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Genetics and Human Disease > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

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
Q

What is Debrisoquine?

A

Antihypertensive

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25
Q

What kind of trait is the inability to metabolize Debrisoquine?

A

Autosomal recessive trait

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26
Q

What is Debrisoquine metabolized by?

A

Metabolized by the cytochrome P450 CYP2D6

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27
Q

How many polymorphisms are there for CYP2D6?

A

Over 70

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28
Q

What are the CYP2D6 polymorphism are associated with poor metabolism?

A
  • CYP2D6*3 allele
  • CYP2D6*4 allele
  • CYP2D6*5 allele
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29
Q

What kind of polymorphism is CYP2D6*3 allele?

A

A deletion on exon 5

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30
Q

What kind of polymorphism is CYP2D6*4 allele?

A

Changes the position of the splice position on intron 3/4

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31
Q

What kind of polymorphism is CYP2D6*5 allele?

A

Entire CYP2D6 gene deleted

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32
Q

What are CYP2D6 ultrarapid metabolizers?

A

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.

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33
Q

How many extra copies do CYP2D6 ultrarapid metabolizers?

A

2-13

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34
Q

What are Ethnic variations in PG polymorphisms?

A

Different racial groups have different frequencies of common pharmacogenetic polymorphisms

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35
Q

What is CYP2C9?

A

An enzyme protein.

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36
Q

What substrates does CYP2C9 work with?

A

S-warfarin

Phenytoin

NSAIDs

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37
Q

Which variant alleles if CYP2C9 have functional effects?

A

CYP2C9*2

CYP2C9*3

38
Q

What is the functional effect of CYP2C9*2?

A

Effect substrate-dependent

39
Q

What is the functional effect of CYP2C9*3?

A

Larger effect and less substrate dependent

40
Q

What is Warfin?

A

Widely used anticoagulant

41
Q

What happens when someone is given an incorrect dosage of warfin?

A

Haemorrhage or clot

42
Q

What kinds of warfarin is there?

A

Mixture of R and S enantiomers

43
Q

Which of the types of warfarin has higher activity?

A

S

44
Q

What is R-warfarin metabolised by?

A

Hydroxylated by CYP3A4 and
CYP1A2

45
Q

What is S-warfarin metabolised by?

A

CYP2C9

46
Q

What happens when a person is a slow warfarin metabolizer?

A

At risk of haemorrhage during warfarin initiation.

47
Q

What happens when warfarin enters the vitamin K cycle?

A

Warfarin inhibits VKOR, impairing the synthesis of clotting factors

48
Q

What is the vitamin K cycle?

A

In the process vitamin K is oxidised and in the next cycle VKOR regenerates reduced vitamin K

49
Q

What happens when vitmain K is reduced?

A

Reduced vitamin K is a cofactor for activation of clotting factors

50
Q

What is the function of VKOR?

A

Vitamin K epoxide reductase reduces vitamin K.

51
Q

What is the connection between CYP2C9 and warfarin?

A

CYP2C9 genotype may be useful as a factor determining dose requirement but not absolute predictor.

52
Q

What is the importance of Vitamin K epoxide reductase for warfarin?

A

Target enzyme for coumarin anticoagulants including warfarin.

53
Q

What is the Regression equation for warfarin dose?

A

Equation to predict warfarin dose requirement based on CYP2C9/VKORC1 genotype, age and height.

54
Q

What does MDR1 code for?

A

p-glycoprotein

55
Q

What is the p-glycoprotein?

A

ATP-dependent efflux pump with broad substrate specificity.

56
Q

Where is MDR1 expressed?

A

Colon

Liver

Kidney

Blood brain barrier

57
Q

What is the function of p-glycoprotein?

A

Mechanism against harmful substances

58
Q

What genotype knockout causes IBDs?

A

MDR1

59
Q

What are the properties of ideal anti-cancer drug?

A

– Kills all tumour cells

– Acts against a target that is only present in tumour cells (To avoid toxicity to normal tissues)

60
Q

Some examples of novel cancer therpies?

A

– Herceptin

– Glivec/Imatinib

61
Q

What is HER2?

A

Human Epidermal growth factor Receptor 2

62
Q

Where is HER2?

A

Transmembrane receptor tyrosine kinase

63
Q

Why is overexpression of HER2 dangerous?

A

Occurs in 25% of breast cancers

64
Q

How could HER2 cause cancer?

A

– Amplification
– Transcriptional upregulation

65
Q

What is herceptin?

A

Monoclonal antibody that binds to HER2.

66
Q

What is the function of herceptin?

A

Stops tumour growth via receptor signalling pathway.

67
Q

How does Herceptin prevent tumour growth in breast cancer?

A
  • Tumour cells with bound antibodies might be attacked by patient’s immune system.
  • Sensitizes cells to cytotoxic drugs.
68
Q

How to determine HER2 overexpression?

A

Semi-quantative DAKO HERCEPT test

Brown is positive result.

69
Q

What is CML?

A

Chronic myeloid leukaemia.

70
Q

When does CML happen?

A

Median at 55 years.

71
Q

Why does a Philadelphia Chromosome occur?

A

Reciprocal translocation

72
Q

What is the Philadelphia Chromosome?

A

specific genetic abnormality of shortness in chromosome 22

73
Q

What is the link between CML patients and the Philadelphia chromosome?

A

Present in 95% of CML patients

74
Q

What is the recombination which occurs at chromosome 22 to make it a Philadelphia chromosome?

A

Recombination with chromosome 9 at the breakage point.

75
Q

What is the abl gene?

A

Encodes a tyrosine kinase of molecular weight 145KDa

76
Q

What is the role of Tyrosine Kinases?

A

Phosphorylate tyrosine residues on themselves and other proteins using a phosphate group donated from ATP.

77
Q

Why is the phosphorylation caused by tyrosine kinase important?

A

Acts an activator of signalling cascades of many pathways involved in regulating cell function

78
Q

What is different about cancer cells abl signal transduction?

A

Loss of regulatory part of the abl protein at the N terminus due the replacement with bcr interferes with the regulatory component.

79
Q

How does the bcr/abl cascade promote leukaemia?

A

Increasing cell proliferation

Inhibiting cell death

Altered adhesion

80
Q

What is STI571?

A

Designed to act as an ATP binding site inhibitor of Abl kinase.

81
Q

What is the important of STI571 (Imatinib)?

A

NO phosphorylation of tyrosine residues on substrate proteins

NO activation of signal transduction pathways that are necessary
for leukemic cell growth

82
Q

What is the role of statin?

A

Lowering cholesterol and preventing heart attacks

83
Q

What are the risks of statin?

A

Myopathy

84
Q

What is the gene that causes the myopathy in the use of statin?

A

C variant SLCO1B1

85
Q

Why is the SLCO1B1 dangerous in the presence of statin?

A

SLCO1B1 encodes OATP1B1 which regulates hepatic uptake of statins.

86
Q

What is OATP1B?

A

The organic anion–transporting polypeptide.

87
Q

What are the current FDA guidelines on pharmacogenetic
tests categories?

A
  • Category 1 -Mandatory
  • Category 2 -Recommended
  • Category 3- Suggested
88
Q

Why is oestrogen important in breast cancer?

A

Growth of normal mammary epithelium is dependent upon oestrogen and is mediated by
oestrogen receptor (ER)

89
Q

What can be used to control the ER effect on breast cancer?

A

Can be therapeutically exploited using ER antagonists

90
Q

Medications that decrease CYP2D6 activity, such as antidepressants will?

A

Decrease the efficacy of tamoxifen treatment.

91
Q

Approximately, how often do SNPs occur?

A

1 per 200 bases

92
Q
A

Genetics and Human Disease (16 decks)

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