Basic Mechanisms of Toxicants III (5) Flashcards
What is oxidative stress?
imbalance of cellular oxidants and antioxidants in favor of oxidants
How does the body directly generate ROS/RNS?
- xenobiotic bioactivation
- redox cycling
- transition metals
- inhibition of mitochondrial electron transport
What indirectly generates ROS/RNS?
- increased Ca2+ (increases electron output - hydrogen peroxide)
- induction of cytochrome P450 enzymes
Look at this image
What are the consequences of ROS/RNS?
- can directly oxidize and affect protein function and can mutate DNA leading to cellular dysfunction
- ROS/RNS oxidatively inactivates Ca2+/ATPases and elevates Ca2+
- ROS and RNS also drain ATP reserves
- ONOO- induces DNA single-strand breaks - compromises ATP synthesis
- lipid per oxidation, cell swelling, cell rupture
How do free radicals initiate peroxidative degradation of lipids?
by hydrogen abstraction from fatty acids
What is formed by the hydrogen abstraction from fatty acids via lipid peroxidation?
converted radical formed is converted to the lipid peroxyl radical (LOO) by oxygen fixation
Review summary
What do mutagens cause?
changes to cell DNA that are passed on when the cell divides
What is a carcinogen?
a mutation causing changes to cell DNA that produces a neoplastic cell and is passed on when the cell divides
T/F: Mutagens = carcinogens. Why or why not?
FALSE - carcinogen if produces a neoplastic cell (affects cell growth)
What 2 major classes of gene are involved in carcinogenesis?
- proto-oncogenes
- tumor-supressor genes
What are proto-oncogenes?
promote cell cycle progression
What do tumor-suppressor genes do?
inhibit cell cycle progression
What is non-genotoxic - carcinogenesis?
affect environment around cell
promote cancer by interfering with cell death and DNA repair processes rather than causing direct DNA mutations. They allow cells with mutations to survive, replicate, and accumulate more mutations, ultimately leading to the formation of tumors
What is a key component of non-genotoxic carcinogenesis?
clonal expansion
silent mutations
What are genotoxic carcinogens?
affect the gene directly and cause DNA damage
not silent, but not lethal
leads to activation of oncogenic proteins or inactivation of tumor suppressor genes
What does CAR-T do?
reprogram T cells (I think it was the example of the girl who survived leukemia because of this immunotherapy)
Review carcinogenesis with apoptosis and mitosis
proto-oncogenes who are activated undergo mitosis
tumor suppressor protein is inactivated (meaning we will have a rapidly growing tumor) will undergo mitosis
- being activated = suppressed
- inactivated = rapidly dividing
What causes the activation of proto-oncogenes and the inactivation of tumor suppressor genes?
mutations (from toxicants for example)
What is teratogenesis?
the creation of birth defects during fetal development
What are teratogens?
substances that induct birth defects
What stage in a developing animal is the most critical phase of organ development i.e. when birth defects are most fatal to them?
embryonic stage
What stage in a developing animal can birth defect changes may be able to be maintained?
fetal period
What do the plant group lupines do? Which disease?
cause midevelopments of limb musculature and connective elements of limb
“Crooked Calf Disease”
What do teratogenic alkaloids do?
interfere with nicotinic ACh receptors in the nervous system, leading to overstimulation and then blockade of nerve transmission
= tremors, difficulty breathing, and convulsions
List examples of teratogenic alkaloids
- lupines
- tree and cultivated tobacco
- hemlock/poison hemlock
Which plant and what toxin causes cyclops birth defects?
corn lily - cylopamine (veratrum californicum)
Toxin and what does the toxin disrupt?
cyclopamine - inhibits the action of the hedgehog signaling pathway
What are manifestations of structural neurotoxicity?
- neuronopathies
- axonopathies
- myelinopathies
What are manifestations of functional neurotoxicity?
neurotransmission-associated abnormalities
What are neuronopathies?
injury or death to neurons —> targets cell bodies
irreversible loss
initial injury followed by apoptosis or necrosis
What happens with axonopathies?
degeneration of the axon, also known as Wallerian degeneration
What do you lose in axonopathies?
loss of axon distal to the lesion
loss of surrounding myelin, and cell body remains intact
chromatolysis and margination of Nissl substance
How irreversible are axonopathies?
CNS is IRReversible
PNS reverse is possible
What does this diagram depict?
axonopathies
What happens in myelinopathies?
intramyelinic edema
How possible is remyelination regarding myelinopathies?
CNS: occurs via oligodendrocytes to a limited extent
PNS: done by Schwann cells (more adaptive)
What happens with neurotransmission-associated abnormalities?
- interruption of impulse transmission
- blockage of trans-synaptic communication
- inhibition of NT uptake
- interference with 2nd messenger systems
Review manifestation of neurotoxicity
