOxygen

6

What Is a Free Radical?

An unbound compound (i.e., free) having one or more unpaired electrons

R O H O H

Hydroxyl group Hydroxyl radical

(good guy) (bad guy)

7

Examples of Free Radicals and their Half-Lives

Hydroxyl radical HO• 1 x 10-9 sec.Singlet oxygen 1 1 x 10-6

Alkoxyl radical RO• 1 x 10-6

Peroxyl radical ROO• 7Semiquinone radical Q•- days

O2

8

Free Radical Formation

Oxidation of substrates with high oxygen affinity (for example, fatty acids)Microbial lysisEnvironmental exposure (sunlight, radiation, high-oxygen levels)

9

Antioxidant Systems of Physiological Relevance in Humans

Water-Soluble− Ascorbate− Glutathione− Urate− Bilirubin

10

Antioxidant Systems of Physiological Relevance in Humans

Lipid-soluble− Alpha-tocopherol− Beta-carotene− Lycopene− Lutein− Zeaxanthin− Ubiquinol-10

11

Antioxidant Systems in Cells

12

Antioxidant Defense Processes

Prevention—Balance between oxidative load and antioxidant functionInterception—Local antioxidant levelsRepair—Mostly enzymatic

13

Antioxidant Defense Processes

Prevention—Vitamin E, ascorbic acid, beta-caroteneInterception—Vitamin E, glutathione, superoxide dismutaseRepair—DNA repair system, reductases

14

Role of Nutrients in Antioxidant Systems

Vitamin E− Protects lipids from the cell membrane bilayer from

attack by free radicalsVitamin C− Quenches 1 in cytosol− Recycles vitamin E after it captures free radicals

O2

15

Role of Nutrients in Antioxidant Systems

Carotenoids− Beta-carotene quenches 1 ; may also inhibit free-radical-

generating reactions− Autoregenerate with release of thermal energy

O2

16

Role of Nutrients in Antioxidant Systems

Selenium− Constituent of glutathione peroxidase

Manganese− Constituent of superoxide dismutase (MnSOD)

Copper, zinc− Constituents of superoxide dismutase (CuZnSOD)

17

Antioxidant Mechanism of Vitamin E

LOO•LOOHk ~ 102

Chainreaction!

•

Vitamin C

18

“Protective” Intake Levels of Antioxidant Nutrients

Protectivelevel* RDA

Vitamin C >600 mg 60Vitamin E >200 IU 10Selenium 70–120 µg 70

* Daily intakes associated with a risk reduction of 25% or more

Section B

Diet and Chronic Diseases

20

Evolution of the Human Diet

15–20

50–70

15–20

10–15

60–75

10–155

12

25–30

40+

20

Fat

Sugar

Starch

Protein

Hunter-Gatherers

PeasantAgriculturists

Modern Affluent Societies

140

5–1560–120

1020

Salt (g/day)Fiber (g/day)

21

Nutrition Transition Fat Consumption Patterns—Japan

05

101520253035404550

% F

at E

nerg

y

1946 1950 1955 1960 1965 1970 1975 1980 1990

Notes Available

22

Diet Constituents Implicated on Disease Risk

Fats CholesterolFiberAntioxidant vitamins and mineralsSugar

ProteinCalcium and vitamin DFolic acidIron

23

Criteria for Diet-Disease Relationships

Strength of associationDose-response relationshipTemporally correct associationConsistency of associationSpecificity of associationBiological plausibility

185-01Notes Available

24

Dietary Fat Intake and Breast Cancer-Related Deaths

Notes Available

25

Fish Consumption and Risk of CVD

Fish Consumption, g/day

0 <18 18–34 >35

MI 1.0 0.88 0.76 0.56

CHD 1.0 0.88 0.84 0.62

CVD 1.0 0.94 0.89 0.74

All causes 1.0 1.02 0.98 0.85

Notes Available

26

Diet and Blood Pressure

SodiumCalciumPotassiumMagnesiumAlcohol

27

The DASH Study

120

122

124

126

128

130

132

BL 1 2 3 4 5 6 7

Weeks

Syst

olic

BP

Control

Fruits and Veg.

DASH diet

Notes Available

28

Dietary Patterns and Blood Pressure: The DASH Diet

Control F & V DASH

Fat (% cal) 36 36 26

Cholesterol (mg) 233 184 150

Fiber (g) 9 31 31

Potassium (mg) 1752 4101 4415

Magnesium (mg) 176 423 480

Calcium (mg) 443 534 1265

Sodium (mg) 3028 2816 2859

Section C

Fats and Cardiovascular Disease

30

Serum Cholesterol and Coronary Heart Disease

0

25

50

75

100

125

<204 205-234 235-264 265-294 >295

Serum Cholesterol (mg/100mL)

CH

D In

cide

nce

Notes Available

31

Cholesterol and CVD

The cholesterol hypothesis of coronary heart diseaseDietary cholesterol, blood cholesterol, and atherosclerosisDietary factors affecting blood cholesterol levelsNon-dietary factors affecting blood cholesterol levels

32

Serum LDL and CHD Risk

0

0.5

1

1.5

2

2.5

1 2 3 4 5

Serum LDL (mg/dL)

Cor

onar

y H

eart

Dis

ease

R

elat

ive

Ris

k

menwomen

200 300 400 500 600

Notes Available

33

Serum HDL and CHD

0

50

100

150

200

20 30 40 50 60 70 75+

Serum HDL Concentration (mg/dL)

Mor

bidi

ty R

atio

menwomen

Notes Available

34

Diet and Atherosclerosis

Low-fat diets− Lower blood cholesterol but also tend to lower LDL and

HDLLow-saturated, high-monounsaturated diets− Lower blood cholesterol and LDL, tend to increase HDL

35

Diet and Atherosclerosis

High-carbohydrate diets− Modest lowering effect on all lipid fractions, but rise in TG

Fish oils− Strong lowering effect on blood TG, but minor effect of

lipoprotein fractions

36

Dietary Factors Affecting Blood Cholesterol

Increase− Saturated fat− Cholesterol− Trans fatty acids

Decrease− Monounsaturated fat− PUFA (fish oil)− Fiber

37

Non-Dietary Factors Affecting Blood Cholesterol

Increase− Smoking− Excess body fat− Alcohol

Decrease− Exercise− Estrogens

38

Other Nutrients Associated with Risk of CHD

Folic acidVitamins andIron

B6 B12

39

Folate and Vitamin B: Interrelationships

Homocysteine

Methionine

Methyl-THF

THF

5,10-methylene-THF

B6

B12

Copyright 2005, Benjamin Caballero and The Johns Hopkins University. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.