Phase I Non-CYP Mediated

Question 1

Describe flavin linked monooxygenases

Answer 1

Microsomal enzyme + FAD prosthetic group

Important in oxidation reactions

5 different forms

Question 2

What is the major FMO hepatic isoform

Answer 2

FMO3

Question 3

What is TMA

Answer 3

Unpleasant smelling compound
Breakdown product of precursors
Gut bacteria involved in TMA formation

Question 4

What is the normal metabolism of TMA

Answer 4

TMA -> TMAO by FMO3

TMAO less volatile and loses odour

Question 5

What causes fish odour syndrome

Answer 5

Lack of FMO3
No TMA -> TMAO

Question 6

What common mutation is associated with fish odour syndrome

Answer 6

Pro153Leu

Question 7

Describe the Pro153Leu polymorphism in fish odour syndrome

Answer 7

Compete loss of activity
Functionally significant

No effect of methimazole metabolism

Question 8

What polymorphism are responsible for fish odour syndrome in children

Answer 8

E158K
E308G

Question 9

Describe the function of arylesterase- paraoxonase

Answer 9

Hydrolyses organophosphates in the liver and serum

Question 10

What polymorphisms of paraoxonase cause low activity

Answer 10

PON1

Question 11

Describe the protective effects of paraoxonase polymorphism

Answer 11

Hydrolyses oxidised LDL-associated cholesterol
Associated with HDL

Question 12

How does PON1 increase the risk of CHD

Answer 12

Low activity of paraoxonase
No links to polymorphism

Question 13

How does the Arg192Gln polymorphism in paraoxonase affect activity

Answer 13

Low activity
Amino acid substitution in promoter substitution

Question 14

What is PXR

Answer 14

CYP3A4 txn regulator

Question 15

Where are the polymorphisms for PXR found

Answer 15

Upstream and coding sequences
-25000 is ATG start site, close to promoter region

Question 16

What are the 2 PXR polymorphisms

Answer 16

C -> T
G -> A

Question 17

Why are the 2 PXR polymorphisms seen together

Answer 17

Linkage disequilibrium

Question 18

When is there increased gene expression in PXR

Answer 18

When promoter regions contains T over C

Question 19

Describe CYP1A1

Answer 19

Extra-hepatic
Induced by tobacco smoke or PAHs

Induction mediated by Ah receptor

Question 20

Where are CYP1A1 polymorphism located

Answer 20

Upstream and ion coding sequence

Question 21

Describe the Arg554Lys polymorphism in AhR

Answer 21

Presence of variant correlates with high induced CYP1A1 activity

Question 22

What is the function of butyrylcholinesterase

Answer 22

Plasma esterase i.e high levels in plasma
Hydrolyses succinylcholine

Question 23

What % of population of is heterozygous for cholinesterases

Answer 23

5%
Associated with poor hydrolysis of compound

Question 24

How can you detect individuals with deficiency in cholinesterases

Answer 24

Inhibition pattern of benzoylchlone hydrolysis
With either dibucaine or fluoride

Atypical variant shows less inhibition than wild-type

Question 25

What are the 3 forms of cholinesterase deficiency

Answer 25

Atypical from: abnormal dibucaine inhibiton Fluoride sensitive: amino acid substitutions Silent form: frameshift or premature stop codon

Question 26

What are the 2 polymorphisms of carboxyesterases

Answer 26

CES1 = high levels in liver CES2 = high levels of extrahepatic tissues

Question 27

What is the consequence of Gly143Glu in CES1

Answer 27

Low activity

Question 28

What is the consequence of Asp260Fs in CES1

Answer 28

No activity Rare

Question 29

Describe dihydropyrimidine dehydrogenase

Answer 29

Converts U -> T dehydro metabolites Metabolised by 5-flurouracil

Question 30

What is the common variant of dihydropyrimidine dehydrogenase

Answer 30

G->A intron 14 = skipping of exon 14 = truncated protein

Question 31

What genotype variant is toxic in dihydropyrimidine dehydrogenase

Answer 31

Heterozygous 2-3% Europeans

Question 32

What are the 2 forms of aldehyde dehydrogenase

Answer 32

ALDH1 (cytosolic) ALDH2 (mitochondrial)

Question 33

What variant of aldehyde dehydrogenase causes low activity

Answer 33

Glu487Lys in ALDH2

Question 34

What is the inheritance of Glu487Lys in ALDH2

Answer 34

Dominant inheritance Heterozygous and homozygous suffer flushing Response

Question 35

Where is the ALDH2 mutation common

Answer 35

East Asia