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PED3005 Pharmacogenetics > Phase I Non-CYP Mediated > Flashcards

Phase I Non-CYP Mediated Flashcards

1
Q

Describe flavin linked monooxygenases

A

Microsomal enzyme + FAD prosthetic group

Important in oxidation reactions

5 different forms

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2
Q

What is the major FMO hepatic isoform

A

FMO3

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3
Q

What is TMA

A

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

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4
Q

What is the normal metabolism of TMA

A

TMA -> TMAO by FMO3

TMAO less volatile and loses odour

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5
Q

What causes fish odour syndrome

A

Lack of FMO3
No TMA -> TMAO

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6
Q

What common mutation is associated with fish odour syndrome

A

Pro153Leu

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7
Q

Describe the Pro153Leu polymorphism in fish odour syndrome

A

Compete loss of activity
Functionally significant

No effect of methimazole metabolism

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8
Q

What polymorphism are responsible for fish odour syndrome in children

A

E158K
E308G

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9
Q

Describe the function of arylesterase- paraoxonase

A

Hydrolyses organophosphates in the liver and serum

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10
Q

What polymorphisms of paraoxonase cause low activity

A

PON1

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11
Q

Describe the protective effects of paraoxonase polymorphism

A

Hydrolyses oxidised LDL-associated cholesterol
Associated with HDL

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12
Q

How does PON1 increase the risk of CHD

A

Low activity of paraoxonase
No links to polymorphism

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13
Q

How does the Arg192Gln polymorphism in paraoxonase affect activity

A

Low activity
Amino acid substitution in promoter substitution

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14
Q

What is PXR

A

CYP3A4 txn regulator

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15
Q

Where are the polymorphisms for PXR found

A

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

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16
Q

What are the 2 PXR polymorphisms

A

C -> T
G -> A

17
Q

Why are the 2 PXR polymorphisms seen together

A

Linkage disequilibrium

18
Q

When is there increased gene expression in PXR

A

When promoter regions contains T over C

19
Q

Describe CYP1A1

A

Extra-hepatic
Induced by tobacco smoke or PAHs

Induction mediated by Ah receptor

20
Q

Where are CYP1A1 polymorphism located

A

Upstream and ion coding sequence

21
Q

Describe the Arg554Lys polymorphism in AhR

A

Presence of variant correlates with high induced CYP1A1 activity

22
Q

What is the function of butyrylcholinesterase

A

Plasma esterase i.e high levels in plasma
Hydrolyses succinylcholine

23
Q

What % of population of is heterozygous for cholinesterases

A

5%
Associated with poor hydrolysis of compound

24
Q

How can you detect individuals with deficiency in cholinesterases

A

Inhibition pattern of benzoylchlone hydrolysis
With either dibucaine or fluoride

Atypical variant shows less inhibition than wild-type

25
Q

What are the 3 forms of cholinesterase deficiency

A

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

26
Q

What are the 2 polymorphisms of carboxyesterases

A

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

27
Q

What is the consequence of Gly143Glu in CES1

A

Low activity

28
Q

What is the consequence of Asp260Fs in CES1

A

No activity
Rare

29
Q

Describe dihydropyrimidine dehydrogenase

A

Converts U -> T dehydro metabolites

Metabolised by 5-flurouracil

30
Q

What is the common variant of dihydropyrimidine dehydrogenase

A

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

31
Q

What genotype variant is toxic in dihydropyrimidine dehydrogenase

A

Heterozygous
2-3% Europeans

32
Q

What are the 2 forms of aldehyde dehydrogenase

A

ALDH1 (cytosolic)
ALDH2 (mitochondrial)

33
Q

What variant of aldehyde dehydrogenase causes low activity

A

Glu487Lys in ALDH2

34
Q

What is the inheritance of Glu487Lys in ALDH2

A

Dominant inheritance
Heterozygous and homozygous suffer flushing Response

35
Q

Where is the ALDH2 mutation common

A

East Asia

PED3005 Pharmacogenetics (10 decks)

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