Phase II Metabolism

Question 1

What are the 2 mutations of glutathione-3-transferases that cause loss of activity

Answer 1

GSTM1
GSTT1

Question 2

What glutathione-s-transferase polymorphism causes a small change in catalytic activity

Answer 2

GSTP1

Question 3

Describe the GSTM1 polymorphism

Answer 3

Expresses in wide range of tissues

Involved in reactions such as detoxification of benzo[a]pyrene diol epoxide

Question 4

How common is the GSTM1 polymorphism

Answer 4

50% Europeans lack enzyme

1% Saudi Arabians have duplication

Question 5

How common is the GSTT1 polymorphism

Answer 5

10-20% Caucasians lack enzyme due to deletion

Question 6

What populations are GSTM1 null

Answer 6

50% Europeans
30% African Americans
81% Polynesians
48% Japanese

Question 7

What populations are GSTT1 null

Answer 7

15% Europeans
22% African Americans
60% East Asians

Question 8

Describe NATs

Answer 8

Transfer acetyl group -> hydroxyl group
Found in cytosol

Question 9

What are the 2 forms of NAT

Answer 9

NAT1 = most tissues
NAT2 = mainly liver and intestines

Show distinct but overlapping substrate specificities

Question 10

Are NATs inducible

Answer 10

No

Question 11

What is the consequence of mutated NAT2

Answer 11

Normal: fast isoniazid acetylators
Mutation: slow isoniazid acetylators

Question 12

What polymorphism is wild type for NAT

Answer 12

4
(1-3) in diff species

Question 13

What polymorphism is responsible for reduced activity in NAT2

Answer 13

*5

Question 14

What polymorphism is responsible for no activity in NAT2

Answer 14

*6 and *7

Question 15

What polymorphism is are slow acetylators in NAT2

Answer 15

*5/7

Question 16

What polymorphism for NAT2 are most common

Answer 16

*5/6
Europeans 50%

*7
10% East Asians

Question 17

Describe UGTs

Answer 17

Carry out glucuronidation
UDP-glucuronic acid required as cofactor

Question 18

Describe the UGT1A1 polymorphism

Answer 18

Inborn error or metabolism
= complete absence of enzyme
= crigler- naijar syndrome (Gilbert’s syndrome)

Question 19

Describe the cause of Gilberts Syndrome

Answer 19

(TA)7TAA instead of (TA)6TAA
Defect in TATA box = affects txn levels

Question 20

How does background affect Gilberts Syndrome

Answer 20

Caucasians: TATA box defect
Asians: AA substitution in exon 1

Both give same phenotype
Relevant to metabolism of irinotecan

Question 21

What is the UGT287 polymorphism

Answer 21

Amino acid substitution

Question 22

What affect does His286Tyr have in UGTs

Answer 22

Causes linkage disequilibrium due to closeness to promoter region

Question 23

What are the 2 variants of His268Tyr substitution

Answer 23

C allele = *1
T allele = *2

TT increases morphine 6-glucuronidation

Question 24

What are the 2 types of SULT polymorphisms

Answer 24

Copy number variation
3’-untranslated region involving regulation by miRNA

Question 25

Describe 3’-UTR polymorphism in SULTs

Answer 25

3’-UTR contains binding site for regulatory and miRNAs
miRNA binding reduces gene expression by inhibiting translation or mRNA cleavage

Question 26

Describe the effect of C973T polymorphism in SULT1A1

Answer 26

Decreased enzyme activity in those carrying 1> allele

Question 27

Describe the frequency of copy number variation in different countries

Answer 27

2 copies in: Caucasians, Indians and Japanese
2< copies in African Americans

Question 28

Describe SAMs

Answer 28

Donate methyl group
Metabolises 6-mercaptopurine