Post-Midterm Flashcards
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
- 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
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?
- 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
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
- 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%)
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
- 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
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?
- 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
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?
- 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
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
- 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
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
- 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)
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
- 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
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
- 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
*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
- 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
*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?
- 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
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
- 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
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)
- 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
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?
- 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
