Genetics of phase II metabolism

Question 1

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

Answer 1

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

Question 2

what is GSTM1 and what is it involved in

Answer 2

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

Question 3

how does GSTM1 activity differ between populations

Answer 3

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

Question 4

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

Answer 4

smaller molecule (e.g. dichloromethane)

Question 5

what _% of caucasians lack GSTT1 due to a _

Answer 5

20
deletion

Question 6

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

Answer 6

a) 50%
b)15%

Question 7

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

Answer 7

a) 30%
b) 22%

Question 8

what is the percentage of Polynsians who are GSTM1 null

Answer 8

81%

Question 9

what is the percentage of japanese who are GSTM1 null

Answer 9

48%

Question 10

what is the percentage of East Asians who are GSTT1 null

Answer 10

60%

Question 11

what does N-acetyltransferases do and where is it found

Answer 11

• 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

Question 12

NAT are inducible T/F

Answer 12

false

Question 13

which NAT is polymorphic

Answer 13

NAT2

Question 14

how was NAT2 identified

Answer 14

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

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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

Question 17

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

Answer 17

slow acetylators

Question 18

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

Answer 18

50%
5/6

Question 19

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

Answer 19

10%
*7

Question 20

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

Answer 20

T

Question 21

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

Answer 21

glucuronidation
UDP-glucuronosyltransferases (UGTs)

Question 22

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

Answer 22

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

Question 23

what is the issue with UGT1A1 absence in newborn

Answer 23

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.

Question 24

what is Gilbert syndrome

Answer 24

small increase inn plasma bilirubin but has no adverse clinical consequences

Question 25

what is the most common UGT polymorphism in caucasians

Answer 25

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

Question 26

what is a UGT polymorphism that effects some asians

Answer 26

amino acid substitution in exon 1 (gives same phenotype)

Question 27

what drug does UGT polymorphism effects the metabolism for

Answer 27

irinotecan (anti cancer drug)

Question 30

what are the two alleles of UGT2B7 involved in C161T polymorphism

Answer 30

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

Question 31

what are the 2 types of polymorphism involved in SULT1A1

Answer 31

- copy number variation - 3'-untranslated region involving regulation by miRNA

Question 32

How many copies do caucasians people normally have of SULT1A1

Answer 32

2 copies

Question 33

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

Answer 33

2 copies

Question 34

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

Answer 34

more than 2

Question 35

how does miRNA and 3'UTR affect gene expression

Answer 35

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

Question 36

what polymorphism is 3'UTR of SULT1A1

Answer 36

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

Question 37

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

Answer 37

0.44 20%

Question 38

how is luciferase used to investiagte SULT1A1 C/T allele

Answer 38

- 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

Question 39

how is 6-mercaptopurine metabolised

Answer 39

by methyltransferase at the thiol group

Question 40

S-adenosylmethionine donates _ group

Answer 40

methyl

Question 41

how many caucasians lack S-adenosylmethionine

Answer 41

0.3%

Question 43

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

Answer 43

be genotyped

Question 44

what is Catechol-O-methyltransferase involved in

Answer 44

- Catecholamine metabolism - Noradrenaline -> normetanephrine - L-DOPA

Question 45

what is the common genetic polymorphism in Catechol O-methyltransferase

Answer 45

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