Post-Midterm Flashcards

1
Q

Hematotoxicology
- Hematopoiesis in fetus in first 8 weeks, months 3-7, childhood, and adulthood
- Primary hematotoxicology
- Secondary hematotoxicology
- 3 consequences of toxicity?
- 3 main symptoms of anemia
- 3 groups of anemia?
- Thalassemia
- 2 things that determine RBC production?
- Where do initial and final steps of Heme/Hb production happen?
- Intermediate steps?
- What’s the last step?
- Enzyme?
- First step?
- Enzyme?
- What does it need to function?
- Sideroblastic anemia cause
- What does this yield in terms of [iron]
- Technique used to visualize it
- Megaloblastic anemia appearance
- Causes
- R-L step of DNA synthesis
- Ingestion of VB12
- Ingestion of VB9

A
  • Yolk sac, liver/spleen, distal long bone, axial skeleton (bone marrow)
  • Directly affects cell component or plasma of blood
  • Hypoxia, hemorrhage, infection
  • Lethargy, dyspnea, weakness
  • Blood loss, decreased production, increased destruction
  • Can’t produce adequate alpha and beta chains
  • Cell division and rate of Hb synthesis
  • Mitochondria
  • Cytoplasm
  • Protoporphyrin IX + Fe = Heme
  • Ferrochelatase
  • Glycine + Succinyl-CoA = delta-aminolevutinic acid
  • Aminolevulinic acid synthase (ALAS)
  • Vitamin B6/PLP/Pyridoxine
  • Blocked incorporation of Fe into porphyrin ring
  • Buildup of iron in the mt
  • Prussian Blue staining
  • Megaloblasts appear bigger than usual
  • B12 malabsorption, B9 malnutrition, or both
  • Deoxyuridylate –> Thymidylate
  • Combines with haptocorrin, then combines with IF in intestines, then binds to cubulin for storage
  • Polyglutamate form, hydrolyzed into monoglutamate, converted to N5-methyl THF, used or stored
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Hematotoxicology
- Type of anemia caused by NSAIDs
- How?
- Type of anemia caused by Lead
- How (2)?
- Type of anemia caused by Isoniazid
- How?
- Type of anemia caused by alcohol?
- How (2)?
- Type of anemia caused by Fluorouracil
- How?
- Type of anemia caused by Methotrexate
- How?

A
  • Iron deficiency anemia
  • COX-1 inhibition, important for gastric mucosal protection, so less absorption
  • Sideroblastic anemia
  • a) Blocking ferrochelatase, an enzyme need for Fe2+ incorporation
    b) Blocking first step of Heme synthesis
  • Blocks aminolevulinic acid, an enzyme needed in first step (R-L step) of heme synthesis by preventing Vitamin B6 recycling OR PLP-ALAS interaction
  • Megaloblastic anemia
  • a) Damage of gastric mucosa = less intrinsic factor production
    b) Damage of intestinal mucosa = less absorption of B9 (jejunum) and B12 (ileum)
  • Megaloblastic anemia
  • Inhibits thymidylate synthase
  • Megaloblastic anemia
  • Inhibits DHF reductase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Hematotoxicology
- Aplastic anemia def and cause
- Bone marrow hypoplasia
- Pancytopenia
- Reticulocytopenia
- Pure red aplasia
- Which pathway reduces ox. stress in RBCs?
- Which molecule is the antioxidant?- Which molecule produces it?
- Which enzyme supplies it?
- Which enzyme uses the antioxidant as a substate to supply H2O2 with 2 H to form 2 H2O?
- 2 manifestations in G6PD deficiency
- Main cause of G6PD deficiency
- Methemoglobinemia
- What detoxifies MetHb?
- Main cause
- Who is more susceptible? Why?
- Secondary enzyme to convert MetHb to Hb
- Which molecules activates it?
- Thrombocytopenia
- Thrombocytosis
- 3 phases of blood clot formation
- Describe each phase
- Intrinsic vs extrinsic pathway
- Where are clotting factors mainly produced?
- 2 sources of Vitamin K

A
  • Inability of stem cells to make mature blood cells due to damage (immune or toxicity) or genetics
  • Can’t form RBCs
  • Deficiency in formed elements
  • Low reticulocyte (< 0.2%, normal range: 0.5-2.5%)
  • Absent, infrequent erythroblasts
  • Pentose phosphate pathway
  • GSH
  • NADPH
  • Glucose 6-phosphate dehydrogenase (G6PD)
  • Glutathione peroxidase (GPx)
  • Bite cells and Heinz bodies
  • X-linked recessive
  • High MetHb due to ox. stress (Fe2+ [Ferrous] to Fe3+ [Ferric])
  • Cytochrome b5 reductase
  • Genetic
  • Infants. Fetal Hb oxidized more rapidly
  • NADPH MetHb reductase
  • Methylene blue –> Leucoblue
  • High platelet destruction/Low production
  • Too many platelets
  • Vascular, Platelet, and Coagulation phases
  • Vascular: procoagulants convert prothrombin –> thrombin
    Platelet: Thrombin converts fibrinogen to fibrin (insoluble)
    Coagulation: Fibrin acts like a net and stops bleeding
  • Blood vessel vs tissue damage
  • Liver
  • Diet and large intestine bacteria (50%)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Hematotoxicology
- Type of anemia caused by Benzene
- How?
- Type of anemia caused by Penicillin
- How?
- Type of anemia caused by vicine and convicine from fava beans
- How?
- Type of anemia caused by NaNO2
- How?
- How does warfarin work?
- Which form of vitamin K is the cofactor?
- Role of epoxide form from hydroquinone

A
  • Aplastic anemia
  • Metabolism to benezine oxide by CYP2E1, then a series of spontaneous/enzymatic modifications yielding ROS, semiquinone radicals, and tt-mucoaldehyde which cause ox. stress and toxicity
  • Immune hemolytic anemia
  • IgM/IgG on antigens on RBC through complement to phagocytic cells
  • Non-immune hemolytic anemia
  • Divicine and isouramil are released on ingestion which become ROS, not detoxified by G6PD- deficient people
  • Methemoglobinemia
  • Turns Fe2+ to Fe3+
  • Interferes with Vitamin K cycle by inhibiting vitamin K epoxide reductase (rate-limiting enzyme)
  • Hydroquinone
  • Vitamin K recycling
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Neurotoxicology
- Type of cells used for neurotoxicity tests
- 3 experiments to measure neurotoxicity?
- What does each measure?
- Easiest CNS aspect to study
- Hardest CNS aspect to study
- 2 reasons why neurons have high energy requirements
- Why is it more dangerous if the pathology is on the cell body?
- 2 reasons why studying the brain is difficult (in context of toxicology)
- Astrocytes function
- Schwann cells function
- Oligodendrocytes function
- Microglials function
- Where is CSF produced?

A
  • Human induced pluripotent stem cells (iPSCs)
  • Electrodes, neuron outgrowth assay, and automated testing system
  • Electrodes: action potentials
    Neuron outgrowth assay: effect on neural growth
    Automated testing: developmental neurotoxicity
  • Motor functions
  • Mood and personality
  • Largest cells + must maintain membrane potential and axonal transport
  • No regeneration unlike axons, myelin, and synapses
  • Difficult to extrapolate between species and neuronal plasticity/networking can mask toxicity for years
  • Microenvironment
  • Myelination in PNS
  • Myelination in CNS
  • Variant macrophages, have pattern recognition receptors (PRRs), can release free radicals and inflammatory cytokines
  • Choroid plexus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Neurotoxicology
- Coniine pharmacology
- 3 Effects
- Carbon monoxide mechanism and interference
- Manganese mechanism and interference
- MPTP mechanism and interference
- Tetrodotoxin mechanism and interference
- 2 similar toxins to tetrodotoxin
- Vinca alkaloids mechanism
- 2 drugs that behave similarly
- Taxol mechanism
- Hexachlorophene mechanism and outcome
- Hexane mechanism
- Arsenic effects
- Methanol mechanism
- Name a direct presynaptic effect
- Name an indirect presynaptic effect
- Trojan-horse effect
- Which toxicant does it apply to?
- What does the toxicant change?
- Domoic acid mechanism
- What does it cause?

A
  • Stimulates, then blocks nR
  • Bradycardia, ascending paralysis, and coma
  • Competitive binding to Hb against O2. Aerobic metabolism
  • aSyn misfolding and oligomerization. Protein folding
  • Astrocytes’ MAO convert MPTP to MPP+, taken up by dopamine transporter in substantia nigra, then targets mt, lowering ATP levels. Intermediate metabolism
  • Blocks Na+ channels. Electrical transmission
  • Conotoxin and betrachotoxin
  • Bind to tubulin monomers, preventing microtubule formation
  • Cisplatin, Vincristine
  • Prevents disassembly
  • Damages myelin sheath. Edema and/or demyelination
  • Interrupts diketone, a metabolite that crosslinks axonal cytoskeleton
  • Nerve damage, cancer, skin damage
  • Converted to formic acid by ADH, then ALDH
  • Increased/decreased NT release
  • Synaptic modulation
  • Masking presence of other contaminants/pathogens
  • Microplastics
  • Microbiome
  • Binds to Kainate glutamate receptors and prolongs opening of Na+ channels
  • Excitation, followed by death of hippocampal neurons and permanent loss of short-term memory
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Immunotoxicology
- 2 diseases caused by Azathioprine
- Molecule that follows azathioprine during metabolism
- 3 enzymes involved in metabolism
- Active metabolite
- By which enzyme?
- How is allopurinol dangerous for the immunity
- 2 diseases caused by Clozapine
- Clozapine proposed mechanism
- Cigarette smoke’s effect on macrophages
- THC and CBC mechanism
- Immune cell with most and least CB2 mRNA levels
- Effects of binding
- Which group of chemicals do halogenated aromatic hydrocarbons (HAHs) resemble?
- 2 organs affected by them

A
  • Myelotoxicity and pancytopenia
  • 6-Mercaptopurine (6-MP)
  • Xanthine oxidase (XO), thiopurine S-methyltransferase (TPMT), and hypoxanthine phosphoribosyltransferase (HPRT)
  • 6-thioguanine nucleotides (6-TGN)
  • HPRT
  • XO inhibitor
  • Neutropenia and agranulocytosis
  • Nitrenium ions by myeloperoxidase (MPO), which depletes ATP and GSH
  • Recruitment still ok, but macrophages have reduced abilities
  • Binding on CB2
  • B and T cells
  • Apoptosis, inhibition of proliferation and suppression of pro-inflammatory cytokines
  • Dioxins
  • Thymus and bone marrow
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Immunotoxicology
- Example of tissue-specific autoimmunity
- Example of systemic autoimmunity
- 2 mechanisms in central tolerance
- 3 mechanisms in peripheral tolerance
- T/F. Women are more susceptible to autoimmunity than men
- Toxicant-induced aberrant cell death mechanism
- Covalent binding of chemicals to tissue proteins mechanism
- Disease caused by Hydralazine and Hydrochloride
- Disease caused by Toluene and Vinyl Chloride (VC)
- What does VC lead to?
- Requirement for hypersensitivity
- Explain each of the 4 classes of hypersensitivity
- Which class is not Ab-dependent?
- Which chemicals causes hypersensitivity
- 4 proposed ways
- Industrial use of it

A
  • Type I diabetes
  • Lupus
  • Deletion, receptor-modification
  • Suppression by T regulatory cells, apoptosis, anergy
  • True
  • Hidden cell material now available to APCs
  • Formation of neo antigens
  • Systemic Lupus Erythomatosus (SLE)
  • Chemical-induced scleroderma disease (CISD)
  • Formation of abormal antigenic proteins
  • Prior exposure
  • a) Type 1: Dendritic cells, T/B cells, (plasma) IgE, mast cell degranulation, reexposure
    b) Type 2: Opsonization and phagocytosis –> pernicous/hemolytic anemia
    c) Type 3: Ag-Ab complexes –> inflammation, tissue damage, SLE
    d) Type 4: T-cell mediated, contact dermatitis, Type 1 diabetes
  • Type 4
  • Toluene diisocyanate (TDI)
  • Damage lung epithelial cells, Ox. stress, neoAg from airway proteins, and Th2 response (hypersensitivity)
  • Production of polyurethanes (adhesives, pillows, mattresses)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Pneumotoxicology
- Which event/era led to high air pollution
- Relationship with diesel and ozone
- Main source of air pollution in North America
- Main source of air pollution in India
- Which city is coined “Smog City”?
- 4 defense mechanisms in respiration
- How does smog form?
- 7 general components of smog

A
  • Industrial revolution
  • Potentiation
  • Power production and agriculture
  • Residential uses (cooking)
  • Windsor, Ontario
  • Layers (epithelial, muscle, cartilage) in bronchi
    Mucociliary escalator
    Clara cells (high CYP450s)
    Alveolar macrophages (do their job, then go to escalator, then enter GI by swallowing)
  • Photochemical reaction of combustion smoke
  • O3, PM, NOx, SOx, NO2, SO2, CO, Lead
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Pneumotoxicology
- O3 reaction
- Where does radical O come from?
- Why is O3 dangerous?
- Where do coarse particles come from?
- Where do fine particles comes from?
- Why are ultrafine particles so dangerous?
- NOx/SOx effect
- SO2/NO2 effect
- 4 geographical contributions to smog formation
- Wildfire smoke mechanism
- 4 examples of indoor air pollution
- 4 sources of indoor air pollution
- 4 questions in risk assessment of air pollution
- 3 things that characterize COPD
- 3 COPD diseases

A
  • O + O2 = O3
  • Sunlight releases O from NO2
  • Injury to epithelium –> Cytokine release + inflammation leading to lung damage, eye irritation, ROS production, asthma, infection
  • Traffic and construction
  • Soil dust, coal, biomass, industrial emissions
  • They can enter circulation
  • React with H2O to form acids = acid rains = lower soil pH and corrosion
  • Trigger airway nociceptors = bronchoconstriction = acute/chronic bronchitis
  • Human activity
    Features of Land: mountains block win
    Seasons: winter = temperature inversion
    Wildfire smokes: 10x more harmful
  • Induce ACE2 expression in alveoli and capillaries
  • Pathogens, allergens, particles, organic compounds
  • Cooking, fireplaces, cleaning agents, gas stoves, mold
  • Acute vs Chronic?
    Other species affected?
    Pollutant-pollutant interactions?
    Does tolerance develop from long-term exposure?
  • Spasms of airways, inflammation, mucus production
  • Bronchitis, emphysema, asthma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

*Eyes and Skin Toxicology**
- Which demographics are most susceptible to skin injury/toxicity? Why?
- Which layer conserves moisture?
- Type of cells that’s immune cells and part of epidermis?
- What do they do?
- What do fibroblasts in the dermis do?
- 3 examples of small lipophilic molecules that cross the stratum corneum
- 3 effects of toxicants
- 2 groups of phase I metabolic enzymes
- T/F. Skin also has some phase II metabolism
- Chronic irritation from what?
- Acute irritation from what?
- Other name for acute irritation
- Name an example an its pH
- Which layer is disrupted in acute irritation?
- Class of hypersensitivity that is allergic dermatitis
- Mechanism of senstization (4 steps)
- Mechanism of subsequent exposure (2 steps)
- 5 sources of toxin
- 4 experimental methods for irritancy test

A
  • Elderly and children b/c of thinner skin, easier absorption
  • Dead keratinocytes in the stratum corneum (epidermis)
  • Langerhans cells
  • Take and process antigens
  • Secrete elastin, collagen, other substances to give elasticity to the skin
  • Toluene, benzene, CCl4
  • Irritant, dissolve lipid barrier, systemically absorbed (NS effect)
  • CYP450s and flavin monooxygenase
  • True
  • Chronic exposure to mild irritants
  • Acids, bases, oxidizing, reducing agents
  • 2nd degree chemical burn
  • 12-14 pH
  • Cornified layer
  • Type 4
  • a) Haptens penetrate lipid layer and attach to carrier proteins
    b) Langerhans recognize + process
    c) Langerhans present antigens to T cells in lymph nodes
    d) T cells activate, proliferate, and accumulate
  • a) T cells release cytokines
    b) Cytokines recruit macrophages and other cells
  • Plants, nickel, latex, glue, drugs
  • Guinea pig maximization test
    Mouse Local Lymph Node Assay (LLNA)
    In vitro cell cultures of keratinocytes and Langerhans
    In vitro skin irritancy test
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

*Eyes and Skin Toxicology**
- Which UV type is the most dangerous?
- Is sensitization required in phototoxicology?
- Group of compounds that cause phytotoxicity
- Example of 1 chemical
- Mechanism w/ and w/o light
- Photocarcinogenicity reaction
- Aside from being carcinogenic, what else can it produce?
- 2 examples of photoallergy
- Class of hypersensitivity that is Urticaria (hives)
- Histamine effect
- 3 most susceptible parts of eyes
- 3 compounds dangerous to eyesight
- T/F. The eyes have phase I and II metabolism
- 4 experimental methods used to assess eye toxicity
- Which one is no longer used? Why?
- What is Atrazine used for?

A
  • UVA
  • No
  • Furanocoumarins
  • Psoralen
  • a) Strongly binds to thymine, causing DNA damage
    b) Binds with thymine through H-bonds
  • Chemical (non-carcinogen) + UV = Photocarcinogen
  • Free radical production (ex: Cl2 –> 2 Cl-)
  • Hexachlorophene, diphenhydramine, and musk
  • Type 1/anaphylactic reaction by IgE and histamine
  • Increase permeability of WBCs and proteins
  • Cornea, conjunctive muscles, eyelids
  • Lead, methanol, methyl mercury
  • True
  • Draize test
    Isolated chicken eyes
    Bovine Corneal Opacity Test
    Short time Exposure in vitro test
  • Draize. Too cruel
  • Insecticide and herbicide
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Cardiotoxicology
- 3 types of CV disease
- Order of backup pacemakers
- Average heart beat
- 5 ways toxins can interfere with heart
- Toxin part of cardiac glycosides
- 2 types of glycosides
- Mechanism of glycosides
- High doses of glycosides effects
- Is atrial fibrillation lethal?
- Is conduction block lethal?
- Digitoxin early symptoms
- Digitoxin at higher doses
- Distribution of Digitoxin
- Metabolism of Digitoxin
- Excretion of Digitoxin
- What class of toxin is Oleandrin?
- Which toxin is from Lilies of the Valley?
- Class of toxin Kalanchoe

A
  • Cerebrovascular disease
    Coronary heart disease
    Peripheral vascular disease
  • SA, AV, His-Purkinje system, Independent ventricular muscles
  • 60/min
  • Interferences with ion channels, contractility, mt function, signaling (EP, NA, 5HT)
    Generation of free radicals
    Apoptosis/Necrosis
    Fibrosis
    Thrombus
  • Non-sugar/Aglycone
  • Cardenolides and Bufadienolides (toads and fauna in the South)
  • a) Block Na/K-ATPase
    b) Intracell. Na accumulation
    c) Increased activity of Ca/Na exchanger
    d) Intracell. Ca accumulation
    e) Higher forces of contraction
  • Off-time contractions = arrhythmias
  • No, AV node can act as backup
  • Yes if prolonged
  • Neurological
  • Ventricular fibrillation, tachycardia, progressive tachycardia, cardiac arrest
  • Concentrated in tissues, not circulation and crosses BBB
  • Poor metabolism by liver
  • Kidneys
  • Cardiac glycoside
  • Convallatoxin
  • Cardiac glycoside
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Cardiotoxicology
- Known classical toxin used to kill by Romans and Celts
- Is there an antidote for it?
- Mechanism
- ECG observation
- Class of toxin moldy hay
- Snake venom mechanism
- Doxorubicin mechanism
- Herceptin mechanism
- Disease caused by Herceptin
- Ephedra 3 main molecular effects
- Disease by Ephedra
- Experimental method used to test cardiotoxicity (3 steps)

A
  • Yew
  • No
  • Block Ca2+ channels = no contractions = blocks excitation-contraction coupling
  • Very wide QRS
  • Cardiac glycoside
  • Formation of pores that block conduction = necrosis of cardiomyocytes = less contractility
  • Affect mitochondria = apoptosis
  • Targets HER2/4 on breast cancer cells but also on heart cells
  • Congestive heart failure (CHF): inadequate CO, heart hypertrophy, peripheral/pulomnary edema, kidney congestion
  • a) Increases NA and EP release
    b) Impairs removal and/or uptake of NTs
    c) Stimulate post synaptically on receptors
  • Ischemic heart disease, severe myocardial infarction, stroke
  • a) Organoids made from human tissue
    b) Expose them to toxins
    c) See fraction of cells that die and score contractility of cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Hepatotoxicity
- 4 general problems if liver is affected
- 2 types of cholestasis
- 2 sources of blood flow to liver
- 4 cells in liver lobule
- Basic unit in liver
- Smallest functional unit
- 3 components of hepatic triad
- 3 zones in acinus and their function
- How does Chlorpromazine cause canalicular cholestasis?
- Bile acid produced from what and from which enzyme?
- Rate-limiting step in bile formation
- 6 possible mechanisms for cholestasis
- What is Cholangiodestructive cholestasis?
- How does paraquat cause it?
- What is hepatic steatosis?
- 4 general pathways of steatosis?

A
  • Excess bleeding (clotting factors), hypoglycemia (glucose), malnutrition (bile production), diminished metabolism
  • Hepatocellular cholestasis and canalicular cholestasis
  • Hepatic portal vein and hepatic artery
  • Hepatocytes, endothelial cells, Kupffer cells (macrophages), and Ito cells (store vitamin A)
  • Liver lobule
  • Acinus
  • Portal venule, portal arteriole, and bile duct
  • Zone 1: Closest to arterioles, best oxygenated, higher GSH, ammonia detox, FA ox.
    Zone 2: Intermediate
    Zone 3: Farthest from arterioles, least oxygenated, and xenobiotic metabolism
  • Impairs bile uptake and canaliculus contractility
  • Cholesterol from CYP7A1
  • Bile excretion
  • Impaired uptake in sinusoidal side
    Diminished transcytosis in canalicular side
    Impaired secretion from canaliculus
    Diminished contractility of canaliculus
    Leaky paracellular junction
    Concentration of reactive species
  • Bile duct destruction that carries bile from liver to GI tract
  • Ox. stress by ROS
  • Buildup of triglycerides in hepatocytes
  • Influx of FA, TG secretion, FA ox., De novo lipogenesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Hepatotoxicity
- CCl4 metabolism
- Which alcohol metabolite is toxic?
- Which protein is increase in chronic OH consumption that causes lipogenesis?
- 4 steps in liver disease progression
- Alcohol Enzyme that is 40x more active
- Alcohol Enzyme that is almost inactive
- VC toxic metabolite and by which enzyme?

A
  • CCl4 –> CCl3 by CYP2E1 = GSH depletion, lipid peroxidation = disrupted lipid homeostasis
  • Acetaldehyde
  • SREBP1c (sterol regulatory element-binding protein 1c)
  • Steatosis, Fibrosis, Cirrhosis, HCC
  • ADH1B*2
  • ALDH2*2/2
  • Chloroethylene oxide (CEO) by CYP2E1