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Mechanisms of toxicity Flashcards

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1
Q

What is required for any mechanism of toxicity?

A

Exposure at the target site

Exposure is critical for the initiation of toxic effects.

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2
Q

Define xenobiotic disposition.

A

Absorption, distribution, biotransformation, and elimination of a toxicant

Each of these processes plays a role in determining target organ toxicity.

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3
Q

What factors can increase or decrease toxicity?

A

Kinetics of absorption, distribution, biotransformation, and elimination

These factors contribute to the severity of a toxic response.

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4
Q

How is absorption defined?

A

The process by which toxicants cross body membranes to enter systemic circulation

Absorption can occur through the gastrointestinal tract, skin, or lungs.

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5
Q

What is presystemic elimination?

A

Elimination of a toxicant prior to reaching systemic circulation

Often occurs in the gastrointestinal tract or liver.

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6
Q

What is first-pass metabolism?

A

Modification of a compound by biotransformation enzymes in the liver after gastrointestinal absorption

This process reduces systemic exposure to a toxicant.

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7
Q

What are the four properties that facilitate tissue distribution of toxicants?

A
  1. Porosity of capillary endothelium
  2. Presence of specialized transport processes
  3. Potential for accumulation in cellular organelles
  4. Binding to proteins or other macromolecules

These properties affect how toxicants reach their target sites.

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8
Q

What role do transporters play in the distribution of toxicants?

A

They regulate uptake and efflux of xenobiotics and endogenous substrates

There are at least 52 families of transporters in the human genome.

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9
Q

What is the significance of amphipathic molecules in toxicity?

A

They can accumulate in cellular organelles like lysosomes or mitochondria

Accumulation can lead to toxicity through mechanisms like phospholipidosis.

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10
Q

How does binding to proteins influence toxicant distribution?

A

It can sequester toxicants and influence target organ toxicity

Examples include keratins and metallothionein binding heavy metals.

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11
Q

What determines the route and rate of excretion of toxicants?

A

The physicochemical properties of the toxicant

Major excretory organs include the liver and kidneys.

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12
Q

What happens to non-volatile compounds during excretion?

A

They are efficiently removed by the liver and kidney

This is especially true for water-soluble, ionized compounds.

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13
Q

Fill in the blank: Enterohepatic circulation is a cycle in which a compound is excreted into bile to enter the intestine where it is modified to facilitate _______.

A

intestinal reabsorption

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14
Q

What is metabolic activation?

A

Biotransformation of xenobiotics that increases toxicity

It generates reactive intermediates that can harm cellular structures.

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15
Q

What is an electrophile?

A

A molecule with an electron-deficient atom that can accept electron pairs from nucleophiles

Electrophiles are often produced from metabolic activation.

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16
Q

How are free radicals formed?

A
  1. Accepting an electron
  2. Losing an electron
  3. Homolytic fission of a covalent bond

Free radicals can amplify toxic responses.

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17
Q

What is the Fenton reaction?

A

A process that describes the reductive homolytic fission of hydrogen peroxide to form hydroxyl radicals

It is catalyzed by transition metal ions.

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18
Q

True or False: Hydroxyl radicals are considered ultimate toxicants for xenobiotics.

A

True

Hydroxyl radicals are highly reactive and can damage cellular components.

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19
Q

What is the ultimate toxicant for xenobiotics?

A

Hydroxyl radical

Hydroxyl radicals are highly reactive and can cause significant cellular damage.

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20
Q

What does peroxynitrite (ONOO−) form when it reacts with carbon dioxide (CO2)?

A

Nitrosoperoxy carbonate

This reaction can lead to the production of nitrogen dioxide and carbonate anion radical.

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21
Q

What are the radical products formed from the spontaneous reaction of ONOO− with CO2?

A
  • Nitrogen dioxide (•NO2)
  • Carbonate anion radical

All these products are oxidants and •NO2 is also a nitrating agent.

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22
Q

What is detoxification?

A

Biotransformation that prevents the formation of a toxic metabolite or eliminates it once formed

Detoxification is crucial for reducing the likelihood of toxicity.

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23
Q

What are some phase II biotransformation reactions involved in detoxification?

A
  • Glucuronidation
  • Sulfation
  • Glutathione conjugation

These reactions help in detoxifying various harmful substances.

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24
Q

What happens when detoxification mechanisms are overwhelmed?

A

Toxicity ensues

Saturation of detoxification processes can lead to adverse effects.

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25
Which enzymes are involved in the detoxification of electrophiles?
* Epoxide hydrolase * Carboxylesterase * NAD(P)H:quinone oxidoreductase (NQO1, NQO2) * Carbonyl reductase * Aldehyde dehydrogenases ## Footnote These enzymes convert harmful substances to less toxic forms.
26
What is glutathione (GSH)?
A tripeptide composed of glycine, cysteine, and glutamic acid ## Footnote GSH is crucial for detoxification and is present in high concentrations in the liver.
27
How does glutathione detoxify electrophilic toxicants?
By conjugation with glutathione ## Footnote This process can occur spontaneously or be catalyzed by glutathione S-transferases.
28
What is the role of superoxide dismutases (SOD) in detoxification?
Convert superoxide anion radical to hydrogen peroxide (HOOH) ## Footnote SODs are crucial for managing oxidative stress in cells.
29
What happens to hydrogen peroxide (HOOH) after it is produced?
It is reduced to water by catalase, glutathione peroxidase, or peroxiredoxin ## Footnote These enzymes prevent the accumulation of harmful HOOH.
30
True or False: Hydroxyl radical (HO•) can be detoxified by enzymes.
False ## Footnote HO• is extremely reactive and has a very short half-life, making it challenging to manage.
31
What is one of the detoxification mechanisms for nucleophiles?
Conjugation at the nucleophilic functional group ## Footnote This prevents the conversion of nucleophiles to free radicals.
32
What are the two phases of metabolism involved in detoxification?
* Phase I: Oxidative reactions introduce functional groups * Phase II: Conjugation reactions ## Footnote These phases help in converting toxicants into inactive forms.
33
What is the function of thioredoxin in detoxification?
Reduces essential disulfide bonds in toxic polypeptides ## Footnote This inactivation is crucial for neutralizing certain venom toxins.
34
What can cause failure of detoxification mechanisms?
* Overwhelming exposure to toxicants * Saturation of detoxification enzymes * Depletion of antioxidants ## Footnote Failure in detoxification can lead to significant toxicity.
35
What happens to the glucuronide of 2-naphthylamine in the urinary bladder?
It is hydrolyzed, releasing a reactive electrophilic arylnitrenium ion ## Footnote This process can lead to bladder cancer due to local activation of a previously detoxified metabolite.
36
Fill in the blank: The detoxification of cyanide to thiocyanate is mediated by _______.
Either rhodanese or mercaptopyruvate sulfurtransferase ## Footnote This is a specific nucleophile detoxification mechanism.
37
What initiates toxicity?
A reaction between the ultimate toxicant and its target molecule ## Footnote This is step 2a in the process of toxicity.
38
What are the determinants of interaction between ultimate toxicants and target molecules?
* Attributes of target molecules * Types of reactions * Effects of toxicants on target molecules
39
What are the three attributes of a target molecule that determine its association with toxicity?
* Ability to react and adversely affect function * Ability to reach effective concentration at target site * Ability to alter the target related to toxicity
40
True or False: Not all targets for chemicals contribute to harmful effects.
True
41
What types of binding are major interactions between toxicants and target molecules?
* Noncovalent binding * Covalent binding * Hydrogen abstraction * Electron transfer * Enzymatic reactions
42
What characterizes noncovalent binding?
A reversible interaction due to low bonding energy ## Footnote Includes interactions like hydrogen bonds and ionic bonds.
43
What is the significance of covalent binding in toxicology?
It is essentially irreversible and alters endogenous molecules permanently.
44
What are soft electrophiles more likely to react with?
Soft nucleophiles
45
What is produced when HOOH reacts with protein thiol groups?
Protein sulfenic acid (Prot-S-OH)
46
What is the consequence of hydrogen abstraction by neutral free radicals?
It converts endogenous compounds into radicals.
47
What is metHb and how is it produced?
Methemoglobin; produced by oxidizing Fe2+ in hemoglobin to Fe3+.
48
Name two toxins that inhibit protein synthesis.
* Ricin * Abrin
49
What type of reactions do toxicants cause to alter the primary structure of molecules?
* Cross-linking * Fragmentation
50
What are haptens?
Small molecules that elicit an immune response only when attached to a larger carrier.
51
What is idiosyncratic toxicity characterized by?
Low incidence, poor predictability, and lack of typical dose-response relationships.
52
What are type B reactions in toxicology?
Idiosyncratic drug reactions
53
What factors contribute to susceptibility in idiosyncratic toxicity?
* Nongenetic factors (e.g., disease states) * Genetic factors (e.g., polymorphisms in enzymes)
54
What is QSP in the context of predicting toxicity?
Quantitative systems pharmacology; an in silico modeling technique.
55
Fill in the blank: Toxicity may also occur by _______ of a site or space.
occupying
56
What can initiate single-strand breaks in DNA?
Hydroxyl radicals causing H abstraction from deoxyribose.
57
What is the role of lipid peroxidation in toxicity?
It destroys lipids in cellular membranes and generates additional toxic free radicals.
58
What do enzymatic reactions by snake venoms typically cause?
Generalized proteolytic degradation of biomolecules.
59
What determines toxicity-induced cellular dysfunction?
The function of the target molecule ## Footnote If the target molecule is involved in cellular signaling and regulation, altered gene expression and/or cellular function occurs. If it is involved in essential processes, dysfunction may compromise cell survival.
60
What are the major effects of toxicity-induced cellular dysfunction?
Altered regulation of cell signaling or maintenance of cell function, including: * Altered gene expression * Impaired cell function * Impaired intracellular homeostasis * Impaired extracellular homeostasis ## Footnote Specific effects may vary depending on the toxicant involved.
61
What is altered gene expression?
The process by which information from a gene is used in the synthesis of a functional gene product ## Footnote This includes transcription from DNA to mRNA and translation into proteins.
62
What types of noncoding RNAs are involved in gene regulation?
Small interfering RNA (siRNA) and microRNA (miRNA) ## Footnote miRNAs typically are 20 to 25 base pairs long and derived from RNA transcripts that fold back on themselves.
63
How do miRNAs affect protein synthesis?
They interfere with complementary nucleotide sequences to repress protein synthesis ## Footnote miRNAs can decrease gene and/or protein expression.
64
What controls gene transcription?
Interplay between transcription factors (TFs) and the regulatory or promoter region of genes ## Footnote TFs bind to distinctive nucleotide sequences to facilitate or impede transcription.
65
What is the role of xenobiotics in transcriptional dysregulation?
They may interact with transcription factors or alter the promoter region of genes ## Footnote This can lead to increased or decreased transcription.
66
What is DNA methylation's role in gene regulation?
It silences genes through hypermethylation or activates them through hypomethylation ## Footnote Methylation patterns are copied during DNA replication, making changes heritable.
67
What are imprinted genes?
Genes that are epigenetically altered in either the male or female germ cells, leading to expression of only one allele in offspring ## Footnote An example is the insulin-like growth factor-2 gene.
68
How do toxicants influence miRNA activity?
Toxicants that increase miRNA activity will decrease gene expression ## Footnote Conversely, a decrease in miRNA increases gene expression.
69
What is signal transduction?
The process by which a chemical or physical signal is transmitted through a cell ## Footnote This often involves kinase or phosphatase activity to modify protein activity.
70
What initiates the MAPK pathway?
The binding of a signaling molecule to a cell surface receptor ## Footnote For example, epidermal growth factor (EGF) binding to epidermal growth factor receptor (EGFR).
71
What is the role of c-Fos and c-Jun in cell division?
They dimerize to form AP-1, which activates cyclin D to drive the G1/S-phase transition ## Footnote This is crucial for regulating cell proliferation.
72
What is the function of the TGF-β signaling pathway?
It influences cell growth, differentiation, and wound repair ## Footnote It involves two transmembrane receptors that function as serine/threonine kinases.
73
What is the effect of xenobiotics on signal transduction?
They can facilitate phosphorylation of signal transducers, promoting mitosis and tumor formation ## Footnote Examples include phorbol esters and fumonisin B.
74
What does hyperphosphorylation of proteins result from?
Increased phosphorylation by kinases or decreased dephosphorylation by phosphatases ## Footnote This can lead to various cellular effects including tumorigenesis.
75
What is an endogenous activator of PKC?
ol (DAG) ## Footnote DAG stands for diacylglycerol, a second messenger involved in signaling pathways.
76
What mimics the action of Ca2+ on PKC?
Pb2+ ## Footnote Lead ions (Pb2+) can increase PKC activity at low concentrations but inhibit it at high concentrations.
77
What can hyperphosphorylation of proteins result from?
Increased phosphorylation by kinases and decreased dephosphorylation by phosphatases ## Footnote Phosphatases like PTEN play a critical role in regulating phosphorylation states.
78
What is the role of Protein Phosphatase 2A (PP2A)?
Reverses growth factor-induced stimulation of MAPK ## Footnote MAPK stands for mitogen-activated protein kinase, involved in cell signaling.
79
Which natural toxicants are potent inhibitors of PP2A?
* Microcystin-LR * Okadaic acid ## Footnote Both compounds can promote tumor growth with chronic exposure.
80
What is IκB's function in relation to NF-κB?
Binds to NF-κB, preventing its transfer into the nucleus ## Footnote NF-κB is a critical regulator of inflammatory processes.
81
What happens when IκB is phosphorylated?
It is degraded by the proteasome, releasing NF-κB ## Footnote This process activates a pro-inflammatory program controlling various cytokines and proteins.
82
True or False: IKK can be phosphorylated by other kinases.
True ## Footnote Other protein kinases like Raf and Akt can activate IKK.
83
What aberrant signals may originate in the GTP/GDP-binding protein?
Ras ## Footnote Ras signaling is terminated by GTPase-activating proteins (GAP).
84
What effect do fatty acids have on Ras signaling?
Inhibit GAP and delay turning off Ras ## Footnote This can lead to increased cell proliferation.
85
What do chemically altered signaling pathways with antiproliferative effects lead to?
Apoptotic death of cells ## Footnote Inhibitors of signaling pathways can induce apoptosis.
86
What role do hormones of the anterior pituitary play?
Exert mitogenic effects on endocrine organs ## Footnote Their production is regulated by negative feedback from peripheral organs.
87
What can decreased secretion of pituitary hormones lead to?
Apoptosis and involution of the target organ ## Footnote An example is estrogens causing testicular atrophy in males.
88
What does ongoing cellular activity control?
Signaling molecules acting on membrane receptors ## Footnote This regulation affects Ca2+ entry and second messenger formation.
89
What types of cells are influenced by xenobiotics?
Excitable cells, such as neurons and muscle cells ## Footnote Chemicals can disrupt normal cellular functions and signaling.
90
What initiates fast signaling in neurons?
Opening of ligand-gated Na+/Ca2+ channels ## Footnote This leads to depolarization and subsequent activation of voltage-gated channels.
91
What is the effect of opening inhibitory receptors coupled to Gi proteins?
Inhibits adenylyl cyclase and opens K+ channels ## Footnote This results in hyperpolarization of the cell membrane.
92
Fill in the blank: Chemicals that block GABA receptors induce _______.
neuronal excitation and convulsions ## Footnote GABA is a major inhibitory neurotransmitter in the CNS.
93
What can alteration in neurotransmitter levels lead to?
Exaggeration or reduction of normal physiological activity ## Footnote This can result in various toxic effects.
94
What is the effect of inhibiting acetylcholinesterase?
Massive stimulation of cholinergic receptors ## Footnote This can lead to a cholinergic crisis.
95
What can the combined use of tricyclic antidepressants and monoamine oxidase inhibitors cause?
Hypertensive crisis ## Footnote This occurs due to different mechanisms blocking norepinephrine elimination.
96
What is the mechanism of action for drugs that alter regulation of neural and muscle activity?
Inhibition or modulation of neurotransmitter activity ## Footnote This can lead to toxicities from drug overdoses and other sources.
97
What contributes to life-threatening arrhythmias?
Overstimulation of β1-adrenergic receptors ## Footnote This overstimulation can lead to serious cardiac complications.
98
What effect does amphetamine have on norepinephrine?
Enhances release and inhibits reuptake ## Footnote This can lead to hypertensive crises when combined with certain antidepressants.
99
What is serotonin syndrome?
Cognitive changes, autonomic dysfunction, neuromuscular abnormalities ## Footnote Induced by drugs that increase serotonin concentration.
100
How do cytotoxic antineoplastic drugs cause nausea and emesis?
By inducing release of 5-HT from enterochromaffin cells ## Footnote This stimulates 5-HT3 receptors on vagal afferent neurons.
101
What does clonidine mimic when it induces β-endorphin release?
Symptoms of morphine poisoning ## Footnote Includes depressed respiration and pinpoint pupils.
102
What are the four types of chemical interactions with neurotransmitter receptors?
* Agonists * Antagonists * Activators * Inhibitors ## Footnote These chemicals can mimic or block physiological responses.
103
What is muscimol?
An agonist at the GABAA receptor ## Footnote It can inhibit CNS activity, leading to sedation and coma.
104
What do glutamate receptor agonists cause?
Neuronal hyperactivity and convulsions ## Footnote Similar effects are seen with GABAA receptor inhibitors.
105
What is the role of TRPV1 receptors?
Mediates the burning sensation from capsaicin ## Footnote Activated by capsaicin, it also stimulates reflex lacrimation.
106
What chemicals can block voltage-gated Na+ channels?
* Tetrodotoxin * Saxitoxin ## Footnote These chemicals can cause paralysis.
107
What is the consequence of Ba2+ inhibition of cation efflux?
Prolonged excitation and neuroexcitatory effects ## Footnote This can lead to lethal outcomes.
108
What role does ATP play in cellular functions?
* Supports intermediary metabolism * Activates endogenous compounds * Fuels cellular motility * Maintains cell morphology ## Footnote ATP is crucial for numerous biosynthetic reactions.
109
What is oxidative phosphorylation?
Synthesis of ATP coupled to hydrogen oxidation ## Footnote Involves electron transport chain and ATP synthase.
110
What are the five classes of chemicals that impede oxidative phosphorylation?
* Class A: Interfere with hydrogen delivery * Class B: Inhibit electron transfer * Class C: Interfere with oxygen delivery * Class D: Inhibit ATP synthase * Class E: Cause mitochondrial DNA injury ## Footnote Each class affects different steps in ATP synthesis.
111
What occurs during ATP depletion?
Loss of ionic and volume-regulatory controls ## Footnote This also leads to cellular acidosis and membrane damage.
112
What is a sustained rise in intracellular Ca2+ harmful?
* Depletes energy reserves * Alters microfilament structure * Activates hydrolytic enzymes * Generates ROS and RNS ## Footnote These changes can lead to cell injury.
113
What causes microfilamental dissociation in cells?
Increased cytoplasmic Ca2+ levels ## Footnote This disrupts cellular morphology and leads to bleb formation.
114
What role do ATPases play in cellular calcium regulation?
ATPases work to eliminate the excess Ca2+.
115
What is a consequence of increased cytoplasmic Ca2+ related to microfilaments?
Microfilamental dissociation, leading to bleb formation in plasma membranes.
116
What are the three main mechanisms by which high Ca2+ concentrations cause cell injury?
* Microfilamental dissociation * Activation of hydrolytic enzymes * Overproduction of ROS and RNS
117
What do calpains do in the context of high Ca2+ concentrations?
Calpains mediate hydrolysis of actin-binding proteins leading to membrane blebs.
118
What is the relationship between intracellular hypercalcemia and ROS/RNS production?
Intracellular hypercalcemia activates enzymes that generate ROS and/or RNS.
119
What is the effect of Ca2+ on mitochondrial function?
Ca2+ influx into mitochondria declines ΔΨm, hindering ATP synthase.
120
What is the result of mitochondrial permeability transition (MPT)?
Formation of a nonspecific pore in mitochondrial membranes leading to biochemical dysfunction.
121
What are the nuclear changes associated with necrotic cell death?
* Pyknosis * Karyolysis * Karyorrhexis
122
What distinguishes necroptosis from necrosis?
Necroptosis is a programmed form of necrosis, tightly regulated and initiated by death receptors.
123
Which proteins are involved in the necroptosis signaling pathway?
* RIPK1 * RIPK3 * MLKL
124
What initiates the intrinsic pathway of apoptosis?
Release of mitochondrial cytochrome c into the cytoplasm.
125
What is the role of cytochrome c in apoptosis?
Forms the apoptosome with Apaf-1 and procaspase-9, initiating the apoptotic cascade.
126
What triggers the extrinsic pathway of apoptosis?
Activation of death receptors such as TNF receptor 1.
127
What is the function of caspases in apoptosis?
Caspases cleave specific cellular proteins leading to morphological and biochemical changes.
128
What is the role of p53 in apoptosis related to DNA damage?
p53 increases expression of proapoptotic proteins and abrogates antiapoptotic proteins.
129
Fill in the blank: Caspases are __________-aspartic proteases that cleave target proteins after aspartate residues.
cysteine
130
What are inhibitors of apoptosis proteins (IAPs)?
Proteins that control caspase activity, with XIAP being the best characterized.
131
What is the major caspase involved in the extrinsic apoptotic pathway?
Caspase-8
132
What occurs in apoptotic cells compared to necrotic cells?
Apoptotic cells shrink and condense, forming membrane-bound apoptotic bodies.
133
What happens to ATP synthesis during mitochondrial permeability transition?
ATP synthesis ceases due to dissipation of ΔΨm.
134
What occurs when MLKL is activated in necroptosis?
MLKL induces cell death by permeabilizing and rupturing the plasma membrane.
135
What is the significance of the death-inducing signaling complex (DISC) in apoptosis?
It contains proteins that activate caspases in the extrinsic pathway.
136
What initiates TNF-α-mediated necroptosis?
Binding of TNF-α to TNFR1 ## Footnote TNFR1 stands for Tumor Necrosis Factor Receptor 1
137
What role does RIPK1 play in necroptosis?
RIPK1 phosphorylates and recruits RIPK3 ## Footnote RIPK1 stands for receptor-interacting protein kinase 1
138
What is the necrosome?
An active complex formed by RIPK3 and MLKL ## Footnote MLKL stands for mixed lineage kinase domain-like protein
139
What distinguishes necroptosis from apoptosis?
Necroptosis is caspase-independent ## Footnote Apoptosis typically requires caspase activation
140
What is necrostatin?
An inhibitor of necroptosis
141
Which stimuli can induce necroptosis?
* Fas ligand * Lipopolysaccharide (LPS) * Toll-like receptors (TLRs) * Genotoxic stress
142
What characterizes ferroptosis?
Accumulation of lipid peroxidation products and ROS from iron metabolism
143
What is the Fenton reaction associated with in ferroptosis?
Generation of ROS from excessive iron
144
How does ferroptosis differ from necrosis, apoptosis, and necroptosis?
No change in nuclear size or chromatin condensation
145
What are the mitochondrial characteristics in ferroptosis?
* Small mitochondria * Reduction or complete loss of mitochondrial cristae * Rupture of the outer mitochondrial membrane
146
What factors increase sensitivity to ferroptosis?
* Activation of VDAC * Increased NADPH oxidase activity * Inhibition of SLC7A11
147
What is the protective role of GPX4 in ferroptosis?
GPX4 activity protects against ferroptosis
148
What determines the mode of cell death?
The severity of the insult
149
What effect does a severe toxic insult have on cell death?
Causes necrotic cell death rather than apoptosis
150
How does lack of ATP affect apoptosis?
Prevents execution of the apoptotic program
151
What is the composition of the active site of caspases?
A pentapeptide with a reactive cysteine (QACXG)
152
What can inactivate caspases?
Soft electrophiles, disulfides, and oxidants
153
What happens when proapoptotic factors are released?
Initiates caspase activation
154
What is mitophagy?
Selective autophagy that removes damaged mitochondria
155
What can cause cell death by mechanisms other than necrosis or programmed cell death?
Toxicants that directly damage the plasma membrane
156
What is a consequence of lysosomal membrane damage?
Tissue degradation by release of lysosomal hydrolases
157
How can toxicants impair external cellular maintenance?
By interfering with specialized support cells
158
What are the final steps in the development of toxicity?
Inappropriate repair and adaptation ## Footnote These processes can intercept the progression of toxic lesions.
159
What are the mechanisms of repair at the molecular level?
Molecular repair includes: * Reversal of chemical alterations * Hydrolytic removal of damaged units * Complete degradation and resynthesis of damaged molecules
160
What role do thiol groups play in protein repair?
Thiol groups are essential for the function of many proteins and can be reversed by reduction ## Footnote Thioredoxins and glutaredoxins are key protein-reducing enzymes.
161
How do heat shock chaperones assist in protein repair?
They prevent protein unfolding by clamping onto exposed hydrophobic regions and using ATP hydrolysis for conformational changes.
162
What are the contrasting effects of Hsp90 and Hsp70 on proteins?
Hsp90 stabilizes proteins and prevents ubiquitination; Hsp70 promotes ubiquitination and proteosomal degradation.
163
What is the function of ubiquitin (Ub) in protein degradation?
Ubiquitin directs target proteins to proteosomal degradation when covalently linked. ## Footnote Mono-ubiquitination triggers endocytosis or autophagy; Lys48-linked Ub chains signal for degradation.
164
What is the primary method for repairing peroxidized lipids?
Phospholipids containing fatty acid hydroperoxides are hydrolyzed by phospholipase A2, replacing peroxidized fatty acids with normal ones.
165
What is the stability of nuclear DNA attributed to?
Nuclear DNA is stable due to being tightly packaged in chromatin and having complex repair mechanisms.
166
What is direct repair in the context of DNA repair?
Direct repair involves enzymes like DNA photolyase that reverse certain covalent modifications to DNA.
167
What is the role of O6-methylguanine-DNA-methyltransferase (MGMT) in DNA repair?
MGMT cleaves minor DNA adducts and inactivates itself in the process.
168
What are the two major mechanisms for excision repair?
Base excision and nucleotide excision.
169
What is the error rate of excision repair?
Less than one mistake in 10^9 bases repaired.
170
What is the role of PARP in DNA repair?
PARP binds to damaged DNA and activates to cleave NAD+ for poly(ADP-ribosyl)ation of nuclear proteins, facilitating DNA repair.
171
What is the function of nonhomologous end joining?
It repairs double-strand breaks (DSBs) by directly ligating broken ends without a homologous template.
172
What proteins are involved in recognizing double-strand breaks in DNA?
Ku protein (Ku70 and Ku80 heterodimer) and DNA-dependent protein kinase (DNA-PKcs).
173
What is the role of proliferating cell nuclear antigen (PCNA) in postreplication repair?
PCNA binds to chromatin and helps tether polymerase to the DNA template.
174
What is autophagy?
A lysosomal process for degrading intracellular substrates and a mechanism for cellular repair.
175
What is the main role of macrophages in axonal regeneration?
Macrophages remove debris and produce cytokines and growth factors to activate Schwann cells.
176
What is the significance of apoptosis in tissue repair?
Apoptosis helps remove damaged cells, aiding in tissue restoration, especially in tissues with renewing cells.
177
What initiates the regenerative process after tissue injury?
Release of chemical mediators from damaged cells, including cytokines and growth factors.
178
What factors promote the transition of quiescent liver cells into the cell cycle?
TNF-α and IL-6.
179
What is the extracellular matrix (ECM) composed of?
A variety of proteins (collagen, elastin), proteoglycans (chondroitin sulfate), and glycosaminoglycans.
180
What does HGF stand for?
Hepatocyte Growth Factor ## Footnote HGF is produced by macrophages and endothelial cells in various organs.
181
What is the role of matrix metalloproteinases (MMPs) in tissue regeneration?
MMPs hydrolyze specific components of the extracellular matrix (ECM) ## Footnote MMPs facilitate remodeling of the ECM during tissue repair.
182
What is TGF-β's role in cell proliferation?
TGF-β is a potent anti-mitogen that contributes to the termination of cell proliferation ## Footnote Its gradual dominance is a factor in ending tissue repair processes.
183
What initiates the alteration of microcirculation and accumulation of inflammatory cells?
Resident macrophages secreting cytokines like TNF-α and IL-1 ## Footnote These cytokines increase capillary permeability.
184
What is the role of ICAM-1 in inflammation?
ICAM-1 promotes leukocyte invasion by facilitating their egress into injured tissue ## Footnote It interacts with integrins on leukocyte membranes.
185
What does ROS stand for in the context of inflammation?
Reactive Oxygen Species ## Footnote ROS are produced during the respiratory burst by macrophages and leukocytes.
186
What are acute-phase proteins?
Proteins whose levels change in response to inflammation, including positive and negative acute-phase proteins ## Footnote Examples include C-reactive protein (positive) and albumin (negative).
187
What is the function of ferritin in the context of adaptation?
Ferritin binds and removes excess iron from the system ## Footnote It is protective against iron overload.
188
What is metallothionein (MT) induced by?
Cadmium ## Footnote Elevated MT levels protect the liver from cadmium toxicity.
189
What is the Keap1-Nrf2 pathway's role in detoxification?
It senses thiol reactivity and activates genes with an electrophile response element (EpRE) ## Footnote This pathway enhances detoxification and cellular export mechanisms.
190
What happens to Nrf2 when it is released from Keap1?
Nrf2 translocates into the nucleus to activate detoxification genes ## Footnote This process is triggered by binding of thiol-sensitive compounds to Keap1.
191
What is the primary receptor for opioids like morphine?
µ-opioid receptor ## Footnote It is a Gi protein-coupled receptor that inhibits adenyl cyclase.
192
What role do heat-shock proteins (Hsp) play in the heat-shock response?
Hsp assist in maintaining protein integrity and support adaptive responses ## Footnote They are regulated by heat-shock transcription factors (HSF).
193
What does UPR stand for in the context of endoplasmic reticulum stress?
Unfolded Protein Response ## Footnote UPR helps restore homeostasis in the endoplasmic reticulum.
194
What is the role of p53 in DNA repair?
p53 is critical for initiating DNA repair pathways ## Footnote It is known as the ‘guardian of the genome’.
195
What is NF-κB's function in tissue repair?
NF-κB transactivates genes that promote cell cycle acceleration and inhibit apoptosis ## Footnote This includes genes like cyclin D1 and Bcl proteins.
196
Fill in the blank: The _______ pathway is a major regulator of general metabolic activity.
mTOR ## Footnote mTOR is activated by the MAPK pathway.
197
What are the mechanisms of adaptation to toxicity?
Adaptation mechanisms include: * Diminished delivery of toxicants * Decreased target susceptibility * Increased repair capacity * Compensation for dysfunction ## Footnote These mechanisms help maintain biological homeostasis.
198
What are inhibitors of apoptosis?
Antiapoptotic Bcl proteins and caspase IAPs ## Footnote These proteins prevent programmed cell death, allowing cells to survive in adverse conditions.
199
What is the role of NF-κB in cellular processes?
Transactivates ferritin, GST, SOD1, HO-1, a proteasome subunit, and gadd45 ## Footnote NF-κB is involved in detoxification and molecular repair.
200
How is the protein synthesis process regulated in proliferating cells?
By the protein kinase mTOR ## Footnote mTOR is a major regulator of metabolic activity.
201
What activates mTOR?
MAPK pathway and PI3K pathway ## Footnote Activation occurs through phosphorylation of Erk and Akt.
202
What happens to mTOR activity under hypoxic conditions?
It is shut down to reduce ATP synthesis ## Footnote This adaptation helps cells cope with low oxygen availability.
203
What is HIF-1α and its role in hypoxia?
A transcription factor that increases under hypoxic conditions ## Footnote It regulates genes involved in erythropoiesis, iron homeostasis, and angiogenesis.
204
What are some genes transactivated by the HIF complex?
* Erythropoietin (EPO) * Vascular endothelial growth factor (VEGF) * Glucose transporter GLUT1 * Proteins correcting acidosis * REDD1 * Matrix metalloproteinase-2 ## Footnote These genes are crucial for adaptation to low oxygen levels.
205
What does AMPK do in response to increased AMP levels?
Boosts ATP production and limits ATP consumption ## Footnote AMPK plays a key role in energy homeostasis.
206
How does AMPK increase ATP levels?
* Increases glucose uptake * Enhances glycolysis * Promotes fatty acid oxidation ## Footnote These actions all contribute to higher ATP production.
207
What processes does AMPK inhibit to reduce ATP consumption?
* Glycogen synthesis * Lipid synthesis * Cholesterol synthesis * Glucose synthesis * Protein synthesis ## Footnote This helps conserve energy when ATP levels are low.
208
What is the role of mTOR in autophagy?
Regulates the initiation of autophagy ## Footnote mTOR inhibits autophagy under nutrient-rich conditions and promotes it under nutrient scarcity.
209
What are the consequences of inappropriate repair mechanisms?
Irreversible organ failure, necrosis, fibrosis, or carcinogenesis ## Footnote Repair mechanisms can become overwhelmed or impaired.
210
What is fibrosis?
Excessive formation and deposition of connective tissue ## Footnote It disrupts normal organ architecture and function.
211
What central mediator is involved in fibrotic disease?
TGF-β ## Footnote It increases ECM production and decreases its degradation.
212
What are proto-oncogenes?
Genes that encode proteins stimulating cell cycle progression or opposing apoptosis ## Footnote Mutations can convert them into oncogenes.
213
What happens when tumor suppressor genes mutate?
Uncontrolled proliferation occurs ## Footnote These genes normally inhibit cell division or promote DNA repair.
214
What are genotoxic mechanisms of carcinogenesis?
Chemical reactions with DNA causing damage ## Footnote This can lead to mutations and uncontrolled cell proliferation.
215
What is an example of a non-genotoxic carcinogen?
Substances that stimulate sustained cell proliferation ## Footnote They may not directly damage DNA but can lead to cancer.
216
What is the role of BRCA1 and BRCA2 in cellular processes?
They contribute to recombinational DNA repair ## Footnote BRCA1 and BRCA2 are crucial for maintaining genomic stability.
217
What does PTEN phosphatase do?
Turns off the PI3K–Akt pathway-mediated proliferative signaling ## Footnote PTEN is a tumor suppressor gene that regulates cell growth.
218
What is the function of TSC2 in cellular mechanisms?
Prevents activation of mTOR ## Footnote TSC2 is part of the tuberous sclerosis complex, involved in growth regulation.
219
What occurs when a mutant tumor suppressor gene is present?
Uncontrolled proliferation occurs ## Footnote This happens because the gene can no longer suppress cell division.
220
How do non-genotoxic carcinogens affect cell proliferation?
They often stimulate sustained cell proliferation ## Footnote This can happen through direct activity on proliferative signaling.
221
What is a consequence of continuous presence of mitogenic growth factors after cell injury?
They may ultimately transform affected cells into neoplastic cells ## Footnote Examples include HGF and TGF-α released from macrophages.
222
What is the impact of DNA methylation on gene expression?
Promoter methylation silences genes ## Footnote This weakens transcription factor binding and triggers histone modifications.
223
What happens to DNA methylation patterns in cancer cells?
They are disrupted, showing global hypomethylation and hypermethylation of tumor suppressor genes ## Footnote This intensifies with increased malignancy of the tumor.
224
What is the role of miRNAs in carcinogenesis?
They can affect carcinogenic mechanisms through effects on DNA repair and non-genotoxic pathways ## Footnote The miR-17-92 cluster promotes mitosis by repressing PTEN and p21.
225
True or False: Genotoxic and non-genotoxic mechanisms of carcinogenesis are mutually exclusive.
False ## Footnote They can complement or amplify each other.
226
What increases the likelihood of carcinogenicity?
Increased mitotic activity ## Footnote It raises the probability of mutations occurring.
227
What effect does failure to execute apoptosis have on preneoplastic cells?
It promotes mutation and clonal growth ## Footnote Inhibition of apoptosis facilitates the fixing of mutations.
228
What is an adverse outcome pathway (AOP)?
A systematic approach that organizes biological events leading to an adverse outcome ## Footnote AOPs emphasize molecular initiating events and key events in toxicity.
229
What are the proposed applications of AOPs?
To advance in vitro methods, extrapolate across species, and identify mechanism-based biomarkers ## Footnote AOPs aim to improve safety evaluation and human safety confidence.
230
What does understanding mechanisms of toxicity help identify?
Key events associated with toxic outcomes and biomarkers of toxicity ## Footnote This knowledge informs predictions of toxicity and mitigation strategies.
231
Fill in the blank: A useful tool for assessing toxicity must encompass the broad aspects of _______.
[chemical disposition and biotransformation] ## Footnote This includes understanding when protective mechanisms are overwhelmed.

Medical Toxicology (13 decks)

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