Midterm 2 Flashcards
1
Q
What are local effects of xenobiotics?
A
Corrosive chemicals on the skin (e.g., strong acids and bases), irritating gases and vapours in the respiratory tract (e.g., ammonia and chlorine gas).
2
Q
What defines systemic effects of xenobiotics?
A
Xenobiotics must be absorbed into the systemic circulation and distributed to the organs/tissues. Many xenobiotics preferentially cause toxic effects in one or a few specific organs (target organs). The target organ may not always have the highest xenobiotic concentration.
3
Q
What is the difference between reversible and irreversible effects?
A
Reversible Effects: Disappear after exposure ends, usually short-term and/or low dose exposures.
Irreversible Effects: Persist or even worsen after exposure ends, e.g., carcinomas, teratogenic effects, neuronal damage, liver cirrhosis, usually long-term and/or high dose exposures.
4
Q
What are examples of immediate (acute) effects of xenobiotic exposure?
A
Cyanide, carbon monoxide poisoning; timeframe: minutes to days.
5
Q
What are examples of delayed (chronic) effects of xenobiotic exposure?
A
Cancer develops 10-20 years after exposure, both in individuals and potentially their offspring – recall diethylstilbestrol. Illustrates the need to conduct long-term and transgenerational toxicological studies.
6
Q
What are morphological effects of toxic substances?
A
Gross or microscopic effects on tissues, commonly irreversible (e.g., thalidomide teratogenicity, histopathological effects on liver cells).
7
Q
How are functional effects of toxic substances generally characterized?
A
Effects on liver or kidney function, reproduction; generally reversible.
8
Q
What initiates virtually all toxic effects at the biochemical level?
A
Alteration in biochemical processes (e.g., receptor binding, enzyme inhibition).
9
Q
What are biochemical markers (biomarkers) and their significance?
A
Biochemical effects often used as early indications or “markers” of toxic effects. These effects are reversible and do not necessarily indicate an adverse morphological or functional effect.
10
Q
What defines allergic effects of xenobiotics?
A
Hypersensitivity reactions requiring prior exposure; xenobiotic reacts with protein to produce an antigen, antibodies are produced and illicit an immune response (e.g., bee venoms and nuts causing severe allergic reactions, perfumes, multiple chemical allergy syndrome, “sick building syndrome”). Autoimmune reactions where xenobiotics can initiate autoimmune diseases such as systemic lupus erythematosus.
11
Q
What characterizes idiosyncratic effects of xenobiotics?
A
Genetically based abnormal reactivity to a xenobiotic with no known cause (e.g., certain drugs producing rare, idiosyncratic reactions).
12
Q
Differentiate between graded and quantal effects of toxic substances.
A
Graded Effects: Continuous response (e.g., effects on body weight, food consumption, enzyme activity).
Quantal Effects: “All-or-none” responses (e.g., mortality, cancer).
13
Q
Why are certain organs targets of xenobiotics?
A
Due to greater susceptibility or higher xenobiotic concentrations, although the explanation is not always clear.
14
Q
Give examples of increased susceptibility of organs to toxic effects.
A
Carbon monoxide (CO) poisoning in highly aerobic tissues (heart and brain) with little anaerobic capacity.
15
Q
What is preferential distribution of xenobiotics and provide examples?
A
Higher blood flow to certain organs (e.g., liver and kidney), MeHg able to cross the blood-brain barrier (BBB).
16
Q
Explain selective uptake with an example.
A
Cadmium (Cd) is preferentially accumulated in kidney tubule cells due to high expression of Cd-binding protein (metallothionein; MT).
17
Q
Why might some organs have insufficient repair mechanisms?
A
Neuron damage in the central and peripheral nervous systems due to insufficient repair capacity.
18
Q
How do dose, duration, and frequency of exposure influence toxicity?
A
The amount (dose), the length of time (duration), and how often (frequency) a xenobiotic is encountered are critical factors that determine its toxic effects.
19
Q
What are intraspecific differences in response to xenobiotics, and what causes these differences among individuals?
A
Differences within a species due to genetics and environmental factors, as well as toxicokinetics (ADME - Absorption, Distribution, Metabolism, Excretion) and toxicodynamics.
20
Q
What are interspecific differences, and how do they impact toxicity assessments?
A
Differences among species are often due to variations in toxicokinetics and toxicodynamics, and these differences are usually greater than those within a species. For example, the acute toxicity (LD50) of dioxin (TCDD) varies significantly between guinea pigs and hamsters.
21
Q
Why are interspecific differences important for human health risk assessments?
A
Toxic responses in animals (e.g., rats and mice) are extrapolated to humans to assess toxicological risks, considering these differences are crucial for accurate assessments.
22
Q
How do differences in toxicity between females and males occur?
A
Usually related to differences in biotransformation enzyme activities and hormone levels, such as those involved in growth, stress response, energy homeostasis, and reproduction.
23
Q
How does age affect sensitivity to toxicants?
A
Young animals are generally 2-10 times more sensitive than adults, often due to toxicokinetic factors. Older animals may also be more sensitive due to diminished clearance or repair mechanisms.
24
Q
How can nutritional status influence toxicity?
A
Certain chemicals in the diet can induce or inhibit CYP enzyme activity (e.g., grapefruit juice inhibits CYP3A4), caloric restriction can reduce tumor growth, high-fat diets can increase exposure to lipophilic contaminants, and diets deficient in protein and fatty acids reduce biotransformation enzyme activity.
25
What role do dietary antioxidants play in toxicity?
They protect against reactive oxygen species and oxidative stress.
26
How can underlying pathology affect xenobiotic toxicity?
Impaired liver or kidney function due to disease can greatly influence the rate of xenobiotic clearance, and interactions between certain diseases and cancer (e.g., hepatitis exacerbating liver cancer) can increase sensitivity to toxicants.
27
How does impaired lung function affect sensitivity to air pollutants?
Conditions like asthma cause greater sensitivity to air pollutants.
28
What environmental factors can influence toxic responses?
Temperature, barometric pressure, photoperiod, electromagnetic radiation, and possibly cell phone exposure.
29
How can social factors like stress and crowded conditions affect toxic responses?
Crowded conditions generally exacerbate toxic responses, as can isolation.
30
Why is understanding the mechanisms of toxicity important for risk assessment?
Elucidation of mechanisms of toxicity bridges hazard detection with risk assessment for human health, ultimately leading to toxicity prediction and prevention.
31
What is one of the most important bridges connecting hazard detection with risk assessment for human health?
Understanding the mechanisms of toxicity.
32
What are the four general mechanisms of toxic action?
Specific localization of xenobiotic
Interference with critical metabolic processes
Bioactivation to electrophiles and increased reactive oxygen species leading to oxidative stress.
Binding to receptors (“mimicry”).
33
What is an example of toxicokinetic mechanisms related to specific localization of xenobiotics?
Tissue binding or active transport.
34
How can xenobiotics interfere with critical metabolic processes?
By disrupting neurotransmission or ATP production.
35
What does bioactivation to electrophiles lead to?
Increased reactive oxygen species and oxidative stress.
36
How do xenobiotics mimic biological processes?
By binding to receptors.
37
What is Step 1 of the Mechanisms of Toxicity?
Delivery
38
What is Step 2a of the Mechanisms of Toxicity?
Interaction with a target molecule
39
What are the attributes of target molecules in toxicology?
Proteins (enzymes, receptors, structural proteins, carriers, cofactors), nucleic acids (DNA, RNA), lipids (cell membranes), carbohydrates.
40
What are the major reaction types involved in interactions with target molecules?
Noncovalent binding and covalent binding.
41
Describe noncovalent binding and its relevance.
Noncovalent binding involves hydrogen and ionic binding, Van der Waals forces, hydrophobic interactions. It is the most common reaction and is reversible. Examples include receptor binding and plasma protein binding.
42
Why is covalent binding significant in toxicology?
Covalent binding causes irreversible damage to molecules unless repaired, involving electrophiles like free radicals and epoxides.
43
What are the minor reaction types in interactions with target molecules?
Hydrogen abstraction, electron transfer (redox reactions), and enzymatic reactions.
44
Provide an example of hydrogen abstraction.
Free radicals can abstract H atoms, e.g., X* + H-Y -> XH + Y*.
45
What is an example of electron transfer in toxicology?
Nitrites can oxidize Fe2+ to Fe3+ in hemoglobin, producing methemoglobinemia.
46
Give an example of enzymatic reactions in toxicology.
Proteolytic snake and spider venom.
47
What are the effects on target molecules due to interaction with xenobiotics?
Dysfunction, destruction, and neoantigen formation.
48
What is the most common effect on target molecules?
Dysfunction, which usually inactivates or inhibits the target molecule (e.g., receptors, enzymes, electron transfer chain, hemoglobin).
49
Provide an example of destruction as an effect on target molecules.
Damage to membrane lipids (lipid peroxidation).
50
What is neoantigen formation and give an example?
Rare, idiosyncratic effect, e.g., toxicant-induced autoimmune diseases such as lupus.
51
What is Step 2b in the Mechanisms of Toxicity?
Alteration of biological movement
52
How can xenobiotics affect biological movement without interacting with target molecules?
By processes like precipitation (e.g., ethylene glycol in kidney tubules forming oxalic acid crystals) or altering membrane lipid fluidity and disrupting ion gradients (e.g., non-polar solvents and detergents).
53
What is Step 3 in the Mechanisms of Toxicity?
Cellular dysfunction and injury
54
What are receptors and their function in cellular processes?
Cellular proteins that serve as receptors for endogenous ligands (e.g., hormones, neurotransmitters, cytokines).
55
What are some examples of xenobiotic targets in cells?
Enzymes, transport proteins, nucleic acids, structural proteins, membrane lipids.
56
How can the targets of xenobiotics extend beyond individual molecules?
They can even be broadened to whole organisms depending on the circumstances.
57
What determines the affinity of a xenobiotic for a receptor?
Its chemical structure (stereochemistry).
58
Provide an example of SAR using polychlorinated biphenyls (PCBs).
PCBs are ubiquitous “legacy contaminants,” highly lipophilic with high log Kow values (5-8), and their toxicity is determined by the affinity for the aryl hydrocarbon receptor (AhR).
59
Why does the position of chlorine atoms in PCB congeners matter?
The further the chlorines get on the same phenyl, the less toxic it becomes.
60
What are stereoisomers and how can they differ in effect?
Stereoisomers (R,S or D,L) have the same molecular formula but different spatial arrangements, leading to different effects. Example: Dextromethorphan (cough suppressant) vs. levorphanol (opioid analgesic).
61
Why is thalidomide teratogenicity an important example in toxicology?
It demonstrates the importance of exposure timing and serves as an example of an adverse outcome pathway and stereoselectivity.
62
What are the normal functions of receptor-mediated cellular signal transduction pathways?
To bind appropriate ligands (e.g., hormone, neurotransmitter) and propagate signals into the cell.
63
What is an agonist in the context of receptor interaction?
A xenobiotic that binds to a receptor and mimics the effect of the endogenous ligand.
64
What is an antagonist in the context of receptor interaction?
A xenobiotic that binds to the receptor and produces no effect, thereby inhibiting or blocking the effect of the endogenous ligand.
65
What is a partial agonist?
A xenobiotic that binds to the receptor and produces a lesser effect than the endogenous ligand.
66
What are the four main types of receptor-mediated cellular signal transduction pathways?
G protein-coupled receptors, nuclear receptors, tyrosine kinase-coupled receptors, ion channel receptors.
67
What does receptor theory state about the interaction between xenobiotics and receptors?
The reversible interaction between xenobiotic (X) and receptor (R) follows the law of mass action and is represented by: [X]+[R]↔[XR]→Effect.
68
How can receptors become desensitized, and what is this a major mechanism for?
Receptors can become desensitized upon continuous exposure to xenobiotics, often due to downregulation (decreased receptor concentration). This is a major mechanism of drug tolerance.
69
What is upregulation of receptors, and how common is it?
Upregulation or sensitization occurs due to increased receptor concentration, but it is rare
70
How have modern molecular biological techniques impacted our understanding of receptors?
They have led to the discovery of many receptor subtypes where only a single type was previously thought to exist.
71
Give an example of receptor subtypes and their endogenous ligand.
α-adrenergic and β-adrenergic receptors that bind norepinephrine (NE).
72
What are the subtypes of α and β adrenoceptors?
α1, α2, β1, β2, β3 (and further subdivisions).
73
Why is the discovery of receptor subtypes significant?
It provides tissue specificity and selectivity, which are crucial for understanding tissue responses to xenobiotics.
74
What effect does norepinephrine (NE) binding to α1 adrenoceptors have?
Causes vasoconstriction in arteriolar smooth muscle, a major control of blood pressure.
75
What effect does norepinephrine (NE) binding to β2 adrenoceptors have?
Causes vasodilation in bronchiolar smooth muscle, used in patients with asthma.
76
What are orphan receptors?
Receptors with no known endogenous ligand.
77
What is a classic example of an orphan receptor and its characterization?
Morphine (a xenobiotic) was used to characterize opioid receptors before discovering endogenous ligands like endorphin, enkephalin, and dynorphin.
78
What are examples of endogenous cannabinoids similar to active ingredients in cannabis?
THC (tetrahydrocannabinol) and CBD (cannabidiol).
79
What is Step 3a in the Mechanisms of Toxicity?
Altered Cellular Regulation
80
What is altered transcription in the context of altered gene expression?
Transcription factors activated in the cell bind to response elements on promoter regions of genes, which increases or decreases mRNA expression.
81
What are ligand-activated transcription factors?
Transcription factors that are activated by binding to a specific ligand, often part of the nuclear receptor family.
82
What can altered transcription result in?
Inappropriate cell division (cancer), apoptosis (cell death), or protein synthesis.
83
Give an example of endocrine disruption chemicals (EDCs) that mimic steroid hormones.
Environmental hormone mimics like xenoestrogens.
84
How do growth factors and cytokines affect transcription factors?
They activate (phosphorylate) or inactivate (dephosphorylate) transcription factors via complex cellular signal transduction pathways.
85
Why is the regulation of mitosis and apoptosis important in toxicology?
It is crucial for maintaining cellular balance and preventing carcinogenesis.
86
What is an example of xenobiotics altering homeostasis?
The "apoptosis-mitosis balance" being disrupted by xenobiotics.
87
How can xenobiotics alter signal production?
By increasing or decreasing the release of hormones from endocrine glands.
88
What complicates the feedback loops involved in hormone synthesis and release?
The intricate balance and regulation of endocrine disrupting chemicals (EDCs).
89
Which cells are affected by xenobiotics that impair ongoing cellular activity?
Electrically excitable cells such as neurons, skeletal, cardiac, and smooth muscle cells.
90
What neurotransmitters are involved in the autonomic and somatic nervous systems?
Acetylcholine (Ach) and norepinephrine (NE).
91
To which receptors does Ach bind?
Nicotinic (N) and muscarinic (M) receptors.
92
To which receptors does NE bind?
Adrenergic receptors.
93
Name other neurotransmitters involved in these systems.
Serotonin and dopamine.
94
What are the four steps at chemical synapses?
Synthesis and storage of neurotransmitter (NT) in vesicles, release of NT into synapse, activation of receptor by NT, inactivation of NT.
95
How do organophosphorus chemicals (Ops) affect neurotransmitter concentration in the synapse?
They inhibit acetylcholinesterase (AChE), causing massive overstimulation of nicotinic and muscarinic receptors.
96
What are clinical symptoms of acute OP poisoning?
SLUDS: salivation, lacrimation, urination, defecation, sweating.
97
How is OP poisoning treated?
Atropine (muscarinic receptor antagonist), Pralidoxime (2-PAM) to reactivate AChE, Benzodiazepine to relieve CNS anxiety and seizures.
98
What is the effect of botulinum toxin on neurotransmission?
Binds presynaptic membrane, blocks the release of Ach, causing paralysis and death.
99
How does black widow spider venom affect neurotransmission?
Causes massive, explosive release of Ach and other NTs, leading to initial overstimulation followed by no neurotransmission due to lack of Ach.
100
What effect does cocaine have on neurotransmitter function?
Blocks reuptake of NE, causing overstimulation of adrenergic receptors, leading to heart attacks and arrhythmias.
101
How do selective serotonin reuptake inhibitors (SSRIs) work? And what’s an example?
Inhibit the reuptake of serotonin, increasing its concentration in the synapse. Example: fluoxetine (Prozac).
102
What is the effect of α-Bungarotoxin on receptors?
Binds irreversibly to nicotinic cholinergic receptors, preventing Ach access and blocking neurotransmission.
103
How do benzodiazepines, barbiturates, GHB, and alcohol affect GABA receptors?
Activate GABA receptors, causing depressed CNS function (sedation).
104
How does tetrodotoxin (puffer fish toxin) affect neurotransmission?
Blocks Na+ channels on the axonal membrane, preventing repolarization and blocking neurotransmission.
105
What is Step 3b in the Mechanisms of Toxicity?
Impaired cellular maintenance
106
What is the primary mechanism of toxic cell death due to impaired ATP synthesis?
Impaired ATP synthesis occurs through oxidative phosphorylation and the targeting of xenobiotics that affect this process.
107
How do xenobiotics affect ATP synthesis? (4)
Delivery of hydrogen to the electron transport chain (ETC) in the form of NADH
Impaired function of the ETC
Delivery of O2 as the terminal electron acceptor
Inhibition of ADP phosphorylation
108
What are the targets of xenobiotics that impact the delivery of hydrogen to the ETC?
Example: Arsenite inhibits the PDH complex.
109
How does fluoroacetate affect the citric acid cycle?
It inhibits the enzyme aconitase.
110
Which xenobiotic inhibits NADH-coenzyme Q reductase?
Rotenone (pesticide).
111
What is the effect of cyanide on the electron transport chain (ETC)?
It inhibits cytochrome c oxidase (Complex IV).
112
How does carbon monoxide affect oxygen delivery?
It displaces O2 on hemoglobin.
113
What is the action of chlordecone on ATP synthesis?
It inhibits ATP synthase.
114
What are the effects of xenobiotics like pentachlorophenol on the electrochemical gradient?
They disrupt the proton gradient, causing leakage back into the inner mitochondrial matrix.
115
Why is the maintenance of calcium ion (Ca2+) concentration crucial for cellular health?
Disruption in Ca2+ homeostasis is a major mechanism of toxic cell death, maintained by active transport and sequestration into mitochondria and ER.
116
What happens if ATP synthase function is reduced?
If ATP synthase is reduced, there will eventually be a tipping point that will cause the cell to die.
117
What role does calcium ion (Ca2+) play in toxic cell death?
Ca2+ is maintained at a much higher concentration extracellularly. Disruption of Ca2+ homeostasis is a major mechanism of toxic cell death, maintained by active transport from the cytoplasm to extracellular space and sequestration into mitochondria and ER.
118
How do xenobiotics affect Ca2+ homeostasis?
Promote influx or inhibit efflux from the cytoplasm.
Cause leakage from mitochondria and ER into the cytoplasm.
119
What are some other mechanisms of cell death caused by xenobiotics? (3)
Disruption of protein synthesis
Destruction of the cytoskeleton, specifically microtubules involved in mitosis and other cellular functions
Direct damage to the plasma membrane
120
What are the implications of impaired external cellular maintenance?
Impaired function of integrated systems, like the inhibition of hepatic synthesis of coagulation factors.
Example: Warfarin inhibits activation of vitamin K needed for clotting factor production.
121
What happens when xenobiotics “uncouple” the electrochemical (proton) gradient across the inner mitochondrial membrane?
This disrupts the "driving force" for ATP synthase. For example, pentachlorophenol causes protons to "leak" back into the inner mitochondrial matrix.
122
What role do mitochondria play in toxic cell death?
Mitochondria act as sensors closely linked to cell death, affected by disruptions in Ca2+ homeostasis and ATP synthesis.
123
How does ethanol contribute to toxic cell death?
Ethanol disrupts protein synthesis.
124
What is the effect of colchicine on cellular functions?
Colchicine destroys the cytoskeleton, specifically microtubules involved in mitosis and other functions.
125
What are some examples of direct plasma membrane damage by xenobiotics?
Nonpolar solvents, detergents, and reactive oxygen species (ROS) can directly damage the plasma membrane.
126
What is the consequence of impaired hepatic synthesis of coagulation factors?
It leads to impaired function of integrated systems, such as blood clotting, as seen with warfarin's inhibition of vitamin K activation needed for clotting factor production.
127
What is Step 4a in the Mechanisms of Toxicity?
Impaired molecular repair
128
What is the most common effect of protein damage?
Oxidation of thiol (-SH) groups.
129
How are oxidized proteins repaired?
By thioredoxin and glutaredoxin, which donate electrons to reduce (repair) oxidized proteins. NADPH is a common electron receptor.
130
What is the significance of protein folding, and how is it impacted by damage?
Proper protein folding is key to its activity. Damage from chemical (ROS) or physical insults (UV radiation) can cause denaturation (misfolding), which disrupts protein function.
131
How is protein misfolding repaired?
Repair is facilitated by molecular chaperones such as Heat Shock Proteins (HSPs).
132
What is the effect of lipid oxidation on cellular membranes?
Lipid oxidation causes lipid peroxidation, damaging membranes and altering cellular homeostasis.
133
How are oxidized lipids repaired?
The complex repair process involves enzymes like glutathione peroxidase and glutathione reductase, along with vitamins E and C.
134
How do xenobiotics cause DNA damage?
Xenobiotics can be bioactivated to electrophiles (e.g., epoxides) that bind covalently to DNA, forming DNA adducts, leading to chemical carcinogenesis if not repaired.
135
What is the primary DNA repair process for damage caused by xenobiotics?
Nucleotide excision repair (NER).
136
What roles do the three key enzymes play in NER?
Endonuclease: snips out the damaged DNA sequence (including xenobiotic).
DNA polymerase: synthesizes the replacement DNA strand.
DNA ligase: glues the new strand into the DNA.
137
What is Step 4b in the Mechanisms of Toxicity?
Impaired cellular repaired
138
How does cellular repair usually occur in most tissues?
In most tissues, the damaged cell dies (via apoptosis or necrosis), and a neighboring cell divides to replace it.
139
What is the exception to cellular repair, and where does it occur?
The exception is in the peripheral neurons, where damaged axons can be repaired. This does not occur in the CNS.
140
What is a common effect of many different toxic metals on peripheral neurons?
Toxic neuropathy, where damaged axons in peripheral neurons can be repaired.
141
What is Step 4c in the Mechanisms of Toxicity?
Impaired tissue repair
142
What does apoptosis mean, and how does it differ from necrosis in terms of being physiological or pathological?
Apoptosis is physiological or programmed cell death, essential for growth and development.
Necrosis is pathological, resulting from acute cellular injury leading to premature cell death.
143
How is apoptosis similar to "suicide" and necrosis to "murder" in terms of cell death?
Apoptosis: Cells initiate and control their own death ("suicide").
Necrosis: External factors such as toxins, infections, or trauma cause cell death ("murder").
144
In what way is apoptosis an active process while necrosis is passive?
Apoptosis is an active process requiring energy and the involvement of specific signaling pathways.
Necrosis is a passive process, not requiring energy.
145
How do apoptosis and necrosis differ in affecting single cells versus clusters of cells?
Apoptosis usually affects individual cells.
Necrosis often affects clusters of cells within a tissue.
146
Compare the cellular changes during apoptosis (condensation) versus necrosis (swelling).
Apoptosis: Cells shrink and condense.
Necrosis: Cells swell and burst.
147
What is the time frame for apoptosis compared to necrosis?
Apoptosis generally occurs within hours.
Necrosis can take hours to days to fully develop.
148
How does protein synthesis differ between apoptosis and necrosis?
Apoptosis involves the synthesis of proteins, particularly those involved in the apoptotic process.
Necrosis involves no synthesis; the process is more destructive.
149
What are the differences in ATP levels between apoptosis and necrosis?
Apoptosis occurs under normal ATP conditions.
Necrosis is often associated with decreased ATP levels.
150
How does inflammation differ in apoptosis compared to necrosis?
Apoptosis does not cause inflammation.
Necrosis triggers an inflammatory response.
151
What does it mean for apoptosis to be specific and necrosis to be nonspecific?
Apoptosis: Specific, controlled pathway involving caspases and other enzymes.
Necrosis: Nonspecific, often chaotic process.
152
How do DNA fragments appear in apoptosis (ladder) versus necrosis (smear)?
Apoptosis: DNA fragments form a characteristic "ladder" pattern during gel electrophoresis.
Necrosis: DNA degradation appears as a "smear" due to random fragmentation.
153
What is apoptosis, and why is it important?
Apoptosis, also known as “physiological cell death” or “programmed cell death,” is a highly evolutionarily conserved process involved in tissue remodeling, deletion of damaged cells, and deletion of cells displaying errors during mitosis. It plays an important role in diseases, with both decreased apoptosis (e.g., cancer) and increased apoptosis (e.g., Parkinson’s, Alzheimer’s, HIV-AIDS) being significant.
154
How does mitosis relate to apoptosis in maintaining cellular balance?
In most tissues, cells divide via mitosis to replace cells deleted by apoptosis, maintaining a critical balance known as the Apoptosis-Mitosis Balance.
155
How are the mechanisms of apoptotic cell death evolutionarily conserved?
The mechanisms of apoptotic cell death are evolutionarily conserved from worms to humans.
156
What happens when repair mechanisms are overwhelmed, leading to toxicity?
Toxicity occurs when damage overwhelms the repair of damaged proteins, DNA, and/or lipids, the elimination of damaged cells by apoptosis, and/or the replacement of lost cells by mitosis. This can result in necrosis.
157
What is fibrosis, and what causes it?
Fibrosis is a pathological condition resulting from excessive deposition of extracellular matrix (ECM) proteins.
158
What is carcinogenesis, and how is it related to dysfunctions in repair processes?
Carcinogenesis is a multifactorial disease involving dysfunctions in repair processes, including failure of DNA repair, failure of apoptosis, and/or failure to stop cell proliferation (mitosis).
159
What causes oxidative stress in cells?
Oxidative stress arises from an imbalance of pro-oxidants (oxidizing molecular species) and cellular antioxidants.
160
How can oxidative stress occur directly and indirectly?
Directly as oxidative cell injury and indirectly through signal transduction and gene regulation.
161
What percentage of the oxygen we breathe is reduced to O2*-?
1% of the oxygen we breathe is reduced to O2*-.
162
What does the stepwise reduction of oxygen lead to?
It leads to the production of reactive oxygen species (ROSs).
163
How many electrons are needed to reduce O2 through ROSs to H2O?
Four electrons are needed.
164
How do reduced xenobiotics become involved in redox cycling and ROS production?
Reduced xenobiotics donate an electron to O2, creating O2*-.
165
What is the amplification effect in ROS production?
A single xenobiotic can produce many O2*-.
166
How long can redox cycling continue?
It can continue for an extended period until the xenobiotic is metabolized.
167
What is the impact of increased exposure to xenobiotics on ROS production?
The more exposure to xenobiotics, the more ROSs produced.
168
Why are quinones readily involved in ROS production?
Because of the two oxygens on opposite sides of the ring.
169
How is ground-level ozone produced?
In the presence of UV, NO2 from motor vehicle exhaust creates oxygen atoms that combine with O2 to produce ozone (O3).
170
What is the reactivity and half-life of ozone as an ROS?
Ozone is an extremely reactive ROS with a half-life of 7 minutes.
171
Why can ozone move away from motorways to residential areas?
Due to its half-life of 7 minutes.
172
What are the toxicological outcomes of oxidative stress?
DNA oxidation, lipid peroxidation, protein oxidation, and signaling (apoptosis, gene expression).
173
How can ROS production lead to cancer?
DNA in every cell is attacked by ROS 150,000 times a day. If protective mechanisms are bypassed and the mutation is retained, it can lead to cancer.
174
How can xenobiotics interfere with critical metabolic processes?
By interfering with processes like neurotransmission and ATP production.
175
What is the role of bioactivation in xenobiotic-induced oxidative stress?
Bioactivation to electrophiles (e.g., epoxides) leads to increased ROS and oxidative stress.
176
What does xenobiotic binding to receptors involve?
Binding to receptors through "mimicry."
177
What cellular components can be oxidized due to oxidative stress?
DNA, lipids, and proteins.
