CYPs

Question 1

What are the 3 loss of function alleles for CYP2D6

Answer 1

*3
*4
*5

Question 2

Describe the CYP2D6 *3 allele

Answer 2

Deletion = frameshift

Question 3

Describe the *4 CYP2D6 allele

Answer 3

Splicing defect

Question 4

Describe the *5 CYP2D6 allele

Answer 4

Complete loss of CYP

Question 5

What alleles have reduced activity in CYP2D6

Answer 5

*9
*10
*17

Question 6

Describe ultra rapid CYP2D6 metabolisers

Answer 6

Amplification
Multiple number of copies

Question 7

What CYP2D6 alleles are common in Europe

Answer 7

*3
*4
*5
*6

Question 8

What CYP2D6 alleles are common in china

Answer 8

*5 and *10

Question 9

Where is amplification of CYP2D6 most common

Answer 9

South Europe and Africa

Question 10

Describe CYP2C19

Answer 10

Low conc in liver
Few drug substrates
Known as mepheytoin hydroxylase

Question 11

What are the 2 forms of CYP2C19

Answer 11

R = PEH + Nirvanol
S = 4-OH mephenytoin

Question 12

What is the R form of CYP2C19 metabolised by

Answer 12

Demethylases

Question 13

What is the S form of CYP2C19 metabolised by

Answer 13

Complete hydroxylases

Question 14

What alleles produce an absence of activity in CYP2C19

Answer 14

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

Question 15

Describe the *2 allele of CYP2C19

Answer 15

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

Question 16

Describe the *3 allele of CYP2C19

Answer 16

Stop codon

Question 17

Describe the *4 allele of CYP2C19

Answer 17

No txn

Question 18

Describe the *7 allele of CYP2C19

Answer 18

Splicing defect
T -> A in intron 5

Question 19

What allele is responsible for lack of activity in CYP2C19

Answer 19

*8

Question 20

How common is the CYP2C19 *8 allele in Europe

Answer 20

3%

Question 21

How common is the CYP2C19 *8 allele in East Asia

Answer 21

20%

Question 22

What polymorphism causes an increase in activity in CYP2C19

Answer 22

*17

Question 23

Describe the *17 polymorphism in CYP2C19

Answer 23

Upstream polymorphism
= more gene txn
= higher activity/ metabolism

Question 24

How common is the *17 allele in CYP2C19

Answer 24

42x more likely in South Europe than East Asia

Few individuals with 17/17 + 17/1

Question 25

What is a pseudogene

Answer 25

Gene w no introns = amplification Past infections from virus which contained reverse transcriptase

Question 26

What are the substrates of CYP2A6

Answer 26

Nicotine, procarcinogens and coumarin

Question 27

How does CYP2A6 affect coumarin metabolism

Answer 27

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

Question 28

What polymorphisms lead to no/decreased activity in CYP2A6

Answer 28

*2 *4 *5

Question 29

Describe the *2 polymorphism in CYP2A6

Answer 29

No haem incorporated

Question 30

Describe the *4 polymorphism in CYP2A6

Answer 30

Large deletion = no enzyme Additional copies of other genes caused by disruption of homologous recombination

Question 31

Describe the *5 polymorphism in CYP2A6

Answer 31

Unstable protein

Question 32

Where is the CYP2A6 *2 allele most common

Answer 32

Europe

Question 33

Where is the CYP2A6 *4 allele most common

Answer 33

East Asia

Question 34

Where is the CYP2A6 *5 allele most common

Answer 34

It’s rare

Question 35

What can cause increased activity in CYP2A6

Answer 35

Evidence of additional copies of WT allele No splicing defect

Question 36

What polymorphism of CYP2C9 cause reduced activity

Answer 36

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

Question 37

Describe the *2 polymorphism in CYP2C9

Answer 37

Effect is substrate dependent E.g warfarin metabolism more affected

Question 38

Describe the *3 polymorphism in CYP2C9

Answer 38

Most detrimental but residual activity remains Lowest catalytic efficiency

Question 39

Describe the *6 polymorphism in CYP2C9

Answer 39

Frameshift = inactive protein

Question 40

How common is the *6 polymorphism of CYP2C9

Answer 40

Rare allele Seen in African Americans No *6/*6 alleles

Question 41

What is the wild type polymorphism for CYP2C9

Answer 41

*1

Question 42

Describe the Km of the CYP2C9 *1 allele

Answer 42

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

Question 43

What are the 2 polymorphisms of CYP3A5

Answer 43

*3 *1

Question 44

Describe the *3 polymorphism of CYP3A5

Answer 44

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

Question 45

Describe the *1 polymorphism in CYP3A5

Answer 45

A at position 6986 = normal hepatic expression *1/*3 genotype associates w expression of CYP3A5

Question 46

How common is the *3 CYP3A5 polymorphism

Answer 46

90% of Europeans

Question 47

What genotype is rare in Europeans for CYP3A5

Answer 47

Homozygosity for *1

Question 48

What polymorphisms of CYP3A4 are responsible for decreased gene expression

Answer 48

*1B *2 *22

Question 49

Describe the *1B polymorphism of CYP3A4

Answer 49

Upstream at -289

Question 50

Describe the *2 polymorphism of CYP3A4

Answer 50

Substrate specific polymorphism Less efficient @ nifedipine metabolism

Question 51

Describe the *22 polymorphism of CYP3A4

Answer 51

Intronic polymoprhism C -> T in intron 6 = reduced activity TT homozygotes have some enzyme expression

Question 52

How frequent is the *2 polymorphism of CYP3A4

Answer 52

2.7% in Caucasians

Question 53

How frequent is the *22 polymorphism of CYP3A4

Answer 53

Allele frequency of 5%

Question 54

Name 4 substrates for CYP2D6

Answer 54

Opioids B-blockers SNRIs Debrisoquine

Question 55

Name 3 substrates for CYP2C19

Answer 55

Omeprazole Diazepam Clopidogrel

Question 56

Name 3 substrates for CYP2A6

Answer 56

Nicotine Coumarin Procarcinogens Disulphiram

Question 57

Name 3 substrates for CYP2C9

Answer 57

Warfarin Phenytoin NSAID’s

Question 58

Name 3 substrates for CYP3A4

Answer 58

Cyclosporin Nifedipine Steroids