Phase II Metabolism Flashcards
What are the 2 mutations of glutathione-3-transferases that cause loss of activity
GSTM1
GSTT1
What glutathione-s-transferase polymorphism causes a small change in catalytic activity
GSTP1
Describe the GSTM1 polymorphism
Expresses in wide range of tissues
Involved in reactions such as detoxification of benzo[a]pyrene diol epoxide
How common is the GSTM1 polymorphism
50% Europeans lack enzyme
1% Saudi Arabians have duplication
How common is the GSTT1 polymorphism
10-20% Caucasians lack enzyme due to deletion
What populations are GSTM1 null
50% Europeans
30% African Americans
81% Polynesians
48% Japanese
What populations are GSTT1 null
15% Europeans
22% African Americans
60% East Asians
Describe NATs
Transfer acetyl group -> hydroxyl group
Found in cytosol
What are the 2 forms of NAT
NAT1 = most tissues
NAT2 = mainly liver and intestines
Show distinct but overlapping substrate specificities
Are NATs inducible
No
What is the consequence of mutated NAT2
Normal: fast isoniazid acetylators
Mutation: slow isoniazid acetylators
What polymorphism is wild type for NAT
4
(1-3) in diff species
What polymorphism is responsible for reduced activity in NAT2
*5
What polymorphism is responsible for no activity in NAT2
*6 and *7
What polymorphism is are slow acetylators in NAT2
*5/7
What polymorphism for NAT2 are most common
*5/6
Europeans 50%
*7
10% East Asians
Describe UGTs
Carry out glucuronidation
UDP-glucuronic acid required as cofactor
Describe the UGT1A1 polymorphism
Inborn error or metabolism
= complete absence of enzyme
= crigler- naijar syndrome (Gilbert’s syndrome)
Describe the cause of Gilberts Syndrome
(TA)7TAA instead of (TA)6TAA
Defect in TATA box = affects txn levels
How does background affect Gilberts Syndrome
Caucasians: TATA box defect
Asians: AA substitution in exon 1
Both give same phenotype
Relevant to metabolism of irinotecan
What is the UGT287 polymorphism
Amino acid substitution
What affect does His286Tyr have in UGTs
Causes linkage disequilibrium due to closeness to promoter region
What are the 2 variants of His268Tyr substitution
C allele = *1
T allele = *2
TT increases morphine 6-glucuronidation
What are the 2 types of SULT polymorphisms
Copy number variation
3’-untranslated region involving regulation by miRNA
Describe 3’-UTR polymorphism in SULTs
3’-UTR contains binding site for regulatory and miRNAs
miRNA binding reduces gene expression by inhibiting translation or mRNA cleavage
Describe the effect of C973T polymorphism in SULT1A1
Decreased enzyme activity in those carrying 1> allele
Describe the frequency of copy number variation in different countries
2 copies in: Caucasians, Indians and Japanese
2< copies in African Americans
Describe SAMs
Donate methyl group
Metabolises 6-mercaptopurine
