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Adv Pharmacogenetics PED3005 > Genetics of CYP450 > Flashcards

Genetics of CYP450 Flashcards

1
Q

what absence of activity polymorphism is relatively common?

A

CYP3A5

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2
Q

what absence of activity polymorphism is relatively rare?

A

CYP2A6

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3
Q

which two decrease in activity polymorphism is relatively common?

A

CYP2D6 & CYP2C19

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4
Q

which CYP has polymorphism which increases activity only?

A

CYP2E1

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5
Q

what is a typical substrate of CYP2D6

A
  • contains a basic nitrogen
  • and hydrophobic region
  • mainly ionised at physiological pH
  • cardiovascular agents, antipsychotics or antidepressants
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6
Q

What is almost exclusively metabolised by CYP2D6 to 4-OHD

A

Debrisoquine

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7
Q

what does the metabolic ratio of debrisoquine mean

A

Metabolic ratio of 1- amount of parent = metabolite
Ratio >1 = more parent, less metabolite
Ratio <1 = less parent, more metabolite

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8
Q

what is the average debrisoquine metabolic ratio

A

0.4 to 0.5

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9
Q

what are the 3 CYP2D6 allele which cause complete loss of function

A

*3 = A2539 deletion = frameshift
*4 = G1846A = splicing defect
*5 = Complete loss of CYP

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10
Q

which CYP2D6 alleles have reduced activity

A

9,10,*17

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11
Q

why are some people ‘ultrarapids’ in relation to CYP2D6

A

amplification, multiple number of copies

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12
Q

What are psuedogenes and how were they hypothesied to occur

A

-gene with no introns which cause amplification
- past infections from a virus which contain reverse transcriptase

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13
Q

what CYP2D6 allele is most common in europe

A

3,4,*5 and *6

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14
Q

what CYP2D6 allele is most common in china

A

*5 and *10

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15
Q

where is amplification of CYP2D6 most common

A

southern Europe and Africa

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16
Q

_ in Spain may reflect migration of population in Northern Africa, where gene _ are more common, when Spain and some of France was occupied by Islamic peoples from Northern Afric

A

Amplification
duplications

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17
Q

what are CYP2C19 known as

A

mephenytoin hydroxylase

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18
Q

_% of Europeans and _% of East Asians lack CYP2C19 activity

A

3 & 20

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19
Q

what are the two forms of mephenytoin

A

R = PEH + Nirvanol = metabolised by demethylases
S = 4-OH mephenytoin= metabolised by complete hydroxylases of ring

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20
Q

What are the CYP2C19 polymorphism which cause an absence of activity

A

2,3,4,5,6,7

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21
Q

what are the mutation responsible for absence of activity in CYP2C19

A

*2 = G681A- splicing defect
*3 = G636A - stop codon
*4 = A1G - no transcription
*5 = C1297T + R433W
*6 = G395A + R132Q
*7 = T->A in intron 5 - splicing defect

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22
Q

What is the CYP2C19 polymorphism which causes a decrease of activity

A

*8 = T358C + W120R

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23
Q

What is the CYP2C19 polymorphism which causes an increase of activity

A

*17 = C806T +C3402T
no gene duplication and polymorphism in upstream control sequence

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24
Q

how does *2 CYP2C19 allele effect

A

the wild type splice site (AGAT) is not efficient as normal AGGA, *2 alleles splice site is GGCA which is prefered over wildtypes’s.
this leads to an aberrant protein (unstable+premature termination of translation)

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25
Q

what type of polymorphism is *17 CYP2C19

A

Upstream polymorphism which causes higher activity due to more gene transcription

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26
Q

how does CYP2C19*17 allele effect drug metabolism (2)

A

-increased metabolism
- able to metabolsim both reactions of mephenytoin

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27
Q

what transcription factor interacts with sequences homologous to CYP2C19*17

A

GATA

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28
Q

who is 42 folds more likely to have the CYP2C19*17 over east asians

A

Mediterranean-southern europeans

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29
Q

true or false
there are very few CYP2C19 17/17 + 17/1 individuals

A

true

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30
Q

what are the substrates of CYP2A6

A
  • Halothane, Valproic acid and Disulphiram
  • Nicotine
  • Procarcinogens
  • Coumarin
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31
Q

why can some people not metabolise coumarin and what is the prevalence in Europe of ears asian

A
  • genetic polymorphism in CYP2A6 causes an absense of coumarin 7-Hydroxylase
    Europe = 0.2%
    East asia = 3%
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32
Q

what are the 3 CYP2A6 polymorphisms which cause either no or decrease activity

A

*2 = L160H - No haem incorporated
*4 = Large deletion - No enzyme
*5 = G479V - Unstable protein

33
Q

What is the cause of increased CYP2A6 activity in some individuals

A

Evidence for additional copies of the wild type allele

34
Q

what is the prevalence of the no/lack of activity of CYP2A6 across the globe

A

*2 - relevant to European
*4 - relevant to east asian
*5 - rare

35
Q

If an individual has deletion what else might they have and why

A

Additional copies of other genes can be caused by disruption of homologous recombination

36
Q

why is the product of CYP2C9 metabolism normally a hydroxylated substrate

A

Substrates tend to have areas of strong hydrogen bond forming potential or ion pair formation 5 to 10 Å from the site of metabolism

37
Q

There is no _ defects reported in CYP2C9

A

splicing

38
Q

what are the 2 main alleles of CYP2C9 which are responsible for reduced activity

A

*2 = Arg144Cys
*3 = Ile359Leu

39
Q

Other alleles responsible for reduced activity of CYP2C9

A

*4 Ile359Thr
*5 Asp360Glu
*6 Del A818 – inactive protein due to frameshift, but not common
*11 Arg335Trp

40
Q

which allele of CYP2C9 is the most detrimental to its activity

A

*3 allele is most detrimental to activity, but there will be some residual activity

41
Q

what is the rarest allele of CYP2C9

A

The *6, some with African American heritage have been described, but so far nobody with two *6 alleles has been reported

42
Q

what is the measurement of catalytic efficiency in relation to warfarin metabolism

A

Vmax/Km

43
Q

what allele of CYP2C9 out of 1,2 or 3 has the lowest catalytic efficiency

A

*3

44
Q

what CYP2C9 allele out of 1,2 or 3 has the highest catalytic efficiency

A

*1 wildtype

45
Q

True or False - there is a significant difference between the Km of CYP2C9 *1 and *2

A

False

46
Q

The effect of CYP2C9*2 seems to be _ _ , _metabolism is more affected that some other substrates.

A

substrate dependent
warfarin

47
Q

what are the substrates for CYP3A4

A

Cyclosporin
Erythromycin
Nifedipine
Various steroids

48
Q

What % of livers express CYP3A5

A

20

49
Q

what is polymorphism is associated with CYP3A4*1B and what is its effect

A

Upstream polymorphism at position -289
-This has not been confirmed in most in vitro studies

50
Q

what is the polymorphims responsible for CYP3A4*2

A

Ser222Pro

51
Q

what is the polymorphims responsible for CYP3A4*22 and what is its effect

A

Intronic polymorphism (allele frequency of 5%) - C to T in intron 6
Associated with reduced activity due to changes in gene expression (not clear)

52
Q

what allele of CYP3A4 is less efficient at nifedipine metabolism

A

*2

53
Q

True or False - effect on km and Vmax for testosterone is significnat

A

False

54
Q

the *2 allele of CYP3A4 polymorphism is __ __

A

substrate specific

55
Q

what is the allele frequency for CYP3A4*22, T is _ and what is the heterozygousy

A

0.05
10%

56
Q

In transfection studies of CYP3A4*22, what is shown about protein expression

A
  • DNA shows the same ratio of C:T with time
  • RNA concentration from C containing constructs increases with time
  • suggesting that the presence of T in intron 6 leads to reduced mRNA expression, hence lower protein expression
57
Q

in CYP3A4*22 -TT homozygotes do still have some enzyme expression - True or false

A

True

58
Q

Around _% of European CYP3A5 alleles have __ in intron 3
What is this allele called

A

90
G6986
*3

59
Q

what is the result of CYP3A5*3 polymorphism

A

Results in creation of an aberrant splice site and 670 bp insertion in mature hepatic mRNA
Leads to a nonsense protein

60
Q

what does CYP3A5*1 have at position 6986
- what is the effect on hepatic expression

A

A
normal hepatic expression of CYP3A5

61
Q

what is the effect on liver expression of CYP3A51 heterozygosity (3*1)

A

associate with expression of CYP3A5

62
Q

what is the effect of CYP3A5 33

A

Still have some metabolism for 33 as different enzymes metabolise the same job

63
Q

Regulation of CYP3A expression is related to (4)

A

CYP3A42, CYP3A422, CYP3A5 and PXR

64
Q

what is PXR

A

CYP3A4 transcriptional regulator

65
Q

where are SNPs found in PXR

A

in the upstream and coding sequence

66
Q

when comparing genotypes of PXR
what is -25000 ?

A

refers to the ATG start site (translation start site).
(There is an untranslated first exon)
-close to promoter region (about 350 bp away from TXN start site).

67
Q

what is the wild type of PXR alleles

A

-25385 = C
-24113 = G

68
Q

what are the two polymorphism associated with PXR

A

-25385, C to T
-24113 G to A

69
Q

why are the two polymorphism for PXR seen together

A

linkage disequilibrium

70
Q

PXR gene expression is increased when the promoter region contained _ over _

A

T over C

71
Q

what is CYP1A1
and how is it expressed

A

extrahepatic
Expressed when induced by tabacco smoke or PAHs

72
Q

Polymorphism in CYP1A1 dont correlate with what
- what type of polymorphism are they (2)

A

induced form activity
-coding sequence and upstream polymorphism

73
Q

CYP1A1 induction is mediated by

A

Ah receptor

74
Q

what are the polymorphism associated with Ah receptors

A

Polymorphisms detected at two positions in the coding region
- Arg554Lys
- Val570Ile

75
Q

what is the allele frequency with the 554 polymorphism in Ah receptor and what is the presence correlates with

A
  • 0.11 in Europeans
  • presence of variant codon correlates with high induced CYP1A1 activity
76
Q

The very high AhR signal on Chro 7 is actually in the __ __, but is in linkage __ with the polymorphism in the coding region

A

upstream region
disequilibrium

77
Q

where is the most significant CYP1A2 SNP found

A

promoter region

78
Q

Ah receptor polymorphism also affects __ intake
what is the responsible for this effect and what is it in association with

A
  • caffeine
  • Most significant SNP is far upstream
  • some association with Arg554Ly

Adv Pharmacogenetics PED3005 (11 decks)

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