CYPs Flashcards
What are the 3 loss of function alleles for CYP2D6
*3
*4
*5
Describe the CYP2D6 *3 allele
Deletion = frameshift
Describe the *4 CYP2D6 allele
Splicing defect
Describe the *5 CYP2D6 allele
Complete loss of CYP
What alleles have reduced activity in CYP2D6
*9
*10
*17
Describe ultra rapid CYP2D6 metabolisers
Amplification
Multiple number of copies
What CYP2D6 alleles are common in Europe
*3
*4
*5
*6
What CYP2D6 alleles are common in china
*5 and *10
Where is amplification of CYP2D6 most common
South Europe and Africa
Describe CYP2C19
Low conc in liver
Few drug substrates
Known as mepheytoin hydroxylase
What are the 2 forms of CYP2C19
R = PEH + Nirvanol
S = 4-OH mephenytoin
What is the R form of CYP2C19 metabolised by
Demethylases
What is the S form of CYP2C19 metabolised by
Complete hydroxylases
What alleles produce an absence of activity in CYP2C19
*2
*3
*4
*5
*6
*7
Describe the *2 allele of CYP2C19
Splicing defect
WT splice site = AGAT
*2 splice site = GGCA
*2 preferred = aberrant protein
Describe the *3 allele of CYP2C19
Stop codon
Describe the *4 allele of CYP2C19
No txn
Describe the *7 allele of CYP2C19
Splicing defect
T -> A in intron 5
What allele is responsible for lack of activity in CYP2C19
*8
How common is the CYP2C19 *8 allele in Europe
3%
How common is the CYP2C19 *8 allele in East Asia
20%
What polymorphism causes an increase in activity in CYP2C19
*17
Describe the *17 polymorphism in CYP2C19
Upstream polymorphism
= more gene txn
= higher activity/ metabolism
How common is the *17 allele in CYP2C19
42x more likely in South Europe than East Asia
Few individuals with 17/17 + 17/1
What is a pseudogene
Gene w no introns = amplification
Past infections from virus which contained reverse transcriptase
What are the substrates of CYP2A6
Nicotine, procarcinogens and coumarin
How does CYP2A6 affect coumarin metabolism
Absence of coumarin-7-hydroxylase
= no metabolism of coumarin
What polymorphisms lead to no/decreased activity in CYP2A6
*2
*4
*5
Describe the *2 polymorphism in CYP2A6
No haem incorporated
Describe the *4 polymorphism in CYP2A6
Large deletion = no enzyme
Additional copies of other genes caused by disruption of homologous recombination
Describe the *5 polymorphism in CYP2A6
Unstable protein
Where is the CYP2A6 *2 allele most common
Europe
Where is the CYP2A6 *4 allele most common
East Asia
Where is the CYP2A6 *5 allele most common
It’s rare
What can cause increased activity in CYP2A6
Evidence of additional copies of WT allele
No splicing defect
What polymorphism of CYP2C9 cause reduced activity
*2
*3
*4
*5
*6
*11
Describe the *2 polymorphism in CYP2C9
Effect is substrate dependent
E.g warfarin metabolism more affected
Describe the *3 polymorphism in CYP2C9
Most detrimental but residual activity remains
Lowest catalytic efficiency
Describe the *6 polymorphism in CYP2C9
Frameshift = inactive protein
How common is the *6 polymorphism of CYP2C9
Rare allele
Seen in African Americans
No 6/6 alleles
What is the wild type polymorphism for CYP2C9
*1
Describe the Km of the CYP2C9 *1 allele
Highest catalytic efficiency
No sig diff between Km of *1 and *2
(Measured by Vmax/Km)
What are the 2 polymorphisms of CYP3A5
*3
*1
Describe the *3 polymorphism of CYP3A5
Complete deletion
Creates aberrant splice site
Insertion @ 670bp in hepatic mRNA
= nonsense protein
Describe the *1 polymorphism in CYP3A5
A at position 6986
= normal hepatic expression
1/3 genotype associates w expression of CYP3A5
How common is the *3 CYP3A5 polymorphism
90% of Europeans
What genotype is rare in Europeans for CYP3A5
Homozygosity for *1
What polymorphisms of CYP3A4 are responsible for decreased gene expression
*1B
*2
*22
Describe the *1B polymorphism of CYP3A4
Upstream at -289
Describe the *2 polymorphism of CYP3A4
Substrate specific polymorphism
Less efficient @ nifedipine metabolism
Describe the *22 polymorphism of CYP3A4
Intronic polymoprhism
C -> T in intron 6
= reduced activity
TT homozygotes have some enzyme expression
How frequent is the *2 polymorphism of CYP3A4
2.7% in Caucasians
How frequent is the *22 polymorphism of CYP3A4
Allele frequency of 5%
Name 4 substrates for CYP2D6
Opioids
B-blockers
SNRIs
Debrisoquine
Name 3 substrates for CYP2C19
Omeprazole
Diazepam
Clopidogrel
Name 3 substrates for CYP2A6
Nicotine
Coumarin
Procarcinogens
Disulphiram
Name 3 substrates for CYP2C9
Warfarin
Phenytoin
NSAID’s
Name 3 substrates for CYP3A4
Cyclosporin
Nifedipine
Steroids
