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Antioxidants & Free radicals
What are Reactive Oxygen Species?
ROS also known as Free oxygen radicals Any molecule with an unpaired electron Extremely chemically reactive Damage cell membranes Responsible for more than 100 human diseases Aging, cancer, heart attacks, stroke and arthritis Some beneficial effects
How are ROS Formed? Primary source is our body during energy
production Environmental contaminants Ionizing and ultraviolet radiation Prolonged low blood flow states
(atherosclerosis, heart attacks and stroke) Diet (fatty and processed foods) Low levels of antioxidants
Protection from ROS Damage
Superoxide dismutase Catalase Glutathion Antioxidants in diet Supplementation
Aging and Effect on Antioxidant Enzymes
Significant decline in SOD Significant decline in catalase and glutathione Significant decline in energy production Cellular, tissue and system aging and failure
Scientific Support for Antioxidants
Animals with longer life spans have higher antioxidant levels
Dietary increase in antioxidants increase life span
Caloric restriction (reduces ROS formation) leads to significantly increased life span
Questions asked
What are free radicals? Types of free radicals Sources of free radicals Oxygen metabolism
Discussion on oxidative damage and oxidative stress
What is antioxidant? Natural free radical defense systems What are Phytochemicals?
NutrientsNutrients Non-nutrientsNon-nutrients
Energy, buildingEnergy, buildingmaterialsmaterials
Factors regulatingFactors regulating metabolismmetabolism
LipidLipid ProteinProtein Carbo-Carbo-hydratehydrate
VitaminsVitamins MineralsMinerals
EFA & EFA & non-EFAnon-EFA GlucoseGlucose
WaterWater
Phyto-Phyto- chemicalschemicals•pigmentspigments•AntioxidantsAntioxidants
FibersFibers
Other food Other food componentscomponents
FoodFood
GSHGSHCysCys
Functional food Functional food or Neutraceuticalsor Neutraceuticals
C, E, C, E, -Car-CarZn, SeZn, Se
EAA & EAA & non-EAAnon-EAA
Free radical-Mediated Diseases
Diseases of the old - Chronic and degenerative diseases
(diabetes, cataracts, Alzheimer’s disease, cancers,
cardiovascular disease, and aging)
Diseases of the young and innocent -Acute and immature diseases
(Eyes: retinopathy of prematurity, Lung: bronchopulmonary displasia, Brain: cerebral pulsy, Pancreas: Type 1 diabetes)
What are free radicals?
Any molecule containing one or more unpaired electrons
Types of Free Radicals Reactive Oxygen Species (ROS) -
Reactive Nitrogen Species (RNS) -
NO. Reactive Metabolites or Intermediates
- metabolic activation of drugs, toxins, pollutants, cigarette smokes, etc.
Reactive Oxygen Species (ROS)
Superoxide (O2.-)
Hydrogen Peroxide (H2O2)
Hydroxyl Radical (OH.) - product of Fenton reaction catalyzed by free Fe and Cu
Singlet Oxygen (1gO2) - oxygen at an excited
state, requiring photosensitizers and photons
Sources of oxygen free radicals In mitochondria:
- generation of energy - ATP
- glucose, fatty acids, amino acids
- O2 2H2O
4e-
- leakage of O2-. (superoxide)
H2O2 (hydrogen peroxide)
In Smooth Endoplasmic Reticulum (microsome)
- detoxification (cytochrome P-450s)
- toxins, drugs and xenobiotics
- O2 + RH R-OH and H2O
- leakage of O2-.
- metabolic activation - X.
In Peroxisomes
- containing oxidases for degradation of various substrates
- glucose, amino acids, xanthine, etc.
- requires O2
- byproduct is H2O2
In Cytoplasm
- nitric oxide (NO.) production from Arginine
- functions as a biological messenger
- in brain, vascular endothelial cells, and macrophages
- NO. + O2-. ONOO. (peroxynitrite)
NO: a Biological Messenger
NO is a neurotransmitter (brain- bNOS) NO regulates blood pressure (vascular
endothelial cells- eNOS) NO is a cytotoxic agent (macrophages-
iNOS)
Production of Singlet Oxygen
- photosensitizers in the biological system
(bilirubin, riboflavin, retinal, porphyrin)
- requires light , O2 and photosensitizers
- chlorophyll in photosynthesis
- photodynamic therapy
Antioxidants
Prevents the transfer of electron from O2 to organic molecules
Stabilizes free radicals Terminates free radical reactions
Free Radical Defense System
Antioxidant Enzymes Antioxidant Quenchers Antioxidant from Foods
– nutrients/non-nutrients
Antioxidant Enzymes
Superoxide Dismutase (SOD) – to get rid of superoxide produced from electron transport chain, the product is hydrogen peroxide. MnSOD (mitochondria). CuZn SOD (cytosol).
Oxygen Radical Defense Enzymes
Oxygen Radical Defense Enzymes
O2•¯ H2O2 H2O + O2
Mn SOD Catalase
GSH Peroxidase
CuZnSOD
OH•
Fe2+
Antioxidant Enzymes - 2
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.
Functions of GSH-dependent Enzymes
L-OHL-OHHH22OO
GSSGGSSG NADPHNADPH
L-OOHL-OOHHH22OO22
GSHGSH NADP+NADP+
XX..
GSXGSX
XX-Mercapturic Acid-Mercapturic Acid
GSH PxGSH Px
GSH-TRGSH-TR
GSH--RxGSH--Rx
Glutathione GSH is a tripeptide, -glutamyl-
cysteinyl-glycine The sulfur atom of the cysteine
moiety is the reactive site which provides electrons
GSH is stable because the bond in glutamyl-cysteine (not the peptide bond) is resistant to cellular peptidases
Glutathione GSH is the most abundant non-protein thiol in
mammalian 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 redox balance
Glutathione Synthesis
ProteinProtein
MethionineMethionine
CysteineCysteineGlutamateGlutamate
-Glutamylcysteine-Glutamylcysteine
GlycineGlycine
Antioxidant Enzymes - 3
Catalase –to get rid of hydrogen peroxide produced in peroxisome.
Antioxidant Quenchers
Cellular proteins which chelate pro-oxidant minerals (iron and copper or others)
Transferrin – iron transport protein Ferritin – iron storage protein Metallothionein – minerals and heavy
metals (Zn/Cu/Cd/Hg) Ceruloplasmin – copper transport and
storage
Antioxidants From Food
Antioxidant nutrients – vitamin E, vitamin C, (vitamin A?), beta-carotene
Phytochemicals – antioxidants from plants
Discovery of Other Functions of Phytochemicals
Anti-oxidant Anti-
inflammatory Anti-estrogenic Anti-allergic
Anti-cholesterolemic
Anti-hemorrhagic Anti-mutagenic Anti-neoplastic