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VBMS410 > Toxicology Exam 1 > Flashcards

Toxicology Exam 1 Flashcards

1
Q

Toxicology

A

the study of the adverse effects of substances on living organisms
- Chemical properties
- Biological effects
- Concentration/dosage, duration, and frequency of exposure

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2
Q

Toxicant

A

any chemical that interferes with life, biological processes, and exert a deleterious effect on an organism

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3
Q

Toxin

A

poison originating from a biological process (an organism)

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4
Q

Biotoxin

A

synonymous with toxin

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5
Q

Bacterial toxin

A

toxin originating from a bacterium; an endotoxin or exotoxin

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6
Q

Zootoxin (venom)

A

toxin originating from an animal

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7
Q

Phytotoxin

A

toxin originating from a plant

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8
Q

Toxicosis

A

the disease or illness that results from exposure to a poison

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9
Q

Intoxication

A

the state produced by exposure to a poison

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10
Q

What are the 4 classifications of toxicity exposures?

A

Acute
Subacute
Subchronic
Chronic

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11
Q

Acute toxicity

A

> /= 1 exposure within a 24 hour period

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12
Q

Subacute toxicity

A

> 1 exposure for 1-30 days

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13
Q

Subchronic toxicity

A

n exposures for 1-3 months

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14
Q

Chronic toxicity

A

n exposures for >3 months

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15
Q

What are toxic effects?

A

the adverse effects produced in an organism when it is exposed to a poison
* Death
* Sickness
* Disease

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16
Q

Teratogenic effects

A

Malformations in a fetus that result from exposure to chemicals in utero

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17
Q

Mutagenetic effects

A

genetic mutations caused by exposure to chemicals

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18
Q

Carcinogenic effects

A

cancer caused by exposure of chemicals

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19
Q

What is the difference of pharmacology vs toxicology?

A

Both pharmacology and toxicology are scientific principles that focus on understanding the properties and actions of chemicals. However, pharmacology emphasizes the therapeutic effects of chemicals, usually drugs or compounds that could become drugs. Whereas toxicology is the study of chemical’s adverse effects and risk assessment
Exposure (unintended) vs Dosage (intended)
Adverse drug reactions

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20
Q

Absorption of toxicants meaning

A

transport across membrane
- Absorption determines toxicity of chemicals
- Absorption of toxicants require movement across one or more membranes

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21
Q

What are the four types of transports/absorptions of toxins?

A

Passive, Active, Facilitated and Endocytosis

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22
Q

Passive transport

A

= diffusion
* Movement is down concentration gradient
* Does not require energy. Most common means of absorption
* Hydrophobic, uncharged molecules

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23
Q

Active transport

A
  • Required a “pump of energy”
  • Pumps against concentration gradient
  • Different pumps for different chemicals
  • Saturable (maximal pumping speed)
  • May be inhibited (stops pumping)
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24
Q

Facilitated diffusion

A
  • Required a channel or pore
  • Requires NO energy
  • May become saturated (maximal transport speed)
  • May be inhibited (stops transporting)
  • Moves chemicals DOWN concentration gradient
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25
Q

Endocytosis

A
  • Large molecules and particles
  • In endocytosis, the cell surrounds the “cargo” with its cell wall. The engulfed cargo separates from the membrane and moves into the interior of the cell
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26
Q

The two main forms of endocytosis are:

A

Phagocytosis (cell-eating) – large particles are engulfed and either transported and/or destroyed within the cell.

Pinocytosis (cell-drinking) – similar, but involves the engulfing of liquids or very small particles

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27
Q

Factors influencing SIMPLE DIFFUSION

A
  1. Ionization
  2. Diffusion (Fick’s law)
  3. Permeability / partition coefficients
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28
Q

How does ionization influence simple diffusion?

A

unionized (has not formed an ion) forms of drugs and toxicants can pass through membranes more readily than ionized formed; Henderson-Hasselbach equation

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29
Q

How does diffusion (Fick’s law) influence simple diffusion?

A

rate of diffusion depends upon concentration gradient, absorptive area, and thickness of membrane

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30
Q

How does permeability / partition coefficients influence simple diffusion?

A

Depends on partitioning, mobility, and thickness of the membrane

Partition coefficients – ratio of solubility in hydrophobic (organic) vs hydrophilic (water solvent). Membranes are more permeable to chemicals with high partition coefficients

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31
Q

Routes of absorption

A

Gastrointestinal, respiratory. skin, mucosa

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32
Q

Gastrointestinal (oral) route of absorption

A

very common route for toxicants in food and water

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33
Q

Respiratory system route of absorption

A

gaseous or vaporous toxicants, some particulates; highly influenced by circulation

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34
Q

Skin route of absorption

A

relatively impermeable, but some chemicals absorbed across it; injury, hair follicles, sebaceous glands, penetration; lipophilic chemicals penetrate more readily

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35
Q

Mucosa route of absorption

A

high degree of absorption

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36
Q

Xenobiotic metabolism (Biotransformation): Good and bad effects

A
  • Alter solubility (hydrophilicity) or enhance exertion (detoxification)
  • Increase toxicity
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37
Q

Phase I reactions

A
  • Degradation (catabolic) reactions

Biotransformation occurs primarily in the ER and cytosol and to a lesser extend in the mitochondria, nuclei, and lysosomes. Functional group can be added.

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38
Q

Phase II conjugation reactions

A
  • Conjugation reactions (anabolic)

o Except for glucuronide formation, most occur in the cytoplasm

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39
Q

What are the different types of phase I reactions?

A
  • Oxidation: loses electrons
  • Reduction: gains electrons
  • Hydrolysis: adds water
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40
Q

What are the types of phase II conjugation reactions?

A

Glucuronide formation
Sulfate formation
Methylation
Acetylation
Amino acid conjugation
Glutathione conjugation

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41
Q

Glucuronide formation
Modification, enzyme, and co-factor

A

– addition of glucoronate, very common mechanism.

Catalyzed by UDP-glucuronly transferase in endoplasmic reticulum

coenzyme = UDPGA

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42
Q

Sulfate formation
Modification, enzyme, and co-factor

A

– addition of a sulfate.

Catalyzed by sulfotransferase in cytosol

coenzyme = PAPS.

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43
Q

Methylation
Modification, enzyme, and co-factor

A

Addition of methyl.

Catalyzed by methyl transferase

coenzyme = SAM

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44
Q

Acetylation
Modification, enzyme, and co-factor

A

Addition of acetyl group.

Catalyzed by N-acetyl transferases

coenzyme = acetyl CoA

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45
Q

Amino acid conjugation
Modification

A

– addition of amino acids

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46
Q

Glutathione conjugation
Modification, enzyme, and co-factor

A

Binding to glutathione GSH

Catalyzed by glutathione S-transferases

cofactor = glutathione

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47
Q

Bioactivation

A

chemically stable compound converted to chemically reactive metabolite. Often catalyzed by cP450 enzymes

  • Reactive metabolite binds to macromolecules (proteins, nucleic acids) causing cell damage (death)
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48
Q

Example of metabolism and consequence

A

Epoxide formation – aromatic compounds converted to epoxide.

–> epoxide is conjugated with GSH; conjugated product is not toxic.

If capacity for conjugation is exceeded, epoxide becomes available to damage tissues (hepatocellular carcinoma).

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49
Q

Routes of excretion

A

Primary routes of excretion:
1. Urinary
2. Fecal/biliary
3. Respiratory

Secondary routes of excretion:
1. Sweat
2. Tears
3. Saliva
4. Milk

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50
Q

Toxidynamics

A

the dynamic interactions of a toxicant with a biological target or site of action, and its biological effects (dose-response)

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51
Q

Threshold concentration

A

concentration above which toxic effects occur.

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52
Q

Toxicokinetics

A

how a toxicant gets into the body and what happens to it within the body (concentration-time course relationship)

  • Movement of toxicant in the body
    o Terminal half-life
    o Volume of distribution.
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53
Q

LOEL

A

lowest observed effect level. Lowest dose at which an effect (even beneficial) is observed

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54
Q

LOAEL

A

lowest observed adverse (judgmental) effect level. Lowest dose at which an adverse effect was detected.

55
Q

NOEL

A

no observed effects level. Highest dose (tested) at which a significant effect (even beneficial) could not be found

56
Q

NOAEL

A

no observed adverse effects level. Highest dose (tested) at which a significant adverse effect could not be found.

57
Q

LD50

A

lethal dose 50%. Statistically derived dose at which 50% of animals will be expected to die

58
Q

Steps of toxicity after xenobiotic exposure

A

Step 1: Toxicant delivery
Step 2: Reaction of the toxicant (metabolite) at the site of action
Step 3: Toxicant-induced cellular dysfunction or injury
Step 4: Adaptation of Repair

59
Q

Toxicant delivery after xenobiotic exposure

A
  • The intensity and nature of the toxic effect depends on the concentration and length of toxicant (metabolite) exposure
  • The concentration of the toxicant (metabolite) at the site of action depends on the balance between the processes that increase and decrease its concentration
60
Q

Reaction of the toxicant (metabolite) at the site of action after xenobiotic exposure

A
  • Depends on attributes of the target molecule, types of reactions, and effects/outcomes
61
Q

Toxicant-induced cellular dysfunction or injury after xenobiotic exposure

A
  • At the cell/organ/tissue/system level
  • Dysfunction involved all aspects of cell physiology
    o Growth/proliferation
    o Differentiation
    o Function
    o Survival
62
Q

Adaptation or repair after xenobiotic exposure

A
  • Cells and tissues will adapt first, succumb second
  • Repair mechanisms for biomolecules and organelles
  • Degradation and turnover
  • Transcriptional regulation of adaptive mechanisms
  • Tissue responses
63
Q

Redox signal transduction

A

signaling process that involved redox reactions

64
Q

Types of reactions mediated by toxicant

A

Non-covalent
Covalent
Hydrogen abstraction
Electron transfer

65
Q

Non-covalent reaction mediated by toxicant

A

Reversible hydrogen / ionic bonds (ion channels and membrane receptors)

66
Q

Covalent reaction mediated by toxicant

A

Irreversible adduct formation by electrophiles (–> nucleophiles)

67
Q

Covalent reaction mediated by toxicant

A

Irreversible adduct formation by electrophiles (–> nucleophiles)

68
Q

Covalent reaction mediated by toxicant

A

Irreversible adduct formation by electrophiles (–> nucleophiles)

68
Q

Covalent reaction mediated by toxicant

A

Irreversible adduct formation by electrophiles (–> nucleophiles)

69
Q

Covalent reaction mediated by toxicant

A

Irreversible adduct formation by electrophiles (–> nucleophiles)

70
Q

Hydrogen abstraction reaction mediated by toxicant

A
  • Free radicals to generate more radicals
  • Protein carbonyls (DNA or protein adducts)
71
Q

Electron transfer reaction mediated by toxicant

A

Oxidation or reduction of molecule

72
Q

Covalent reactions by Electrophiles

A
  • Covalent binding forms irreversible bonds between a toxicant and the target molecule
  • Between electrophilic (electron-seeking) toxicants and nucleophilic (electron-donating) compounds.
  • Nucleophilic compounds are abundant in biological systems (proteins, nucleic acids, and phospholipids)
  • Covalent binding of toxicants can inhibit or alter enzymes, protein function, or damage cellular components.
73
Q

Oxidation

A

–> is the loss of electrons or an increase in the oxidation state of an atom

o Compounds that easily take up electrons can often oxidize other molecules – oxidants

74
Q

Reduction

A

–> is the gain of electrons or a decrease in the oxidation state of an atom

o Compounds that easily donate electrons have a tendency to reduce other molecules – reductants

75
Q

Redox Cycling

A

Repetitively coupled reduction and oxidation reactions, often involving oxygen and reactive oxygen species (ROS)

76
Q

Oxidative stress

A

an increase in the steady state levels of ROS (or derived oxidative modifications) that surpasses the ability of the cell to counteract them (oxidant systems, repair/ turnover mechanisms). Imbalance between ROS generation and antioxidant systems

77
Q

Reactive oxygen species

A

A type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A build up of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death. Reactive oxygen species are free radicals.

78
Q

Reactive nitrogen species

A

Reactive oxygen species/reactive nitrogen species derived from oxygen and nitrogen plays a vital role in propagation of liver injury by damaging cell membrane, micro, and macromolecules. Excess ROS production leads to various diseases especially liver which have its main function as detoxification.

79
Q

ROS or RNS

A

are chemically reactive molecules containing oxygen

o RNS are considered a subtype of ROS as they contain oxygen

  • ROS / RNS are by products of metabolism or ROS-generating enzymes activated during inflammation
80
Q
A

Polyunsaturated acyl chains of phospholipids or polyunsaturated fatty acids (PUFAs) such as arachidonic acid and linoleic acid are highly susceptible to peroxidation and breakdown forming a variety of lipid-derived aldehydes and ketones

o When lipid encounters a free radical, will split and become a lipid radical
o Compounds are not stable, fragment from membrane and produce aldehydes (which are toxic)

81
Q

Inflammation

A

is a reaction to injurious agents (microbes, damaged cells, or xenobiotics) that leads to the systemic responses mediated by the release of cytokines

  • Transcriptional regulation of gene expression
    Inflammation is a protective response, the ultimate goal of which is to clear the organism of both the initial cause of cell injury and the consequences of such injury
82
Q
  • Acute inflammation
A

is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues

83
Q

Chronic inflammation

A

is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.

84
Q

Inflammation- Induced Oxidative Damage

A

Oxidative stress can cause chronic inflammation. Infections and injuries trigger the body’s immune response. Immune cells called macrophages produce free radicals while fighting off invading germs. These free radicals can damage healthy cells, leading to inflammation.

85
Q

NADPH Oxidases (NOx’s)

A

are transmembrane proteins responsible for transporting electrons across biological membranes, which leads to reduction of oxygen into superoxide
o Oxidative burst in response to pathogens

86
Q

Nitric oxide synthases (NOSs)

A

Are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule

87
Q

What are the cell death pathways

A

Apoptosis
Necrosis
Autophagy

88
Q

Apoptosis

A

Programmed cell death. Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay.

o clearance by phagocytic cells

89
Q

Necrosis

A

Accidental; release of the intracellular content. Irreversible and accidental cell injury. Loss of plasma membrane integrity, cell/organelle swelling, robust inflammatory response

90
Q

Autophagy

A

Uncontrolled or when targeting vital organelles; mostly a protective mechanism. Homeostatic mechanisms are involved in the turnover or degradation of cellular components of pathogens.

o Cargo is engulfed in double-membraned autophagosomes to be later degraded upon fusion with lysosomes
o Involved activation of a # of signaling platforms: initiation, elongation, maturation, fusion, recycling

91
Q

What determines how a cell dies?

A
  • Intensity and length of toxic stimuli
  • Signaling pathways activated
  • Integrity and functionality of signaling machinery (apoptosis)
  • Mitochondria injury
92
Q

How do xenobiotics induce anemia?

A

Xenobiotics affect the production, function, or survival of erythrocytes resulting in decrease cell mass (anemia).

Erythrocytes and heme–> principle transport vehicle for O2 transportation from the lung to peripheral tissues, and CO2 from tissues to the lung.

93
Q

Proliferation (Erythropoietin)

A

EPO tells your body to make red blood cells. When you have kidney disease, your kidneys cannot make enough EPO. Low EPO levels cause your red blood cell count to drop and anemia to develop.

94
Q

Xenobiotic effects on proliferation

A

Toxicants can affect the supply of nutrients (iron) or growth factors (erythropoietin). Erythropoietin (EPO) is a glycoprotein hormone, naturally produced by the peritubular cells of the kidney, that stimulates red blood cell production.

95
Q

Heme formation

A

Erythrocyte production depends on cell division and high rates of heme production.

96
Q

Pb (Lead) effect on anemia

A

Inhibits the ability to produce hemoglobin by interfering with enzymatic steps in the heme synthesis pathway and diminishes red blood cells, thereby increasing risk of anemia. The absorption of lead can cause iron deficiency and may further cause anemia

Defects in the synthesis of the porphyrin ring of heme lead to sideroblastic anemia. Accumulation of iron in bone marrow.

97
Q

Enzymes of Pb (lead) effecting anemia

A

Defects in the synthesis of the porphyrin ring of heme lead to sideroblastic anemia. Accumulation of iron in bone marrow.

98
Q

Enzymes of Pb (lead) effecting anemia

A

Defects in the synthesis of the porphyrin ring of heme lead to sideroblastic anemia. Accumulation of iron in bone marrow.

  • Porphobilinogen synthase (or ALA dehydratase or aminolevulinate dehydratase) synthesizes porphobilinogen from aminolaevulinic acid.
  • Ferrochelatase catalyzes the insertion of iron into protoporphyrin IX.
    Ferrochelatase and ALA dehydratase are inhibited by lead.
99
Q

How does carbon monoxide impair O2 delivery?

A

Carbon monoxide (CO) – an odorless, colorless gas. Causes sudden illness and dead by impairing O2 binding to hemoglobin.

When carbon monoxide binds to hemoglobin, less oxygen gets transported to body tissues and vital organs such as the brain and heart. The bond between carbon monoxide and hemoglobin is approximately 250 times stronger than the bond between oxygen and hemoglobin.

100
Q

How do xenobiotics trigger leukemogenesis?

A

Proliferative disorders of hematopoietic tissue that originate from bone marrow and cells

101
Q

Myeloid leukemogenesis

A

(myeloblasts, RBCs, and platelets) or lymphoid (lymphocytes)

102
Q

Acute leukemogenesis

A

(poorly differentiated) or chronic (well differentiated)

103
Q

Main difference between myloid and acute leukemogenesis

A

Myeloid affects the production of myeloblasts, red blood cells, and platelets, whereas Acute mainly affects the production of lymphocytes

104
Q

Examples of how xenobiotics trigger leukemogenesis

A

o Ionizing radiation
o Chemicals

 Benzene –> occupational exposure to benzene via inhalation is associated with acute myeloid leukemia. Travels to bone marrow where it can undergo different biosynthetic pathways.
 Alkylating agents

105
Q

Mechanisms involved in effects of Toxicants in the Immune System

A

Elimination or control: recognition, memory, response

Bone marrow (origin; NK cells), thymus (T cells; activated and memory), spleen and lymph nodes (B-cells; antigen presenting)

106
Q

Three effects of toxicants on immune system:

A
  1. Immunosuppression and immunodeficiency
  2. Hypersensitivity and allergy
  3. Autoimmunity
107
Q

Immunosuppression and immunodeficiency

A

increase risk to infections and diseases associated with it

108
Q

Autoimmunity

A

antibodies to endogenous antigens. Mode of action of drugs or toxicants appears to be through covalent binding of the drug or its metabolites to tissue macromolecules,

109
Q

Types of hypersensitivity reactions

A

Anaphylactic, cytolysis, immune complexes, and cell mediated (nickle)

110
Q

Anaphylactic hypersensitivity reaction

A

antigens crosslink IgE and release vasoactive molecules

111
Q

Cytolysis hypersensitivity reaction

A

antigen binds to IgM or IgG on the foreign/ host cell leading to its death

112
Q

Immune complexes hypersensitivity reactions

A

soluble antigen-antibody immune complexes not cleared by immune cells leave the plasma and are deposited in tissues triggering an inflammatory reaction

113
Q

Cell-mediated (nickel) hypersensitivity reaction

A

development of activated and memory T-cells

114
Q

Vulnerable targets in cardiomyocyte function

A

Heart and blood vessels

115
Q

How is the heart affected by xenobiotics

A

alteration of the electrophysiology of the heart resulting in the impairment of its mechanical function

o Most vulnerable mechanisms: energy

116
Q

How are blood vessels affected by xenobiotics?

A

permeability, damage, atherosclerosis

117
Q

Effect of xenobiotics on cardiac action potential

A
  • Local anesthetics –> Na + channel blockage
  • General anesthetics and antipsychotic drugs –> Ca 2+ channel blockages
  • Antihistamines –> K+ channel blockers
118
Q

Glycosides

A

Found in plants

o Inhibition of the Na+ / K+ ATPase
o Cardiac arrythmias or arrest, hemorrhage, myocarditis, and myocardial ridges
o Digitonin from Digitalis purpurea

119
Q

Alkaloids

A

Found in plants

o Acetylcholinesterase inhibitors (regulation of HR via muscarinic Ach-receptors and K+ channels)
o Ca 2+ antagonists

120
Q

Indexes of cardiotoxicity

A
  1. Changes in the electrocardiogram (ECG)
    Increase in the amplitude of the T-wave and St-segment elevation
  2. Serum levels of troponin T and I
  3. Levels of creatinine kinase CK, MB, FABP3, and Lactate Dehydrogenase LDH-1
121
Q

Biomarkers for cardiac toxicity and where they act

A

Creatine kinase –> myocardium
Myoglobin –> myocardium
B-type natriuretic peptide BNP –> ventricular myocardium
Cardiac troponins –> cardiomyocytes

122
Q

Key characteristics of cardiovascular toxicants:

A
  1. Impairs regulation of cardiac excitability
  2. Impairs cardiac contractility and relaxation
  3. Induces cardiomyocyte injury and death
  4. Altern hemostasis (bleeding prevention and stop)
  5. Impairs mitochondrial function
  6. Modifies autonomic nervous system activity
  7. Induces oxidative stress
  8. Causes inflammation
123
Q

What is an endocrine disruptor?

A

Endocrine disruptors are chemicals that interfere with the hormone systems and produce adverse developmental, reproductive, neurological, and immunological effects in mammals.

  • Present in the environment and foods
  • Derives from different sources: pharmaceuticals, pesticides, plastics, byproducts of combustion metals
124
Q

How do endocrine distrupters act?

A
  1. Mimic or interfere with the action of hormones
  2. Affect the synthesis, storage, and release of hormones
125
Q

What can endocrine disruptive chemicals induce?

A
  • Developmental toxicity
  • Reproductive toxicology
  • Neurotoxicity
  • Immune toxicity
  • Mutagenesis
  • Obesity and diabetes
126
Q

General signaling by nuclear hormone receptors

A

Nuclear receptor signaling (steroids) –> hormone is a ligand that needs to bind to a receptor

127
Q

How does Nuclear receptor signaling work?

A
  • Ligand-regulated transcription factors activated by hormones
  • Their ligands cross the plasma membrane and interact with nuclear receptors inside the cell
  • Once activated, nuclear receptors directly regulate transcription of genes that control a wide variety of biological processes
128
Q

Epigenetics

A

alterations of genes that do not include alterations in the DNA sequence. Regulation of phenotypic trait variations (cellular or physiological) by external or environmental factors that switch genes on and off and affect how cells read genes without alterations in the DNA sequence.

129
Q

What is the role of DNA methylation + histone modifications?

A

DNA methylation is essential for silencing retroviral elements, regulating tissue-specific gene expression, genomic imprinting, and X chromosome inactivation. Importantly, DNA methylation in different genomic regions may exert different influences on gene activities based on the underlying genetic sequence

DNA methyltransferases catalyze the transfer of a methyl group to DNA using SAM as the methyl donor

130
Q

Obesogens

A

are foreign chemical compounds that are hypothesized to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity

Agents that act in a variety of ways to promote fat storage and adipose tissue production, often by disrupting hormonal signaling

Tributyltin –> peroxisome proliferator
Glucocorticoid receptor

131
Q

What is the contribution of obesogenic xenobiotics to the epidemic of obesity?

A

Effects perpetuated through generations, presumably via epigenetic mechanisms

132
Q

Mechanisms of toxicity by goitrogenic substances

A

Goitrogens are naturally occurring substances that can interfere with the function of the thyroid gland. Goitrogens get their name from the term ‘goiter’ which means the enlargement of the thyroid gland. This triggers the pituitary to release thyroid-stimulating hormone (TSH), which then promotes the growth of thyroid tissue, eventually leading to goiter.

133
Q

Mechanisms of toxicity by goitrogenic substances

A

Goitrogens are naturally occurring substances that can interfere with the function of the thyroid gland. Goitrogens get their name from the term ‘goiter’ which means the enlargement of the thyroid gland. This triggers the pituitary to release thyroid-stimulating hormone (TSH), which then promotes the growth of thyroid tissue, eventually leading to goiter.

VBMS410 (6 decks)

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