Module 2

Question 1

What are intraspecific differences and how does that relate to to modifying factors of toxicity?

Answer 1

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

Question 2

What are interspecific differences and how does that relate to modifying factors of toxicity?

Answer 2

Interspecific differences are differences found between two species, these are less common and caused by differences in toxicokinetics and toxicodynamic factors

Question 3

What are some of the differences in age that can cause differences in response to a xenobiotic?

Answer 3

Hormone levels and biotransformation enzymes are different between male and females

Question 4

What are some of the differences in age that can cause differing responses to a xenobiotic?

Answer 4

older animals- dysfunction in repair mechanisms
younger animals- toxicokinetic factors, i.e. enzymes

Question 5

How can nutrition affect an individuals response to a xenobiotic?

Answer 5

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

Question 6

How does disease affect an individuals response to a xenobiotic?

Answer 6

asthma can cause greater sensitivity to air pollution
impaired liver or kidney functions can influence rate of xenobiotic clearance
hepatitis can exacerbate liver cancer

Question 7

What are examples of physical factors that can affect a response to a xenobiotic?

Answer 7

temperature, barometric pressure, photoperiod, electromagnetic radiation

Question 8

What are examples of social factors that can affect a response to a xenobiotic?

Answer 8

crowded conditions or isolation can exacerbate toxic responses

Question 9

What are the four general mechanisms of toxic action?

Answer 9

1. specific localization of xenobiotics (toxicokinetic mechanisms)
2. interference with critical metabolic process
3. bioactivation to electrophiles and increased ROS
4. binds to receptors (mimicry)

Question 10

What are the four steps involved in toxicity?

Answer 10

1. Delivery
2. Interaction with target molecule and alteration of biological environment
3. Cellular dysfunction or injury
4. Inappropriate repair and adaptation

Question 11

What are the four types of common target molecules?

Answer 11

Proteins, lipids, nucleic acids and carbs

Question 12

What are the two major reaction types involved in binding to targets?

Answer 12

Noncovalent binding: most common and reversible
Covalent binding: irreversible unless repaired (e.x. epoxides)

Question 13

What are the three minor reaction types involved in target binding?

Answer 13

Hydrogen abstraction- free radicals can abstract H atoms
Electron transfer-redox
Enzymatic reactions-e.x. proteolytic snake and spider venoms

Question 14

What are the three effects on target molecules?

Answer 14

Dysfunction, destruction and neoantigen formation

Question 15

What are some examples of alteration on the biological environment?

Answer 15

precipitation of ethylene glycol in kidney to produce oxalic acid crystals
non-polar solvents and detergents that alter membrane fluidity and disrupt ion gradients

Question 16

What is an example of how stereochemistry affects affinity for a receptor?

Answer 16

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

Question 17

What are some examples of how stereoisomers affect toxicity?

Answer 17

Thalidomide- R is very toxic

cough medicine vs codeine

Question 18

What are some of thalidomides mechanisms of toxicity?

Answer 18

blocks G rich promoters which affects Integrin avB3 which is critical for angiogenesis and limb bud development

Question 19

What is an agonist?

Answer 19

xenobiotics that bind to the receptor and mimic the effect of the endogenous ligand

Question 20

What is meant by the term antagonist?

Answer 20

xenobiotics that bind to a receptor and produce no effect

Question 21

What is meant by the term partial agonist?

Answer 21

xenobiotics that bind to the receptor and produce a lesser effect than the endogenous ligand

Question 22

What are three common receptor mediated cellular signal transduction pathways?

Answer 22

1. G-protein coupled receptors
2. Nucelar receptors
3. Tyrosine kinase-coupled receptors
4. Ion channel receptors

Question 23

What is the significance of having subtypes of receptors (e.x. a1 and B2 adrenergic receptors)

Answer 23

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

Question 24

What is an orphan receptor?

Answer 24

Receptors with no known endogenous ligand, e.x. PCBs, morphine used to be one and cannabinoids

Question 25

What are specific targets within altered gene expression?

Answer 25

Altered transcription, altered signal production and altered signal transduction

Question 26

How can a xenobiotic alter transcription and give examples?

Answer 26

xenobiotics can bind to promoters which increase or decrease mRNA expression inappropriate cell division or apoptosis, e.x. endocrine disrupting chemicals

Question 27

How can a xenobiotic alter signal transduction?

Answer 27

growth factors and cytokines phosphorylate or dephosphorylate transcription factors via signal transduction pathways. Very important for the regulation of mitosis and apoptosis balance

Question 28

How does a xenobiotic alter signal production?

Answer 28

increased or decreased release of hormones from endocrine glands e.x. EDCs

Question 29

What receptors does ACh bind to?

Answer 29

nicotinic and muscarinic receptors

Question 30

What receptors does NE bind to?

Answer 30

Adrenergic receptors

Question 31

What are the three targets of xenobiotics in electrically excitable cells?

Answer 31

1. Altered neurotransmitter concentration in the synapse 2. Altered receptor function 3. Altered action potential

Question 32

What are the four examples given in class of xenobiotics that affect neurotransmitter concentration and explain.

Answer 32

1. OP- inhibit AChE causing overstimulation and parasympathetic domination, causes SLUDS an treated with atropine, pralidoxime and benzodiazepine 2. botulism- binds presynaptic membrane and blocks release of ACh 3. Black widow spider venom- massive overrelease of NTs and then none at all 4. Cocaine-no reuptake of NE 5. SSRIs-

Question 33

What are the two examples given in class of xenobiotics that alter receptor function and explain them.

Answer 33

Cobra venom-binds irreversibly to nicotinic cholinergic receptors, no ACh access Benzodiazepines, barbiturates, GHB and alcohol-all activate GABA receptors and depress CNS

Question 34

What are the two examples given in class of xenobiotics that alter action potential and explain them.

Answer 34

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

Question 35

What are the mechanisms of toxic cell death?

Answer 35

Impaired ATP synthesis, sustained extracellular [Ca2+], disrupting protein synthesis, destroy cytoskeleton, and direct damage to plasma membrane

Question 36

What are the ways xenobiotics can impair ATP synthesis?

Answer 36

Delivery of hydrogen to ETC Impaired function of ETC Impaired delivery of O2 as terminal electron acceptor Inhibition of ADP phosphorylation

Question 37

What are some examples of xenobiotics that target the delivery of hydrogen to the ETC?

Answer 37

arsenite- inhibits pyruvate dehydrogenase, no conversion of pyruvate to acetyl CoA fluoroacetate (rodenticide)- inhibits actionase in citric acid cycle

Question 37

What are some examples of xenobiotics that impair the function of the ETC?

Answer 37

rotenone (pesticide)-inhibits NADH-coenzyme Q reductase (complex I) cyanide inhibits cytochrome c oxidase (Complex IV)

Question 38

What are some examples of xenobiotics that impair the delivery of oxygen as the terminal electron acceptor?

Answer 38

Carbon monoxide

Question 39

What are some examples of xenobiotics that inhibit the phosphorylation of ADP?

Answer 39

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.

Question 40

How do xenobiotics affect the [Ca2+]?

Answer 40

promote influx or inhibit efflux from cytoplasm or cause leakage from mitochondria and ER into cytoplasm

Question 41

What are xenobiotics that disrupt protein synthesis?

Answer 41

ethanol

Question 42

What is a xenobiotic that destroys the cytoskeleton?

Answer 42

colchicine (old chemo drug)

Question 43

What are some xenobiotics that cause direct damage to the plasma membrane?

Answer 43

nonpolar solvents, detergents and ROS

Question 44

What is an example of impaired function of system integration?

Answer 44

Inhibition of hepatic synthesis of coagulation factors, warfarin-inhibits activation of Vit. K

Question 45

What are the repair mechanism for a denatured protein?

Answer 45

Molecular chaperones like heat shock proteins

Question 46

What are the three levels of impaired repair processes?

Answer 46

Molecular, cellular and tissue repair

Question 47

What are the repair mechanisms for oxidation of a thiol group on a protein?

Answer 47

Thioredoxin and glutaredoxin will donate electrons to reduce proteins

Question 48

What are the repair mechanism for damaged lipids by oxidation

Answer 48

glutathione reductase and glutathione peroxidase, Vit. C and E are also involved

Question 49

What is the repair mechanism for damaged DNA and the three enzymes involved?

Answer 49

Nucleotide excision repair Endonuclease, DNA polymerase and DNA ligase

Question 49

What are the processes involved in cellular repair?

Answer 49

Apoptosis or necrosis, damaged PNS neurons can regenerate themselves

Question 50

What are some differences between cell apoptosis and cell necrosis?

Answer 50

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

Question 51

What is the role of the mitochondria in celling signalling for apoptosis and necrosis?

Answer 51

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

Question 52

What are the three potential outcomes resulting from repair failure?

Answer 52

Necrosis Fibrosis-excessive deposition of ECM proteins Carcinogenesis-caused by failure of DNA repair, failure of apoptosis or failure to stop cell proliferation

Question 53

What are some examples of how oxidative stress can affect us?

Answer 53

infections (actually good), cancer, aging, AIDS, neurodegenerative diseases, ischemia and rheumatoid diseases

Question 54

What are some examples of ROS that are produced from the oxygen we breathe

Answer 54

superoxide anion radical hydrogen peroxide hydroxyl radical (the worst)

Question 55

What are some of the steps involved in xenobiotic cycling and its role in ROS production.

Answer 55

Xenobiotics like paraquat, are reduced and donate electrons to O2 created O2-, this continues as one xenobiotic can create multiple O2-

Question 56

What is one common molecule involved in ROS production?

Answer 56

Quinones

Question 57

What detoxifies quinones?

Answer 57

NADPH-quinone reductase

Question 58

What is an environmental example of an ROS

Answer 58

ozone

Question 59

What are some of the outcomes of oxidative stress on cells?

Answer 59

Cancer, apoptosis, DNA oxidation, protein oxidation, cell signalling

Question 60

What signaling response is caused by ROS?

Answer 60

activation of tfs, or acitivation of kinases which leads to cell proliferation, adaptation or damage