Phase I pharmacogenetics

Question 1

Result of FMO3 deficiency

Answer 1

No conversion of TMA to TMAO
Build up of TMA
Fish odour syndrome

Question 2

Most common FMO3 mutation

Answer 2

Pro –> Leu
Loss of activity

Question 3

What is the relevance of FMO3 polys in cancer therapy

Answer 3

FMO3 metabolises Sulindac (NSAID in chemoprevention)
Better outcome in those with polymorphism due to slower metabolism

Question 4

Most common paraoxonase poly

Answer 4

In PON1
Arg to Gln at codon 192

Question 5

PON1 poly substrate effects

Answer 5

Paraoxon: low activity with Gln form
Phenylacetate: no effect
Diazoxon: higher activity with Gln form

Question 6

How to phenotype for cholinesterase deficiency

Answer 6

Inhibition pattern of benzoylcholine hydrolysis with dibucaine

Question 7

What substrate’s metabolism is affected by cholinesterase polys & clinical application

Answer 7

Succinylcholine
Patients need ventilation after treatment with succinylcholine due to apnoea

Question 8

What are the two carboxyesterases

Answer 8

CES1 - poly of functional significance
CES2 - no functionally important polys

Question 9

Most common CES1 poly

Answer 9

Gly to Glu - low activity

Question 10

DPYD deficiency molecular basis

Answer 10

G to A base change in intron 14
exon skipping
Risk of toxicity if given 5FU treatment

Question 11

ALDH2 deficiency molecular basis

Answer 11

Glu to Lys
Unstable protein
Accumulation of acetaldehyde - nausea after ethanol consumption