L16: Reactive Oxygen Special and Detoxification Pathways Flashcards
radical
- single unpaired electron
biradical
- two single unpaired electrons
free radical
- independent ability to interact with other molecules
superoxide radical
- produced in ETC
- O2*
hydrogen peroxide
- interacts with iron and copper to produce hydroxyl radicals
hydroxyl radicals
- OH*
- most reactive species
how super oxide is formed in ETC
- coenzyme Q interacts with and transfers electrons to O2
CCl4
- common cleaning solvent that is converted to CCl3* radical
- by cytochrome P450
- initiates damage to ER - cell death and liver damage
ionizing radiation
- splits H2O into hydroxyl and hydrogen radicals
monoamine oxidase
- inactivates dopamine in neurons
- generates H2O2 at mitochondrial membranes causing neuronal damage
lipid peroxidation
- can spread through membrane
- lipid degradation
- membrane integrity disrupted
protein damage
- certain protein residues are oxidized and protein fragments, degrades or cross links
- pro, his, arg, cys, met
DNA damage
- base alterations
- strand breaks
nitric oxide
- neurotransmitter and hormone
- single electron
nitric oxide synthesis
- from arginine via citruline
nitric oxide single electron
- can combine with O2 or superoxide to form reactive oxygen species with both nitrogen and oxygen
macrophages and NO
- use NO at high concentrations to kill pathogens
NO in inflammation
- combines with superoxide to form peroxynitrite that can damage proteins, lipids, and DNA by oxidation and nitration
respiratory burst
- phagocytic immune cells respond to pathogens by rapid consumption of O2
respiratory burst reaction
- O2 -> O2- via NAPH oxidase
- O2- -> H2O2
- H2O2 form HOCl by myeloperoxidase
- effective against bacteria\
- H2O2 forms hydroxyl radicals
neutrophils
- for NO when activated by inducible nitric oxide synthase
- and also activate NADPH oxidase
- forms superoxide
superoxide dismutase
- converts superoxide to H2O2
catalase
- converts H2O2 to H2O and O2
glutathione peroxidas
- reduces H2O2 to water and lipid peroxides to alcohols
- requires NADPH to replenish via glutamine reductase
antioxidants
- donate a hydrogen to neutralize radicals
vitamin E
- fat soluble
- protect membranes
- terminates lipid peroxidation radical to form more stable lipid peroxide
vitamin C
- regenerates vitamin E
uric acid
- traps free radicals in plasma and production reaction products that are excreted
xenobiotics
- potentially toxic compounds and drugs
- body metabolizes
- liver is primary site of detox
phase I reactions
- reduction, oxidation, hydroxylation, hydrolysis
- form hydroxyls
- make less toxic
phase II reactions
- add negatively charged groups
- conjugation, sulfating, methylation, glucouronidation
- allows it to be excreted
cytochrome P450-dependent monooxygenases
- phase I enzymes
NADPH-cytochrome P450 reductase + cytochrome P450
- NADPH donates electrons to reductase then transfers them to cytochrome P450
- P450 binds O2 and chemical substrates
- oxidizes substrates
CYP34A
- metabolizes greatest number of drugs
- competition amongst drugs for this enzyme could cause reduced drug potency
vinyl chloride
- used in plastics
- carcinogenic
vinyl chloride phase I
- converted to chloroethylene oxide by CYPE21
- an epoxide
- binds to proteins to cause cell damage
vinyl chloride phase II
- converted to chloroacetaldehyde
- conjugated to glutathione via glutathione-s-transferase
- excreted
what to avoid with vinyl chloride detox
- avoid buildup of chloroethylene oxide
normal pathway of acetaminophen
- normally excreted safety after glucoronylation or sulfation
high doses of acetaminophen
- CYP2E1 produces NADPQI (toxic intermediate)
NADPQI
- conjugated with glutathione and excreted safely
CYP2EI and alcohol
- induced by alcohol (MEOS system)
- alcohol consumption causes more acetaminophen to be directed to NAPQI and greater toxicity for a given dose
