free radicals

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pro-oxidant state: higher than nomral levels of free radicals existing in a cell tissue or organism - this is the result of too much free radical production and not enough anitoxidants
Why is ROS important?: -toxic
-ubiquitous
-pathogenic
Sources of reactive oxygen species with examples: 1. chemical - visible light, UVB, UVA, ionization radiation, X rays, gamma rays

2. Chemicals from reactions - fenton reaction, haber-Weiss, TRANSITION METALS THAT can undergo redox cycling

3. Biochemical - nonenzymatic and enzymatic (oxygenated heme proteins, and electron transfering enzymes - NADPH oxidases, ETC)
5. Phagocytes - generate ROS by an enzymatic reaction
NADPH dependent oxidase respiratory burst
6. Enviornmental - ozone, cirgarettes, etc
the fenton reaction: either with iron or copper, generates OH radical from H202

H202 + Fe +2 --> Fe+3 + *OH + OH-

and

H202 + Cu+ --> Cu+2 + *OH + -OH
What enzyme generates bleach?: MPO myeloperoxidase!
What reactions generate superoxide?: - ETC
-NADPH oxidase, often in association with a macrophage
What is the imporance of NADPH to ROS?: - NADPH dependent oxidase generates superoxide
-Macrophages utilize NADPH dependent reactions for killing
-caled a respiratory burst
Peroxyl radical: -a radical formed lipid oxidation chain recation
-half life is very long - that why it can cause damage
-formed by autooxidation of polyunsaturated fats
What are sources of Nitric oxide? and what are the uses of nirtic oxide?: -nitric oxide synthase reaction

-a biological secondary messenger involved in blood flow (vasodilator), neurotransmission, inflammatory response and host defense, and a FREE RADICAL
Reaction that generates nitric oxide?: nitric oxide synthase rxn:

arginine + O2 --> cirtullnie + *NO
Bad toxic reaction involving *NO: - peroxynitrite can be generated from *NO

- *NO + O2*- --> ONOO-
Which NO species cause lipid damage? Which NO species cause protein damage?: lipid damage - ONOO- (peroxynitrile) + NO2 (nitrogen dioxide)

protein damage - N2O3
What is the main order of ROS generation?: 1. superoxide (autooxidation, ETC)
2. H2O2 (SOD)
3. HOCl (MPO)
3. hydroxyl radial (Fenton, H-W)
What are the steps in lipid peroxidation?: Called RANCIDITY

1. have a PUFA
-initiation
-rearrangement
-susceptibility to peroxidation
-leads to the formation of a LIPID PEROXYL RADICAL

-generation of mutagenic aldehydes
What are the consequences of lipid peroxidation?: -loss of PUFAs
-altered membrane fluidity
-altered membrane transport
-altered membrane permeability
release of materials from subcellular compartments
-damage from reactive aldehydes
what is the most common type of protein oxication, and why is that important?: S-nitration -addition of NO+ to a thiol residue - leads to altered function and activity of proteins

think N2O3

B/C when cystine and Met side chains are attacked this breaks a lot of the disulfide bonds important in stabilizing protein structure
S-nitration: addition of NO+ to a thiol residue
consequences of protein oxidations?: - modified enzyme activity,
-modified ion transport/alters ion balance
-impaired receptors
Which ROS are likely to cause DNA damage?: - hydroxyl radical
-NO (produces a number of modified DNA sugar +/or bases
-copper and iron due to the fenton reaction
What two chemicals indicate oxidative stress?: -B-oxoguanine
-Thymine glycol
These are both DNA base damages that indicate the presence of ROS
What are the main examples of disease that are associated with ROS?: -atherosclerosis
-aging
-neurodegenerative disorders - parkinsons
-reperfusion following ischemia
-CANCER
-RED BLOOD CELL DISORDERS
-CATARACTS
-EMPHESYMA
-ARDS (adult respiratory distress syndrome)
-Arthritis
-AIDS
B-oxoguanine: indicates ROS presence
Thymine glycol: indicates ROS presence
How are ROS implicated in cancer?: -because ROS can cause DNA mutation that can initiate carcinogenesis and cause changes tot eh gene expression and chromsomal damage that leads to cancer
neurodegeneration and ROS: - brain consumes the lots of oxygen
-brain is high in lipids, can lead to ROS damage
-EAA (glutamate and related excitatory AAs) can kill neurons - by calcium and ROS
RBC disorders and ROS: THINK LOTS OF IRON AND PORPHYRINS
- can generate superoxide from Hb + Fe++

-also fenton reaction is possible?
Aging and ROS: -aging is associated with an accumulation of lipofuscin or age pigment (peroxidizedd lipids cross linked to proteins
+ amyloid deposition (EC fibrous proteins produce H202 that attacks nerve cells)
cataracts & ROS: - oxidation of crystallines
-hydrogen peroxide accumulates in the vitreous humor and damages the lense
Emphysema & ROS: -protein oxidation
HYPOCHLORITE released from phagoytes during inflammation , can inactivate a protease inhibitor, allowing proteases to be overactive
ARDS & ROS: -damage caused by sepsis
- damage caused by ROS secret by neutrophils , also proteases
Arthritis & ROS: -persistant inflammatory state
-build up of pressure in the synovial cavity
-synovial reperfusion is inihibited leading to oxidant generation via X/XO from the capillary endothelium
AIDS and ROS: low glutathione levels
inappropriate activation of NfkB
What is N acetyl cysteine useful for? how is it relevant to ROS related pathologies: -Nacetyl cysteine can reduce disulfide bonds and restor glutathione levels
-useful for AIDS patients (who have low glutathione levels
What are the different cell responses depending on the concentration of ROS?: -low --> mitogenic (cell signaling), proliferative (kinase cascade activation & gene expression)

intermediate --> age arrest, senescence

high --> cell death/ necrosis/ apoptosis
peroxidases: catalyzes the break down of peroxidases
What are the two major types of antioxidants?: -chain breaking donor antioxidants
-preventative antioxidants
Give examples of Enzymatic antioxidants: 1. SOD superoxide dismutases
(ECM, Cu,Zn & Mn types)

2. Catalyse

3. Glutathione
(selenium dependent, phospholipid hydroperoxide, and selenium-independent)
Give examples of types of non-enzymatic antioxidants: 1. donor chain breaking
-alpha-tocopherol
2. Ascorbic acid (Vitamin C)
3. Glutathione
4. uric acid, N-acetyl cysteine, and Melatonin
3 types of non-enzymatic antioxidants: 1. lipid soluble (vitamin E)
2. Water soluble (vit C, glutathine, uric acid, n-acetyl cyseine, melatonin)
3. gas (NO)
Preventative antioxidants: metal binding proteins and chelators
-examples transferrin, lactoferrin, EDTA
SOD: -basically converts superoxide to H2O2 by a dismutation reactino

3 types - ECM, Cu,Zn, and Mn
Cu, Zn SOD: found in cytoplasm
Mn SOD: found in mitochondria
Catalyse: -an enzymatic antioxidant
-not very common mainly for overload
-removes H202 and converts it into water
-for PEROXISOMES
Reactions that can get rid of hydrogen peroxide: -mainly the enzymatic ones

2. Catalase (in peroxisomes when there is overload)
3. glutathione
enzymatic glutathione peroxidsase: -enzymatic, uses reduced glutathione
-MAINLY FOR LIPID OR PHOSPHOLIPID HYDROPEROXIDE antioxidation

several different types:
1. selenium glutathione peroxidases
2. phospholipid hydroperoxides
& cholesterol
3. selenium independt - reduces lipid hydroperoxides
lipid hydroperoxides antioxidant: glutathione (non selenium & lipid hydroperoxide types mainly)
which type of enzymatic glutathione can detoxify h202?: -selenium glutathione peroxidase
selenium glutathione peroxidase reaction: ROOH + 2GSH --> ROH + GSSG + H2O
SOD reaction: O2*- + 2H+ --> O2 + H2O2
what reaction generates H202?: SOD reaction
Catalyase reaction: 2H202 --> H20 + O2
Most antioxidant compounds that reduce or trap free radicals and become oxidized in return are called ...: donor, chain breaking antioxidants
they are typically non-enzymatic antioxidant
A lipid soluble non enzymatic antioxidant: alpha-tocopherol (Vitamin E)

(it hinhibits the propagation step of lipid peroxidation )
inhibits the propagation step of lipid peroxidation: alpha-tocopherol (Vitamin E)
quinones like coenzyme Q10: lipid soluble non-enzymatic antioxidants
Bilirubin: lipid soluble non-enzymatic antioxidants
water soluble non-enzymatic antioxidants: -ascorbic acid (Vitamin C)
-uric acid
-n-acetyl cysteine
-melatonin
potent known scavenger of the hydroxy radical: melatonin
Ascorbic acid: -scavenges superoxide, HO2*-, hydroxyl radical, hypochlorite, organic radicals

-works synergistically with alpha tocopherol to prevent lipid peroxidation (it's an H donor to the tocopherol)
non-enzymatic glutathione: -tripeptide
-can act directly to scavenge peroxy radical, singlet oxygen, and hydroxy radical
mechanism of metal binding proteins and chelators: -reduce the effective concentration of transition metals that can react with hydroperoxides
Fe++ binders chelators: transferrin
heme
lactoferrin
EDTA
Copper binding chelators: ceruloplasmin
albumin
What is the difference between haploglobin and Hemopexin: haploglobin binds free hemoglobin preventing reaction wtih h202

hemopexin binds free HEME and prevents reaction iwht H202
What are two food additives that are added to foodstuffs to maintain freshnesses, color, smell and prolong shelf life: -BHT and BHA
Beneficial effects of Vitamin C: - has been shown to prevent cancer and cardiovascular disesae in some studies
-boosts your immune system
-can be toxic at really high levels
Sources of Vitamin C: -citrus fruit
-strawberries
-cantaloupe
-tomatoes
-brocolli
-raw green vegetables,
potatoes & peppers
ACEROLA
Benefits of Vitamin E: -lipid soluble antioxidants INHIBITS LIPID PEROXIDATION
-shown to prevent cardiovascular disease and cancer in some studies
-may be toxic at high doses
Sources of Vitamin E: - OIL
source of carotinids: carrots
LYCOPE (tomato base)
source of selenium: brazil nuts
LYCOPE: (tomato base)
Selenium: -potent anti-oxidant works with Vitamin E
-required co-factor for glutathione
-shown to prevent cancer in some studies
Phytochemicals: -include flanonoids
-chemicals from plants
-associated with protection against disease and disorders
-found in fruits and vegetables
What ROS toxicities have not previously been discussed?: - heavy metal nephrotoxicity
-alcohol induced liver disease
-ethanol induced cardiomyopathy
study on the relationship between antioxidant levels and disease?: - the higher the amount of antioxidants in the blood the small your CHD risk (good inverse relationship (to Vitamin E)
Relationship between fruit and vegetable intake and cancer prevention: - bascially looked at a total of 170 studies at different sites
-in 132 studies fruit and vegetable intake had a protective effect, only in 6 studies was it found to be harmful
Breakfast foods that cause an increase in free radicals: -sugar
-fast food sandwich
-ice cream
-milk
Breakfast foods that cause a decrease in free radicals: -orange juice
-fruit
- 1 glass of tomato juice
RDA: recommended dietary allowances -the minimum amount of a nutrient needed to prevent deficiency
DRI: Dietary Reference Intake - expand upon RDAs by focusing on optimal health and the use of nutrients in promoting long-term health
UL: upper limit - determines the maximum nutrient intake without risk of side effects, with the scientificic evidence available
Selenium RDA (M/F) UL: RDA M 70 ug/day
RDA F 55 ug/day

UL 400 ug/day
Vit C RDA (M/F) UL: RDA M 60 mg/day
RDA F 60 mg/day

UL 2 g/day
Vitamin E RDA (M/F) UL: RDA M 10 mg/day
RDA F 8 mg/day

UL 1000 mg/day
Variable factors in RDA: - RDAs are age and gender dependent
-can vary by weight, lifestyle, etc.
Upper toxicity levels: have to be careful, when you take a supplement you are adding to endogenous antioxidants
Dietary restrictions: -lowers levels fo ROS in the bloodstream - have very different levels in oxidized stress
-correlation between dietary restrictions and longevity & health
Nurses Health Study: Vitamin E intake significantly decreases the incidence of CHD by 41% in 87,000 women
Cambridge Heart Antioxidant Study: Vitamin E supplements significatntly decreased the incidence of CHD by 35% in 2000 men
Heart Outcome Prevention evaluation: taking vitamin E had no effect on patients with high risk for coronoary events
Physicians Health Sutdy: Lycopene had an inverse relationship with the development of prostate cancer in abt 600 men
Nutrition Intervention Trial: -Taking selenium + Vitamin E + B-carotene resulted in a 9% reduction in cacner
The Finnish Study: Vitamin E has no effect on cancer but decreased risk of MI in male smoking patients,

Beta carotene taking male smokers were at increased risk for MI after 3 years
Combined fruit and Veggie Study: Higher fruit and vegetable consumption lowers risk of cancer
coronary heart disease studies: Nurses health Study
Cambridge Heart Antioxidant Study
Heart Prevention outcomes Evaluation
Cancer studies: Physicians Helath Study
Nutrition Invervention Trial
The Finnish Study
Combined fruit and vegetable studies

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