Genetics and Human Disease > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

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1
Q

What are pharmacogenetics?

A

Study of variations in DNA sequences and drug response

The aim is to identify right drug and dose for each patient.

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2
Q

What is pharmacogenetics polymorphism?

A

Genetical differences in the we react to drugs.

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3
Q

What kind of markers can we observe to predict the reaction of a patient to a drug?

A

Minisatellite

Microsatellite

SNP

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4
Q

What is a minisatellite?

A

Tandem repeats of sequence that vary from 14 to 100 base pairs in length.

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5
Q

What is a microsatellite?

A

Short sequence of tandem repeats.

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5
Q

What is a SNP?

A

Single nucleotide polymorphism.

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6
Q

What are copy number variations?

A

Duplication and deletions

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7
Q

What are the consequences of polymorphism?

A

Responses to drugs vary

Disease susceptibility

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8
Q

In what way does polymorphism affect the response to drugs?

A

Toxicity and efficacy

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9
Q

What is Thiopurine S-methyltransferase (TPMT)?

A

Purine antimetabolite prodrug used in cancer chemotherapy

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10
Q

What is Azathioprine?

A

Precursor of 6MP and is used as an immunosuppressant drug

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11
Q

What is Methyltransferase?

A

Enzyme which methylates and
inactivates 6-mercaptopurine.

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12
Q

What is the process of Thiopurine Metabolism?

A

Azathioprine converted to 6-mercaptopurine.

Can become oxidised or add methyl to make it inactive.

Or it can become active 6-thioguanine nucleotides.

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13
Q

What is the function of 6-thioguanine nucleotide?

A

Active metabolites, incorporated into DNA and trigger apoptosis

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14
Q

What is used to add methyl and inactivate 6-mercaptopurine in thiopurine metabolism?

A

TPMT

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15
Q

How many types of TMPT are there?

A

3 groups with varying activity, homo and hetero.

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16
Q

What causes low levels of TPMT?

A

Due two SNPs which influence protein stability.

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17
Q

What are the clinical consequence of low TMPT?

A

– Increased thiopurine toxicity

– Homozygotes experience life-threatening myelosuppression

– Possibly improved survival

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18
Q

What are the clinical consequence of high TMPT?

A

– Some evidence of a decreased therapeutic effect

– Likely due to increased drug metabolism

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19
Q

What are Cytochromes P450?

A

Multigene family of enzymes that oxidise both drugs and other foreign compounds.

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20
Q

What do Cytochromes P450 need?

A

Requirement for NADPH and O2.

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21
Q

Where are Cytochromes P450 expressed?

A

Liver

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22
Q

What is the role of Cytochromes P450?

A

Most have a nonessential physiological role

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23
Q

What is important about Debrisoquine?

A

Some individuals are unable to metabolize it,

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24
What is Debrisoquine?
Antihypertensive
25
What kind of trait is the inability to metabolize Debrisoquine?
Autosomal recessive trait
26
What is Debrisoquine metabolized by?
Metabolized by the cytochrome P450 CYP2D6
27
How many polymorphisms are there for CYP2D6?
Over 70
28
What are the CYP2D6 polymorphism are associated with poor metabolism?
* CYP2D6*3 allele * CYP2D6*4 allele * CYP2D6*5 allele
29
What kind of polymorphism is CYP2D6*3 allele?
A deletion on exon 5
30
What kind of polymorphism is CYP2D6*4 allele?
Changes the position of the splice position on intron 3/4
31
What kind of polymorphism is CYP2D6*5 allele?
Entire CYP2D6 gene deleted
32
What are CYP2D6 ultrarapid metabolizers?
Individuals can have extra copies of the CYP2D6 gene adjacent to the wild-type CYP2D6, which means they have more enzymes and metabolise drugs faster.
33
How many extra copies do CYP2D6 ultrarapid metabolizers?
2-13
34
What are Ethnic variations in PG polymorphisms?
Different racial groups have different frequencies of common pharmacogenetic polymorphisms
35
What is CYP2C9?
An enzyme protein.
36
What substrates does CYP2C9 work with?
S-warfarin Phenytoin NSAIDs
37
Which variant alleles if CYP2C9 have functional effects?
CYP2C9*2 CYP2C9*3
38
What is the functional effect of CYP2C9*2?
Effect substrate-dependent
39
What is the functional effect of CYP2C9*3?
Larger effect and less substrate dependent
40
What is Warfin?
Widely used anticoagulant
41
What happens when someone is given an incorrect dosage of warfin?
Haemorrhage or clot
42
What kinds of warfarin is there?
Mixture of R and S enantiomers
43
Which of the types of warfarin has higher activity?
S
44
What is R-warfarin metabolised by?
Hydroxylated by CYP3A4 and CYP1A2
45
What is S-warfarin metabolised by?
CYP2C9
46
What happens when a person is a slow warfarin metabolizer?
At risk of haemorrhage during warfarin initiation.
47
What happens when warfarin enters the vitamin K cycle?
Warfarin inhibits VKOR, impairing the synthesis of clotting factors
48
What is the vitamin K cycle?
In the process vitamin K is oxidised and in the next cycle VKOR regenerates reduced vitamin K
49
What happens when vitmain K is reduced?
Reduced vitamin K is a cofactor for activation of clotting factors
50
What is the function of VKOR?
Vitamin K epoxide reductase reduces vitamin K.
51
What is the connection between CYP2C9 and warfarin?
CYP2C9 genotype may be useful as a factor determining dose requirement but not absolute predictor.
52
What is the importance of Vitamin K epoxide reductase for warfarin?
Target enzyme for coumarin anticoagulants including warfarin.
53
What is the Regression equation for warfarin dose?
Equation to predict warfarin dose requirement based on CYP2C9/VKORC1 genotype, age and height.
54
What does MDR1 code for?
p-glycoprotein
55
What is the p-glycoprotein?
ATP-dependent efflux pump with broad substrate specificity.
56
Where is MDR1 expressed?
Colon Liver Kidney Blood brain barrier
57
What is the function of p-glycoprotein?
Mechanism against harmful substances
58
What genotype knockout causes IBDs?
MDR1
59
What are the properties of ideal anti-cancer drug?
– Kills all tumour cells – Acts against a target that is only present in tumour cells (To avoid toxicity to normal tissues)
60
Some examples of novel cancer therpies?
– Herceptin – Glivec/Imatinib
61
What is HER2?
Human Epidermal growth factor Receptor 2
62
Where is HER2?
Transmembrane receptor tyrosine kinase
63
Why is overexpression of HER2 dangerous?
Occurs in 25% of breast cancers
64
How could HER2 cause cancer?
– Amplification – Transcriptional upregulation
65
What is herceptin?
Monoclonal antibody that binds to HER2.
66
What is the function of herceptin?
Stops tumour growth via receptor signalling pathway.
67
How does Herceptin prevent tumour growth in breast cancer?
* Tumour cells with bound antibodies might be attacked by patient's immune system. * Sensitizes cells to cytotoxic drugs.
68
How to determine HER2 overexpression?
Semi-quantative DAKO HERCEPT test Brown is positive result.
69
What is CML?
Chronic myeloid leukaemia.
70
When does CML happen?
Median at 55 years.
71
Why does a Philadelphia Chromosome occur?
Reciprocal translocation
72
What is the Philadelphia Chromosome?
specific genetic abnormality of shortness in chromosome 22
73
What is the link between CML patients and the Philadelphia chromosome?
Present in 95% of CML patients
74
What is the recombination which occurs at chromosome 22 to make it a Philadelphia chromosome?
Recombination with chromosome 9 at the breakage point.
75
What is the abl gene?
Encodes a tyrosine kinase of molecular weight 145KDa
76
What is the role of Tyrosine Kinases?
Phosphorylate tyrosine residues on themselves and other proteins using a phosphate group donated from ATP.
77
Why is the phosphorylation caused by tyrosine kinase important?
Acts an activator of signalling cascades of many pathways involved in regulating cell function
78
What is different about cancer cells abl signal transduction?
Loss of regulatory part of the abl protein at the N terminus due the replacement with bcr interferes with the regulatory component.
79
How does the bcr/abl cascade promote leukaemia?
Increasing cell proliferation Inhibiting cell death Altered adhesion
80
What is STI571?
Designed to act as an ATP binding site inhibitor of Abl kinase.
81
What is the important of STI571 (Imatinib)?
NO phosphorylation of tyrosine residues on substrate proteins NO activation of signal transduction pathways that are necessary for leukemic cell growth
82
What is the role of statin?
Lowering cholesterol and preventing heart attacks
83
What are the risks of statin?
Myopathy
84
What is the gene that causes the myopathy in the use of statin?
C variant SLCO1B1
85
Why is the SLCO1B1 dangerous in the presence of statin?
SLCO1B1 encodes OATP1B1 which regulates hepatic uptake of statins.
86
What is OATP1B?
The organic anion–transporting polypeptide.
87
What are the current FDA guidelines on pharmacogenetic tests categories?
* Category 1 -Mandatory * Category 2 -Recommended * Category 3- Suggested
88
Why is oestrogen important in breast cancer?
Growth of normal mammary epithelium is dependent upon oestrogen and is mediated by oestrogen receptor (ER)
89
What can be used to control the ER effect on breast cancer?
Can be therapeutically exploited using ER antagonists
90
Medications that decrease CYP2D6 activity, such as antidepressants will?
Decrease the efficacy of tamoxifen treatment.
91
Approximately, how often do SNPs occur?
1 per 200 bases
92
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