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PED3011 Toxicology > Genotoxicolgy > Flashcards

Genotoxicolgy Flashcards

1
Q

Define genotoxic carcinogens

A

Carcinogens that directly alter genetic material

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2
Q

Describe microlesisons

A

Mutagenesis = effect of DNA bases

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3
Q

Describe macrolesions

A

Effect on chromosomes

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4
Q

Define mutagenesis

A

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

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5
Q

Define clastogenesis

A

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

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6
Q

Define aneugenesis

A

Loss or gain of compete chromosome

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7
Q

What are the of consequences of DNA damage caused by mutagens

A

Response mechanism
Mutations in somatic cells
Mutations in germinal cells

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8
Q

Describe response mechanisms

A

Try to repair, remove damage prior to replication

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9
Q

Describe mutations in somatic cells

A

Damage can lead to mutagenesis -> carcinogenesis

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10
Q

What can happen if there is mutations in germinal cells

A

Genetic diseases

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11
Q

What are the 2 types of carcinogens

A

Genotoxic carcinogens (most)
Non-genotoxic carcinogens

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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

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13
Q

Describe to non-genotoxic carcinogens

A

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

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14
Q

Define a pro-carcinogen

A

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

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15
Q

How can you determine if a chemical is mutagenic

A

Study in human populations and study in lab

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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

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17
Q

What are the problems with studying human populations

A

Other chemical exposures
Cancer development can occur many years after exposure

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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

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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

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20
Q

Who determines how carcinogens are classified

A

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

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21
Q

Describe category IARC1 and EPA A

A

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

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22
Q

Describe category IARC 2B

A

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

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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

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24
Q

Describe DNA alkylation

A

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

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25
Q

What are the 2 types of alkylating agents

A

Monofunctional
Bifunctional

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26
Q

Describe monofunctional agents

A

Single alkylation step

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27
Q

Describe bifunctional agents

A

Lead to alkylation + crosslinking of 2 strands by binding 2 guanines

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28
Q

Describe phosphoramide effect on DNA

A

Electrophilic attack of N7
Release of Cl-
Formation of bridge between 2 strands (intrastrand)
Cytotoxic

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29
Q

Which base is more susceptible to electrophilic attack

A

Guanine

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30
Q

Whats the effect of benzo[a]pyrene on DNA

A

Bulky adduct
Alteration of base pairing
Base transversion pairing G with A

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31
Q

How is BaP activated

A

Metabolised to BaP-diol epoxide
Reacts with DNA

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32
Q

What are other direct but not covalent interactions of carcinogens with DNA

A

Intercalation
DNA damage by removal of purine or pyrimidine
ROS
Strand breaks

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33
Q

Describe non covalent intercalation of carcinogens

A

Planar molecules that intercalate between stacked base pairs of ds DNA

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34
Q

Describe how DNA is damaged by removal of purines or pyrimidines

A

Gives ‘apurinic’ or ‘apyrimidinic’ site
May result in replacement after replication
= incorrect base or frameshift

35
Q

How can ROS interact with DNA

A

Formation of 8-oxydeoxyguanosine
= mispairing with A instead of C

Deamination of 5-methylcytosine = C -> T

Single strand breaks

36
Q

Describe strand breaks in DNA caused by carcinogens

A

Single strand induced by chemicals
Double strand breaks typically due to radiation exposure

37
Q

What types of mutations are observed after chemical exposure

A

Base substitutions
Frameshift

38
Q

What can base substitutions lead to

A

Change in amino acid
Altered regulation
Truncated protein

39
Q

What can frameshift lead to

A

Profound effect on gene product if in coding sequence

40
Q

Describe what enzymes are involved in the activation of the pro-carcinogen BaP

A

1 - CYP1A1
2 - Epoxide hydrolase
3 - CYP1A1

41
Q

What affect does BaP have on DNA

A

Diol epoxide does adduct with guanine
= G -> A transversion

42
Q

What CYP activates aflatoxin B1

A

CYP3A4

43
Q

How is aflatoxin B1 detoxified

A

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
Q

What metabolites of AFB1 form DNA adducts

A

Aflatoxin B1 aldehyde and AFBO

45
Q

What do you need to determine when studying carcinogens

A

Is a molecule genotoxic by direct covalent reaction or by non-covalent mechanism
Does a molecule induce cancer by non-genotoxic carcinogen

46
Q

Define carcinogenesis

A

When normal cells are transformed into cancer cells
Series of mutations in genes controlling

47
Q

What are the 3 stages in carcinogenesis

A
  1. Tumour initiation
  2. Tumour promotion
  3. Tumour progression
48
Q

What are tumour promotors

A

Not carcinogens but increase the effect of carcinogen when given simultaneously
Involved in tumour promotion stage

49
Q

What are solid state carcinogens

A

Not directly genotoxins but they can produce tumours of mesenchymal origin

50
Q

How can asbestos cause mesothelioma

A

Asbestos can generate OH radicals from H2O2

51
Q

When is p53 in a latent stage

A

MDM2-p53
No stress

52
Q

What happens to p53 in response to stress

A

DNA damage = phosphorylation of p53 = activation of p53 and release of MDM2

53
Q

What is the downstream response that is coordinated by p53

A

Halts cell cycle in G1 phase
Activates DNA repair proteins
Initiate apoptosis to remove damaged cells

54
Q

Is the p53 pathway active in cancers

A

No (most cancers)

55
Q

What are the mutated hot spots in smoking-related lung cancers

A

Codons 157, 248, 273
TP53 gene

56
Q

What are the 4 types of DNA repair mechanisms

A

Base excision repair
Nucleotide excision repair
Methyl group removal
Repair of strand breaks

57
Q

Describe base excision repair

A

Repairs non-bulky damage to bases
Results from oxidation methylation, deamination or spontaneous loss of DNA base

58
Q

Describe the steps of base excision repair

A

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
Q

Describe nucleotide excisions repair

A

Removal of bulky adducts
Multi-enzyme repair complex recognises damage
Removes 25-30 nucleotides surrounding site
DNA polymerase and ligase carry out repair

60
Q

What is the role of MGMT

A

Enzyme removes methyl and ethyl groups from guanine at O6 position

61
Q

When is MGMT effective

A

Damage caused by mono functional alkylating agents
Not against bifunctional agents

62
Q

What type of repair do bifunctional agents require

A

NER

63
Q

What is not required for MGMT

A

DNA polymerase
(Necessary for BER and NER)

64
Q

What inter-individual variations are seen in a persons susceptibility to DNA damage

A

Ability to activate and detoxicate certain carcinogens
DNA repair capacity

65
Q

What are examples of in vitro testing for mutagenicity of chemicals

A

Bacterial test
Metaphase or micronucleus test
Mammalian cell mutation test

66
Q

What are examples of in vivo testing for mutagenicity of chemicals

A

Cytogenetic test
Gene mutation test

67
Q

What happens if in vitro and in vivo tests are equivocal?

A

Need additional tests:
Comet assay
Transgenic animal mutation test

68
Q

What the aims of the Ames assay

A

Bacterial assay
To evaluate a chemicals genotoxicity by measuring its ability to induce reverse mutations at a locus in a bacterial strain

69
Q

What are the advantages of the Ames assay

A

Predictive, good correlation w rodent carcinogens
Short term
Relatively cheap
High throughput

70
Q

What are the disadvantages of the Ames assay

A

Non-mammalian system
Not 100% predictive

71
Q

What is the aims of the mammalian mutation cell assay

A

Evaluate in vitro’s a chemicals genotoxicity by measuring its ability to induce reverse mutations at locus in mammalian cells

72
Q

What is the aim of the micronucleus test in vitro

A

Evaluate in vitro a chemicals ability to modify chromosome structure and segregation

73
Q

What are the 2 types of in vivo testing for possible mutations

A

Micronucleus test using erythrocytes from bone marrow
Transgenic mouse models (indirect reporter)

74
Q

What is the LC-MS assay

A

Detects DNA damage (8-OHdG)
Sensitive assay

75
Q

What is the limitations of LC-MS method

A

Only measures oxidative DNA damage

76
Q

Describe the COMET assay

A

Quantifies overall damage
Cells lysed, strands unwound and separated in alkali buffer
= electrophoresis -> analysed under microscope

77
Q

What is the COMET assay also known as

A

Single cell gel electrophoresis

78
Q

What does the COMET assay primary detect

A

Single trans DNA breaks and AP sites
Distinguish oxidative damage from covalent adducts

79
Q

What are the positives of the COMET assay

A

Low cost, relatively fast and simple test

80
Q

What are the limitations of the COMET assay

A

Depends on cell cycle stage
Quiescent cells less likely to undergo damage

81
Q

What is the difference between in vitro and in vivo COMET assays

A

In vitro: cells exposed to mutagens in tissue culture
In vivo: measure DNA damage in primary cells

82
Q

What is more complicated: in vivo or ion vitro COMET assay

A

In vivo

83
Q

When would you run germ cell toxicity tests

A

To give information on risk to offspring after adminsteration of toxic compound

84
Q

Describe frustrated phagocytosis caused by asbestos

A

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)

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