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PED3005 Pharmacogenetics > CYPs > Flashcards

CYPs Flashcards

1
Q

What are the 3 loss of function alleles for CYP2D6

A

*3
*4
*5

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2
Q

Describe the CYP2D6 *3 allele

A

Deletion = frameshift

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3
Q

Describe the *4 CYP2D6 allele

A

Splicing defect

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4
Q

Describe the *5 CYP2D6 allele

A

Complete loss of CYP

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5
Q

What alleles have reduced activity in CYP2D6

A

*9
*10
*17

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6
Q

Describe ultra rapid CYP2D6 metabolisers

A

Amplification
Multiple number of copies

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7
Q

What CYP2D6 alleles are common in Europe

A

*3
*4
*5
*6

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8
Q

What CYP2D6 alleles are common in china

A

*5 and *10

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9
Q

Where is amplification of CYP2D6 most common

A

South Europe and Africa

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10
Q

Describe CYP2C19

A

Low conc in liver
Few drug substrates
Known as mepheytoin hydroxylase

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11
Q

What are the 2 forms of CYP2C19

A

R = PEH + Nirvanol
S = 4-OH mephenytoin

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12
Q

What is the R form of CYP2C19 metabolised by

A

Demethylases

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13
Q

What is the S form of CYP2C19 metabolised by

A

Complete hydroxylases

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14
Q

What alleles produce an absence of activity in CYP2C19

A

*2
*3
*4
*5
*6
*7

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15
Q

Describe the *2 allele of CYP2C19

A

Splicing defect
WT splice site = AGAT
*2 splice site = GGCA
*2 preferred = aberrant protein

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16
Q

Describe the *3 allele of CYP2C19

A

Stop codon

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17
Q

Describe the *4 allele of CYP2C19

A

No txn

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18
Q

Describe the *7 allele of CYP2C19

A

Splicing defect
T -> A in intron 5

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19
Q

What allele is responsible for lack of activity in CYP2C19

A

*8

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20
Q

How common is the CYP2C19 *8 allele in Europe

A

3%

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21
Q

How common is the CYP2C19 *8 allele in East Asia

A

20%

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22
Q

What polymorphism causes an increase in activity in CYP2C19

A

*17

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23
Q

Describe the *17 polymorphism in CYP2C19

A

Upstream polymorphism
= more gene txn
= higher activity/ metabolism

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24
Q

How common is the *17 allele in CYP2C19

A

42x more likely in South Europe than East Asia

Few individuals with 17/17 + 17/1

25
Q

What is a pseudogene

A

Gene w no introns = amplification

Past infections from virus which contained reverse transcriptase

26
Q

What are the substrates of CYP2A6

A

Nicotine, procarcinogens and coumarin

27
Q

How does CYP2A6 affect coumarin metabolism

A

Absence of coumarin-7-hydroxylase
= no metabolism of coumarin

28
Q

What polymorphisms lead to no/decreased activity in CYP2A6

A

*2
*4
*5

29
Q

Describe the *2 polymorphism in CYP2A6

A

No haem incorporated

30
Q

Describe the *4 polymorphism in CYP2A6

A

Large deletion = no enzyme

Additional copies of other genes caused by disruption of homologous recombination

31
Q

Describe the *5 polymorphism in CYP2A6

A

Unstable protein

32
Q

Where is the CYP2A6 *2 allele most common

A

Europe

33
Q

Where is the CYP2A6 *4 allele most common

A

East Asia

34
Q

Where is the CYP2A6 *5 allele most common

A

It’s rare

35
Q

What can cause increased activity in CYP2A6

A

Evidence of additional copies of WT allele
No splicing defect

36
Q

What polymorphism of CYP2C9 cause reduced activity

A

*2
*3
*4
*5
*6
*11

37
Q

Describe the *2 polymorphism in CYP2C9

A

Effect is substrate dependent
E.g warfarin metabolism more affected

38
Q

Describe the *3 polymorphism in CYP2C9

A

Most detrimental but residual activity remains
Lowest catalytic efficiency

39
Q

Describe the *6 polymorphism in CYP2C9

A

Frameshift = inactive protein

40
Q

How common is the *6 polymorphism of CYP2C9

A

Rare allele
Seen in African Americans
No 6/6 alleles

41
Q

What is the wild type polymorphism for CYP2C9

A

*1

42
Q

Describe the Km of the CYP2C9 *1 allele

A

Highest catalytic efficiency
No sig diff between Km of *1 and *2
(Measured by Vmax/Km)

43
Q

What are the 2 polymorphisms of CYP3A5

A

*3
*1

44
Q

Describe the *3 polymorphism of CYP3A5

A

Complete deletion
Creates aberrant splice site
Insertion @ 670bp in hepatic mRNA
= nonsense protein

45
Q

Describe the *1 polymorphism in CYP3A5

A

A at position 6986
= normal hepatic expression

1/3 genotype associates w expression of CYP3A5

46
Q

How common is the *3 CYP3A5 polymorphism

A

90% of Europeans

47
Q

What genotype is rare in Europeans for CYP3A5

A

Homozygosity for *1

48
Q

What polymorphisms of CYP3A4 are responsible for decreased gene expression

A

*1B
*2
*22

49
Q

Describe the *1B polymorphism of CYP3A4

A

Upstream at -289

50
Q

Describe the *2 polymorphism of CYP3A4

A

Substrate specific polymorphism
Less efficient @ nifedipine metabolism

51
Q

Describe the *22 polymorphism of CYP3A4

A

Intronic polymoprhism
C -> T in intron 6
= reduced activity

TT homozygotes have some enzyme expression

52
Q

How frequent is the *2 polymorphism of CYP3A4

A

2.7% in Caucasians

53
Q

How frequent is the *22 polymorphism of CYP3A4

A

Allele frequency of 5%

54
Q

Name 4 substrates for CYP2D6

A

Opioids
B-blockers
SNRIs
Debrisoquine

55
Q

Name 3 substrates for CYP2C19

A

Omeprazole
Diazepam
Clopidogrel

56
Q

Name 3 substrates for CYP2A6

A

Nicotine
Coumarin
Procarcinogens
Disulphiram

57
Q

Name 3 substrates for CYP2C9

A

Warfarin
Phenytoin
NSAID’s

58
Q

Name 3 substrates for CYP3A4

A

Cyclosporin
Nifedipine
Steroids

PED3005 Pharmacogenetics (10 decks)

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