Module 2 Flashcards
What are intraspecific differences and how does that relate to to modifying factors of toxicity?
Intraspecific differences are the common differences that occur in populations from the SAME species, there are genetic, environmental, toxicokinetic and toxicodynamic factors that affect responses to xenobiotics
What are interspecific differences and how does that relate to modifying factors of toxicity?
Interspecific differences are differences found between two species, these are less common and caused by differences in toxicokinetics and toxicodynamic factors
What are some of the differences in age that can cause differences in response to a xenobiotic?
Hormone levels and biotransformation enzymes are different between male and females
What are some of the differences in age that can cause differing responses to a xenobiotic?
older animals- dysfunction in repair mechanisms
younger animals- toxicokinetic factors, i.e. enzymes
How can nutrition affect an individuals response to a xenobiotic?
calorie deficiencies can suppress tumour growth
high fat diets can cause greater exposure to legacy contaminants
diets deficient in protein and fatty acids reduce biotransformation enzyme activity
High antioxidant diet protects against ROS
How does disease affect an individuals response to a xenobiotic?
asthma can cause greater sensitivity to air pollution
impaired liver or kidney functions can influence rate of xenobiotic clearance
hepatitis can exacerbate liver cancer
What are examples of physical factors that can affect a response to a xenobiotic?
temperature, barometric pressure, photoperiod, electromagnetic radiation
What are examples of social factors that can affect a response to a xenobiotic?
crowded conditions or isolation can exacerbate toxic responses
What are the four general mechanisms of toxic action?
- specific localization of xenobiotics (toxicokinetic mechanisms)
- interference with critical metabolic process
- bioactivation to electrophiles and increased ROS
- binds to receptors (mimicry)
What are the four steps involved in toxicity?
- Delivery
- Interaction with target molecule and alteration of biological environment
- Cellular dysfunction or injury
- Inappropriate repair and adaptation
What are the four types of common target molecules?
Proteins, lipids, nucleic acids and carbs
What are the two major reaction types involved in binding to targets?
Noncovalent binding: most common and reversible
Covalent binding: irreversible unless repaired (e.x. epoxides)
What are the three minor reaction types involved in target binding?
Hydrogen abstraction- free radicals can abstract H atoms
Electron transfer-redox
Enzymatic reactions-e.x. proteolytic snake and spider venoms
What are the three effects on target molecules?
Dysfunction, destruction and neoantigen formation
What are some examples of alteration on the biological environment?
precipitation of ethylene glycol in kidney to produce oxalic acid crystals
non-polar solvents and detergents that alter membrane fluidity and disrupt ion gradients
What is an example of how stereochemistry affects affinity for a receptor?
PCBs- legacy contaminants, high Kow values, highly toxic, there are 209 different types, affinity for the aryl hydrocarbon receptor determines the toxicity of the cogeners
What are some examples of how stereoisomers affect toxicity?
Thalidomide- R is very toxic
cough medicine vs codeine
What are some of thalidomides mechanisms of toxicity?
blocks G rich promoters which affects Integrin avB3 which is critical for angiogenesis and limb bud development
What is an agonist?
xenobiotics that bind to the receptor and mimic the effect of the endogenous ligand
What is meant by the term antagonist?
xenobiotics that bind to a receptor and produce no effect
What is meant by the term partial agonist?
xenobiotics that bind to the receptor and produce a lesser effect than the endogenous ligand
What are three common receptor mediated cellular signal transduction pathways?
- G-protein coupled receptors
- Nucelar receptors
- Tyrosine kinase-coupled receptors
- Ion channel receptors
What is the significance of having subtypes of receptors (e.x. a1 and B2 adrenergic receptors)
They have tissue specificity and selectivity, e.x. NE binding a1 in arteriolar sm causes vasoconstriction while Ne binding B2 in bronchiolar sm causes vasodilation
What is an orphan receptor?
Receptors with no known endogenous ligand, e.x. PCBs, morphine used to be one and cannabinoids
What are specific targets within altered gene expression?
Altered transcription, altered signal production and
altered signal transduction
How can a xenobiotic alter transcription and give examples?
xenobiotics can bind to promoters which increase or decrease mRNA expression
inappropriate cell division or apoptosis, e.x. endocrine disrupting chemicals
How can a xenobiotic alter signal transduction?
growth factors and cytokines phosphorylate or dephosphorylate transcription factors via signal transduction pathways. Very important for the regulation of mitosis and apoptosis balance
How does a xenobiotic alter signal production?
increased or decreased release of hormones from endocrine glands e.x. EDCs
What receptors does ACh bind to?
nicotinic and muscarinic receptors
What receptors does NE bind to?
Adrenergic receptors
What are the three targets of xenobiotics in electrically excitable cells?
- Altered neurotransmitter concentration in the synapse
- Altered receptor function
- Altered action potential
What are the four examples given in class of xenobiotics that affect neurotransmitter concentration and explain.
- OP- inhibit AChE causing overstimulation and parasympathetic domination, causes SLUDS an treated with atropine, pralidoxime and benzodiazepine
- botulism- binds presynaptic membrane and blocks release of ACh
- Black widow spider venom- massive overrelease of NTs and then none at all
- Cocaine-no reuptake of NE
- SSRIs-
What are the two examples given in class of xenobiotics that alter receptor function and explain them.
Cobra venom-binds irreversibly to nicotinic cholinergic receptors, no ACh access
Benzodiazepines, barbiturates, GHB and alcohol-all activate GABA receptors and depress CNS
What are the two examples given in class of xenobiotics that alter action potential and explain them.
tetrodotoxin-pufferfish toxin, blocks Na channels on axonal membrane, no action potential therefore no neurotransmission
DDT-overstim of Na channels, preventing repolarization and blocking neurotransmission
What are the mechanisms of toxic cell death?
Impaired ATP synthesis, sustained extracellular [Ca2+], disrupting protein synthesis, destroy cytoskeleton, and direct damage to plasma membrane
What are the ways xenobiotics can impair ATP synthesis?
Delivery of hydrogen to ETC
Impaired function of ETC
Impaired delivery of O2 as terminal electron acceptor
Inhibition of ADP phosphorylation
What are some examples of xenobiotics that target the delivery of hydrogen to the ETC?
arsenite- inhibits pyruvate dehydrogenase, no conversion of pyruvate to acetyl CoA
fluoroacetate (rodenticide)- inhibits actionase in citric acid cycle
What are some examples of xenobiotics that impair the function of the ETC?
rotenone (pesticide)-inhibits NADH-coenzyme Q reductase (complex I)
cyanide inhibits cytochrome c oxidase (Complex IV)
What are some examples of xenobiotics that impair the delivery of oxygen as the terminal electron acceptor?
Carbon monoxide
What are some examples of xenobiotics that inhibit the phosphorylation of ADP?
chlordecone (insecticide) inhibits ATP synthase
Pentachlorophenol (fungicide) ionophore that causes protons to leak back into inner mito. membrane
Dinitrophenols (herbicides) donate protons to innter mito. membrane.
How do xenobiotics affect the [Ca2+]?
promote influx or inhibit efflux from cytoplasm or cause leakage from mitochondria and ER into cytoplasm
What are xenobiotics that disrupt protein synthesis?
ethanol
What is a xenobiotic that destroys the cytoskeleton?
colchicine (old chemo drug)
What are some xenobiotics that cause direct damage to the plasma membrane?
nonpolar solvents, detergents and ROS
What is an example of impaired function of system integration?
Inhibition of hepatic synthesis of coagulation factors, warfarin-inhibits activation of Vit. K
What are the repair mechanism for a denatured protein?
Molecular chaperones like heat shock proteins
What are the three levels of impaired repair processes?
Molecular, cellular and tissue repair
What are the repair mechanisms for oxidation of a thiol group on a protein?
Thioredoxin and glutaredoxin will donate electrons to reduce proteins
What are the repair mechanism for damaged lipids by oxidation
glutathione reductase and glutathione peroxidase, Vit. C and E are also involved
What is the repair mechanism for damaged DNA and the three enzymes involved?
Nucleotide excision repair
Endonuclease, DNA polymerase and DNA ligase
What are the processes involved in cellular repair?
Apoptosis or necrosis, damaged PNS neurons can regenerate themselves
What are some differences between cell apoptosis and cell necrosis?
Apoptosis: active, programmed, single cell, normal ATP, no inflammation, cell shrinkage, takes hours
Necrosis: passive, cluster of cells, decreased ATP, inflammation, cell swelling and rupturing and takes hours to days
What is the role of the mitochondria in celling signalling for apoptosis and necrosis?
Mito is the sensor that releases signals to initiate cell death
if signals are present in few mito- cell survives just mito autophagy
if signals are present in more mito-caspase activation and apoptosis
if signals are present in all mito-ATP depletion and necrosis
What are the three potential outcomes resulting from repair failure?
Necrosis
Fibrosis-excessive deposition of ECM proteins
Carcinogenesis-caused by failure of DNA repair, failure of apoptosis or failure to stop cell proliferation
What are some examples of how oxidative stress can affect us?
infections (actually good), cancer, aging, AIDS, neurodegenerative diseases, ischemia and rheumatoid diseases
What are some examples of ROS that are produced from the oxygen we breathe
superoxide anion radical
hydrogen peroxide
hydroxyl radical (the worst)
What are some of the steps involved in xenobiotic cycling and its role in ROS production.
Xenobiotics like paraquat, are reduced and donate electrons to O2 created O2-, this continues as one xenobiotic can create multiple O2-
What is one common molecule involved in ROS production?
Quinones
What detoxifies quinones?
NADPH-quinone reductase
What is an environmental example of an ROS
ozone
What are some of the outcomes of oxidative stress on cells?
Cancer, apoptosis, DNA oxidation, protein oxidation, cell signalling
What signaling response is caused by ROS?
activation of tfs, or acitivation of kinases which leads to cell proliferation, adaptation or damage
