Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

PED3011 Toxicology > Genotoxicolgy > Flashcards

Genotoxicolgy Flashcards

1
Q

Define genotoxic carcinogens

A

Carcinogens that directly alter genetic material

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Describe microlesisons

A

Mutagenesis = effect of DNA bases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Describe macrolesions

A

Effect on chromosomes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Define mutagenesis

A

Mutation of DNA
Permanent small DNA change
Carried on to daughter cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Define clastogenesis

A

Induction of chromosomal aberrations due to loss/addition/rearrangement of DNA
Part of the chromosome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Define aneugenesis

A

Loss or gain of compete chromosome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the of consequences of DNA damage caused by mutagens

A

Response mechanism
Mutations in somatic cells
Mutations in germinal cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Describe response mechanisms

A

Try to repair, remove damage prior to replication

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Describe mutations in somatic cells

A

Damage can lead to mutagenesis -> carcinogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What can happen if there is mutations in germinal cells

A

Genetic diseases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the 2 types of carcinogens

A

Genotoxic carcinogens (most)
Non-genotoxic carcinogens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Describe genotoxic carcinogens

A

Directly binds with DNA = directly inducing DNA damage
Covalent bonds leads to adducts
Some intercalated with the DNA ladder
Some oxidise bases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Describe to non-genotoxic carcinogens

A

Leads to DNA instability -> interferes with other processes
Don’t directly change DNA code
Less common

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Define a pro-carcinogen

A

Require metabolic activation to become carcinogenic
E.g PAHs, aromatic amines etc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

How can you determine if a chemical is mutagenic

A

Study in human populations and study in lab

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Describe how chemicals are studied in human populations

A

No experimental date but epidemiological data
- measurement of DNA adducts
- other measures of damage in exposed humans

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the problems with studying human populations

A

Other chemical exposures
Cancer development can occur many years after exposure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe how chemicals can be studied in a lab

A

Battery of tests to detect DNA damage from genotoxic chemicals
E.g animal and cell study

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are the problems with studying chemicals int the lab

A

Metabolic activation of chemical may be needed
Extrapolation of animal data to humans

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Who determines how carcinogens are classified

A

International and nationals agencies
E.g IARC (WHO), EPA (US)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Describe category IARC1 and EPA A

A

Human Carcinogen
Occurrence of tumours at high rate
Sufficient evidence of carcinogens from animal studies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Describe category IARC 2B

A

Positive results in only one studies, strain or study
Inadequate evidence in humans

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What are the 3 main mechanism of direct interactions with DNA

A

Alkylation of bases
Addition on bulky adducts on DNA
Formation of cross links between DNA strands

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Describe DNA alkylation

A

Reaction of DNA with alkyl group (methyl or higher)
Electrophilic and attack N7 and O6 of guanine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
What are the 2 types of alkylating agents
Monofunctional Bifunctional
26
Describe monofunctional agents
Single alkylation step
27
Describe bifunctional agents
Lead to alkylation + crosslinking of 2 strands by binding 2 guanines
28
Describe phosphoramide effect on DNA
Electrophilic attack of N7 Release of Cl- Formation of bridge between 2 strands (intrastrand) Cytotoxic
29
Which base is more susceptible to electrophilic attack
Guanine
30
Whats the effect of benzo[a]pyrene on DNA
Bulky adduct Alteration of base pairing Base transversion pairing G with A
31
How is BaP activated
Metabolised to BaP-diol epoxide Reacts with DNA
32
What are other direct but not covalent interactions of carcinogens with DNA
Intercalation DNA damage by removal of purine or pyrimidine ROS Strand breaks
33
Describe non covalent intercalation of carcinogens
Planar molecules that intercalate between stacked base pairs of ds DNA
34
Describe how DNA is damaged by removal of purines or pyrimidines
Gives ‘apurinic’ or ‘apyrimidinic’ site May result in replacement after replication = incorrect base or frameshift
35
How can ROS interact with DNA
Formation of 8-oxydeoxyguanosine = mispairing with A instead of C Deamination of 5-methylcytosine = C -> T Single strand breaks
36
Describe strand breaks in DNA caused by carcinogens
Single strand induced by chemicals Double strand breaks typically due to radiation exposure
37
What types of mutations are observed after chemical exposure
Base substitutions Frameshift
38
What can base substitutions lead to
Change in amino acid Altered regulation Truncated protein
39
What can frameshift lead to
Profound effect on gene product if in coding sequence
40
Describe what enzymes are involved in the activation of the pro-carcinogen BaP
1 - CYP1A1 2 - Epoxide hydrolase 3 - CYP1A1
41
What affect does BaP have on DNA
Diol epoxide does adduct with guanine = G -> A transversion
42
What CYP activates aflatoxin B1
CYP3A4
43
How is aflatoxin B1 detoxified
1 - AFBO + conjugation with GSH via GST = AFB1-GSH conjugate 2 - AFBO + epoxide hydrolase = AFB1 dihydrodiol 3- AFB1 dialdehyde + aldehyde reductase + NADPH = AFB1 dialcohol
44
What metabolites of AFB1 form DNA adducts
Aflatoxin B1 aldehyde and AFBO
45
What do you need to determine when studying carcinogens
Is a molecule genotoxic by direct covalent reaction or by non-covalent mechanism Does a molecule induce cancer by non-genotoxic carcinogen
46
Define carcinogenesis
When normal cells are transformed into cancer cells Series of mutations in genes controlling
47
What are the 3 stages in carcinogenesis
1. Tumour initiation 2. Tumour promotion 3. Tumour progression
48
What are tumour promotors
Not carcinogens but increase the effect of carcinogen when given simultaneously Involved in tumour promotion stage
49
What are solid state carcinogens
Not directly genotoxins but they can produce tumours of mesenchymal origin
50
How can asbestos cause mesothelioma
Asbestos can generate OH radicals from H2O2
51
When is p53 in a latent stage
MDM2-p53 No stress
52
What happens to p53 in response to stress
DNA damage = phosphorylation of p53 = activation of p53 and release of MDM2
53
What is the downstream response that is coordinated by p53
Halts cell cycle in G1 phase Activates DNA repair proteins Initiate apoptosis to remove damaged cells
54
Is the p53 pathway active in cancers
No (most cancers)
55
What are the mutated hot spots in smoking-related lung cancers
Codons 157, 248, 273 TP53 gene
56
What are the 4 types of DNA repair mechanisms
Base excision repair Nucleotide excision repair Methyl group removal Repair of strand breaks
57
Describe base excision repair
Repairs non-bulky damage to bases Results from oxidation methylation, deamination or spontaneous loss of DNA base
58
Describe the steps of base excision repair
1- DNA glycosylase recognises damage and cleaves glycosidic bond 2- AP endonuclease cleaves phosphodiesterase bond near AP site 3- Small section on DNA including AP site removed and replaced 4- DNA polymerase initiates repair 5 - DNA ligase ligates the break
59
Describe nucleotide excisions repair
Removal of bulky adducts Multi-enzyme repair complex recognises damage Removes 25-30 nucleotides surrounding site DNA polymerase and ligase carry out repair
60
What is the role of MGMT
Enzyme removes methyl and ethyl groups from guanine at O6 position
61
When is MGMT effective
Damage caused by mono functional alkylating agents Not against bifunctional agents
62
What type of repair do bifunctional agents require
NER
63
What is not required for MGMT
DNA polymerase (Necessary for BER and NER)
64
What inter-individual variations are seen in a persons susceptibility to DNA damage
Ability to activate and detoxicate certain carcinogens DNA repair capacity
65
What are examples of in vitro testing for mutagenicity of chemicals
Bacterial test Metaphase or micronucleus test Mammalian cell mutation test
66
What are examples of in vivo testing for mutagenicity of chemicals
Cytogenetic test Gene mutation test
67
What happens if in vitro and in vivo tests are equivocal?
Need additional tests: Comet assay Transgenic animal mutation test
68
What the aims of the Ames assay
Bacterial assay To evaluate a chemicals genotoxicity by measuring its ability to induce reverse mutations at a locus in a bacterial strain
69
What are the advantages of the Ames assay
Predictive, good correlation w rodent carcinogens Short term Relatively cheap High throughput
70
What are the disadvantages of the Ames assay
Non-mammalian system Not 100% predictive
71
What is the aims of the mammalian mutation cell assay
Evaluate in vitro’s a chemicals genotoxicity by measuring its ability to induce reverse mutations at locus in mammalian cells
72
What is the aim of the micronucleus test in vitro
Evaluate in vitro a chemicals ability to modify chromosome structure and segregation
73
What are the 2 types of in vivo testing for possible mutations
Micronucleus test using erythrocytes from bone marrow Transgenic mouse models (indirect reporter)
74
What is the LC-MS assay
Detects DNA damage (8-OHdG) Sensitive assay
75
What is the limitations of LC-MS method
Only measures oxidative DNA damage
76
Describe the COMET assay
Quantifies overall damage Cells lysed, strands unwound and separated in alkali buffer = electrophoresis -> analysed under microscope
77
What is the COMET assay also known as
Single cell gel electrophoresis
78
What does the COMET assay primary detect
Single trans DNA breaks and AP sites Distinguish oxidative damage from covalent adducts
79
What are the positives of the COMET assay
Low cost, relatively fast and simple test
80
What are the limitations of the COMET assay
Depends on cell cycle stage Quiescent cells less likely to undergo damage
81
What is the difference between in vitro and in vivo COMET assays
In vitro: cells exposed to mutagens in tissue culture In vivo: measure DNA damage in primary cells
82
What is more complicated: in vivo or ion vitro COMET assay
In vivo
83
When would you run germ cell toxicity tests
To give information on risk to offspring after adminsteration of toxic compound
84
Describe frustrated phagocytosis caused by asbestos
Fibres small enough to pas the nostril hairs and mucocilliary elevator Alveolar macrophages try to digest but can’t Macrophages lyse and release contents

PED3011 Toxicology (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions