Oxidative Stress and Antioxidants Flashcards
free radical
atom/molecule/ion with an unpaired valence electron
aka ROS
superoxide
oxygen gains an electron
not very reactive, can be used as second messanger
hydrogen peroxide
H202
reactive, second messangers
hydroxyl radical
most reactive and dangerous
3 electrons added to oxygen
produced by H2O2 in Fenton rxn w/ Fe2+ and Cu+
sources of ROS
- Mitochondria ETC
- cytochrome P450 oxidase
- MEOS and Alcohol induced liver damage
- NADPH dependent oxidase system (phagocytic cells)
- xanthine oxidase
- iron and copper ions
- radiation
mitochondrial ETC
superoxide radicals released from UQH (b/t complex I and III)
cytochrome p450 oxidase
normal mechanism
membrane of ER @ liver
heme-iron center of active site
step 1: one electron transferred from NADPH and one oxygen hydroxylates the substrate
step 2: second electron transferred from NADPH, another oxygen makes water
MEOS and alcohol induced liver damage
gets activated w/ chronic alc consumption
CYP450E1 converts ethanol to acetaldehyde via redox
can potentially produce large amounts of hydrogen peroxide and hydroxyethyl radical
hydroxy radical is mutagenic = DNA mutations = liver cancer
skin lesions in PCT
responsible
uroporphyrins NOT MEOS
light gets absorbed then energy is transferred to oxygen = ROS
NADPH-dependent oxidase
in phagocytic cells
gets activated by inflamation from bacterial infections
produce superoxide radicals via respiratory burst > converted to hydroxyl radicals = destroy bacteria
good thing
chronic granulomatosis disease
deficiency in NADPH oxidase = respiratory burst compromised
inc susceptibility to bacterial and fungal infections
xanthine oxidase
part of purine degradation = uric acid
2 molecules hydrogen peroxide made
iron and copper ions
both are redox reactive so participate in one electron transfers = hydroxyl radicals
since so damaging kept in low concentrations in blood by being bound to proteins or tetrapyrroles (heme or cytochrome)
fenton reaction
iron + superoxide radical + hydrogen peroxide = hyroxyl radicals
hereditary hemochromatosis
iron storage disease from mutations in HFE gene
acc iron> deposited in cells = excess iron> oxidative stress = destroy liver, pancreas, heart
pt will have bronze skin
iron overload
other causes
thalassemia and sickle cell (bc hemolysis so hemoglobin and heme more prone to ROS when released from RBC)
frequent blood transfusions
radiation
direct: directly destroy DNA, proteins, and lipids
indirect: water molecule split into hydrogen and hydroxyl radicals
-radicals> double strand breaks in DNA = mutations and destruction esp if actively dividing
indirect used for tumor therapy
antioxidant categories
antioxidative enzymes
vitamins
metabolic antioxidants
antioxidative enzymes
- superoxide dismutase
- catalase
- glutathione peroxidase
superoxide dismutase
SOD
converts superoxide radical > hydrogen peroxide
catalase
detoxifies hydrogen peroxide > water
heme containing enzyme in peroxisomes
glutathione peroxidase
detox hydrogen peroxide and lipid peroxidases
uses GSH to reduce hydrogen peroxide > water
GSH > GSSG
vitamins
- C (absorbic acid)
- E
- A
absorbic acid
vitamin C
reduces superoxide radicals and lipid peroxyl radicals
water soluble
important for recycle vitamin E
becomes a radical itself after donating
vitamin E
alpha tocopherol (most effective form in humans and major form of E in diet)
lipid soluble, has membrane stabilizing activity
prevents damage from singlet oxygen, free radicals, lipid peroxidation
need vitamin c to recycle tocopherol radical back to alpha
vitamin A
aka retinoid (animals) or beta-carotene (plants)
is lipid soluble
quenches vibration energy of singlet oxygen w/conjugated double bond system
metabolic antioxidants
- glutathione (GSH)
- polyphenols/flavonoids
- uric acid
- bilirubin
glutathione
GSH
glutamate + cysteine + glycine
donate electron = reactive
readily reacts w/ another GSH = GSSG (oxidized and inactive)
glutathione
as co-factor
GPx uses GSH for hydrogen peroxide > water reduction = GSSG
GSSG is reduced by glutathione reductase w/NADPH from PPP
used by RBC to prevent oxidative damages
polyphenols
flavonoids
found in plant extracts (green tea, grapes) red wine, dark chocolate
is water soluble
uric acid
antioxidant in serum
bilirubin
unconjugated bilirubin donate electron to radicals
lipid soluble
oxidation converts bilirubin > biliverdin
antioxidant chain of reactions
- radical
- PUFA
- vitamin E
- vitamin C
- GSH
- NADPH (from PPP)
order of accepting electrons
PUFA = polyunsaturated fatty acid
oxidative stress
definitions
irreversible damage caused by attack of ROS upon proteins/lipids/DNA of cells OR
from disbalance b/t ROS (pro-oxidants) and antioxidants
RBC protectors
- PPP and reduced GSH, important for plasma membrane and hemoglobin
- glutathione peroxidase- destroys hydrogen and organic peroxides w/ reduced GSH, recovery by GSH reducatse
- methemoglobin reductase- reduces Fe3+ back to 2+ to recover hemoglobin, bhemoglobin is converted to methemoglobin w/ Fe3+ so cannot bind oxygen,
lipid peroxidation
stress in cell membranes
hydroxyl radicals cause peroxidation of PUFAs = destroy integrity and function
hydroxyl radical + e from PUFA = lipid radical
lipid radical + oxygen = lipid peroxyl radical
-unstable so can get more electrons from PUFA = propagation, PUFA supply drained OR
-break down into malondialdehyde (mutagenic bc reacts w/ purines of DNA)
lipid peroxidation defense
- vitamin E
- glutathione peroxidase- reduces lipid peroxides by convert to lipid alcohols
stress in DNA
hydroxyl radicals =
double strand breaks in DNA (direct) OR
bind guanine to make 8-oxoguanine that needs repair (indirect)
