Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Adv Pharmacogenetics PED3005 > Genetics of CYP450 > Flashcards

Genetics of CYP450 Flashcards

1
Q

what absence of activity polymorphism is relatively common?

A

CYP3A5

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what absence of activity polymorphism is relatively rare?

A

CYP2A6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

which two decrease in activity polymorphism is relatively common?

A

CYP2D6 & CYP2C19

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

which CYP has polymorphism which increases activity only?

A

CYP2E1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is almost exclusively metabolised by CYP2D6 to 4-OHD

A

Debrisoquine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what is the average debrisoquine metabolic ratio

A

0.4 to 0.5

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

which CYP2D6 alleles have reduced activity

A

9,10,*17

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

why are some people ‘ultrarapids’ in relation to CYP2D6

A

amplification, multiple number of copies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what CYP2D6 allele is most common in europe

A

3,4,*5 and *6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what CYP2D6 allele is most common in china

A

*5 and *10

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

where is amplification of CYP2D6 most common

A

southern Europe and Africa

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what are CYP2C19 known as

A

mephenytoin hydroxylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

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

A

3 & 20

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the CYP2C19 polymorphism which cause an absence of activity

A

2,3,4,5,6,7

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the CYP2C19 polymorphism which causes a decrease of activity

A

*8 = T358C + W120R

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
what type of polymorphism is *17 CYP2C19
Upstream polymorphism which causes higher activity due to more gene transcription
26
how does CYP2C19*17 allele effect drug metabolism (2)
-increased metabolism - able to metabolsim both reactions of mephenytoin
27
what transcription factor interacts with sequences homologous to CYP2C19*17
GATA
28
who is 42 folds more likely to have the CYP2C19*17 over east asians
Mediterranean-southern europeans
29
true or false there are very few CYP2C19 *17/*17 + *17/*1 individuals
true
30
what are the substrates of CYP2A6
- Halothane, Valproic acid and Disulphiram - Nicotine - Procarcinogens - Coumarin
31
why can some people not metabolise coumarin and what is the prevalence in Europe of ears asian
- genetic polymorphism in CYP2A6 causes an absense of coumarin 7-Hydroxylase Europe = 0.2% East asia = 3%
32
what are the 3 CYP2A6 polymorphisms which cause either no or decrease activity
*2 = L160H - No haem incorporated *4 = Large deletion - No enzyme *5 = G479V - Unstable protein
33
What is the cause of increased CYP2A6 activity in some individuals
Evidence for additional copies of the wild type allele
34
what is the prevalence of the no/lack of activity of CYP2A6 across the globe
*2 - relevant to European *4 - relevant to east asian *5 - rare
35
If an individual has deletion what else might they have and why
Additional copies of other genes can be caused by disruption of homologous recombination
36
why is the product of CYP2C9 metabolism normally a hydroxylated substrate
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
There is no _ defects reported in CYP2C9
splicing
38
what are the 2 main alleles of CYP2C9 which are responsible for reduced activity
*2 = Arg144Cys *3 = Ile359Leu
39
Other alleles responsible for reduced activity of CYP2C9
*4 Ile359Thr *5 Asp360Glu *6 Del A818 – inactive protein due to frameshift, but not common *11 Arg335Trp
40
which allele of CYP2C9 is the most detrimental to its activity
*3 allele is most detrimental to activity, but there will be some residual activity
41
what is the rarest allele of CYP2C9
The *6, some with African American heritage have been described, but so far nobody with two *6 alleles has been reported
42
what is the measurement of catalytic efficiency in relation to warfarin metabolism
Vmax/Km
43
what allele of CYP2C9 out of 1,2 or 3 has the lowest catalytic efficiency
*3
44
what CYP2C9 allele out of 1,2 or 3 has the highest catalytic efficiency
*1 wildtype
45
True or False - there is a significant difference between the Km of CYP2C9 *1 and *2
False
46
The effect of CYP2C9*2 seems to be _ _ , _metabolism is more affected that some other substrates.
substrate dependent warfarin
47
what are the substrates for CYP3A4
Cyclosporin Erythromycin Nifedipine Various steroids
48
What % of livers express CYP3A5
20
49
what is polymorphism is associated with CYP3A4*1B and what is its effect
Upstream polymorphism at position -289 -This has not been confirmed in most in vitro studies
50
what is the polymorphims responsible for CYP3A4*2
Ser222Pro
51
what is the polymorphims responsible for CYP3A4*22 and what is its effect
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
what allele of CYP3A4 is less efficient at nifedipine metabolism
*2
53
True or False - effect on km and Vmax for testosterone is significnat
False
54
the *2 allele of CYP3A4 polymorphism is __ __
substrate specific
55
what is the allele frequency for CYP3A4*22, T is _ and what is the heterozygousy
0.05 10%
56
In transfection studies of CYP3A4*22, what is shown about protein expression
- 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
in CYP3A4*22 -TT homozygotes do still have some enzyme expression - True or false
True
58
Around _% of European CYP3A5 alleles have __ in intron 3 What is this allele called
90 G6986 *3
59
what is the result of CYP3A5*3 polymorphism
Results in creation of an aberrant splice site and 670 bp insertion in mature hepatic mRNA Leads to a nonsense protein
60
what does CYP3A5*1 have at position 6986 - what is the effect on hepatic expression
A normal hepatic expression of CYP3A5
61
what is the effect on liver expression of CYP3A5*1 heterozygosity (*3*1)
associate with expression of CYP3A5
62
what is the effect of CYP3A5 *3*3
Still have some metabolism for *3*3 as different enzymes metabolise the same job
63
Regulation of CYP3A expression is related to (4)
CYP3A4*2, CYP3A4*22, CYP3A5 and PXR
64
what is PXR
CYP3A4 transcriptional regulator
65
where are SNPs found in PXR
in the upstream and coding sequence
66
when comparing genotypes of PXR what is -25000 ?
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
what is the wild type of PXR alleles
-25385 = C -24113 = G
68
what are the two polymorphism associated with PXR
-25385, C to T -24113 G to A
69
why are the two polymorphism for PXR seen together
linkage disequilibrium
70
PXR gene expression is increased when the promoter region contained _ over _
T over C
71
what is CYP1A1 and how is it expressed
extrahepatic Expressed when induced by tabacco smoke or PAHs
72
Polymorphism in CYP1A1 dont correlate with what - what type of polymorphism are they (2)
induced form activity -coding sequence and upstream polymorphism
73
CYP1A1 induction is mediated by
Ah receptor
74
what are the polymorphism associated with Ah receptors
Polymorphisms detected at two positions in the coding region - Arg554Lys - Val570Ile
75
what is the allele frequency with the 554 polymorphism in Ah receptor and what is the presence correlates with
- 0.11 in Europeans - presence of variant codon correlates with high induced CYP1A1 activity
76
The very high AhR signal on Chro 7 is actually in the __ __, but is in linkage __ with the polymorphism in the coding region
upstream region disequilibrium
77
where is the most significant CYP1A2 SNP found
promoter region
78
Ah receptor polymorphism also affects __ intake what is the responsible for this effect and what is it in association with
- caffeine - Most significant SNP is far upstream - some association with Arg554Ly

Adv Pharmacogenetics PED3005 (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions