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Adv Pharmacogenetics PED3005 > Genetics of phase II metabolism > Flashcards

Genetics of phase II metabolism Flashcards

1
Q

what are the 3 types of Glutathione S-transferases (GST) polymorphisms

A
  • GSTM1 = loss of activity
  • GSTT1 = loss of activity
  • GSTP1 = small change in catalytic activity
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2
Q

what is GSTM1 and what is it involved in

A
  • expressed in many tissues
  • involved in reactions such as detoxication of benzo[a]pyrene diol epoxide
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3
Q

how does GSTM1 activity differ between populations

A
  • approx 50% of white europeans lack this enzyme activity
  • small number (1% of saudi Arabians) have duplication
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4
Q

What type of substrate does theta class GST (GSTT1) prefer

A

smaller molecule (e.g. dichloromethane)

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5
Q

what _% of caucasians lack GSTT1 due to a _

A

20
deletion

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6
Q

what is the percentage of europeans who are
a) GSTM1 null
b) GSTT1 null

A

a) 50%
b)15%

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7
Q

what is the percentage of African americans who are
a) GSTM1 null
b) GSTT1 null

A

a) 30%
b) 22%

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8
Q

what is the percentage of Polynsians who are GSTM1 null

A

81%

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9
Q

what is the percentage of japanese who are GSTM1 null

A

48%

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10
Q

what is the percentage of East Asians who are GSTT1 null

A

60%

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11
Q

what does N-acetyltransferases do and where is it found

A
  • NATs transfer acetyl group to hydroxyl group
  • both human NATs found in cytosol, NAT1 expressed in most tissue and NAT2 mainly in liver and intestine
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12
Q

NAT are inducible T/F

A

false

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13
Q

which NAT is polymorphic

A

NAT2

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14
Q

how was NAT2 identified

A

Isoniazid metabolism
- mutation = slow acetylators
- normal = fast acetylators

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15
Q

what is the wildtype allele for NAT2 and why is that?

A

*4
because 1-3 are WT in different animal species

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16
Q

what NAT2 alleles produced reduced activity and which produced effectively mo activity

A

*5 = reduced
*6 + *7 = no activity

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17
Q

what would someone with a NAT2 genotype of 5/7 be called

A

slow acetylators

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18
Q

what percent of europeans are slow acetylators
- what is the most common allele in this populations

A

50%
5/6

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19
Q

what percent of east asians are slow acetylators
- what is the most common allele in this populations

A

10%
*7

20
Q

N-acetylation does not influence the pharmacological activity of caffeine -T/F

A

T

21
Q

what is the most widely used phase II reaction and what enzyme is involved

A

glucuronidation
UDP-glucuronosyltransferases (UGTs)

22
Q

what is conjugated by UGTs and what is needed as a cofactor

A

steriods, vitamins, bile acids and bilirubin
UDP-glucuronic acid

23
Q

what is the issue with UGT1A1 absence in newborn

A

Crigler-Najjar syndrome
- Haem gets converted to bilirubin which is insoluble, and requires glucuronidation to become soluble prior to excretion.
- Accumulation becomes toxic to organs and tissues.

24
Q

what is Gilbert syndrome

A

small increase inn plasma bilirubin but has no adverse clinical consequences

25
Q

what is the most common UGT polymorphism in caucasians

A

(TA)7TAA in TATA box instead of (TA)6TAA
appears to affect transcriptional levels

26
Q

what is a UGT polymorphism that effects some asians

A

amino acid substitution in exon 1 (gives same phenotype)

27
Q

what drug does UGT polymorphism effects the metabolism for

A

irinotecan (anti cancer drug)

28
Q
A
29
Q
A
30
Q

what are the two alleles of UGT2B7 involved in C161T polymorphism

A

C allele = *1
T allele = *2
TT suggested to be associated with increased morphine 6-glucuronidation in vivo

31
Q

what are the 2 types of polymorphism involved in SULT1A1

A
  • copy number variation
  • 3’-untranslated region involving regulation by miRNA
32
Q

How many copies do caucasians people normally have of SULT1A1

A

2 copies

33
Q

How many copies do Indian & Japanese people normally have of SULT1A1

A

2 copies

34
Q

How many copies do African-American
and south African people normally have of SULT1A1

A

more than 2

35
Q

how does miRNA and 3’UTR affect gene expression

A

they’re binding reduces gene expression by inhibiting translation or by mRNA cleavage

36
Q

what polymorphism is 3’UTR of SULT1A1

A

C973T
decreased enzyme activity in those carrying one or two T alleles

37
Q

what is the allele frequency of T allele in SULT1A1. What is the % of white US population homologous for T alleles

A

0.44
20%

38
Q

how is luciferase used to investiagte SULT1A1 C/T allele

A
  • constructs containing C at 973 will show lower extent of miRNA binding, and hence more luciferase activity; more miRNA binding with T at 973, less luciferase activity
  • Predicted using computer program that miR-631 would downregulate SULT1A1 expression more robustly in subjects carrying 973T than in those with C allele
39
Q

how is 6-mercaptopurine metabolised

A

by methyltransferase at the thiol group

40
Q

S-adenosylmethionine donates _ group

A

methyl

41
Q

how many caucasians lack S-adenosylmethionine

A

0.3%

42
Q
A
43
Q

if your treated with anti cancer drugs what do you have to do first

A

be genotyped

44
Q

what is Catechol-O-methyltransferase involved in

A
  • Catecholamine metabolism
    • Noradrenaline -> normetanephrine
    • L-DOPA
45
Q

what is the common genetic polymorphism in Catechol O-methyltransferase

A

Codon - G158A - Val to Met substitution
Met form of enzyme more thermolabile than Val and associated with lower activity

Adv Pharmacogenetics PED3005 (11 decks)

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